The History of Neuroscience in Autobiography

VOLUME 9

The History of Neuroscience in Autobiography

VOLUME 9

Edited by Thomas D. Albright
and Larry R. Squire

Society for Neuroscience

Society for Neuroscience

The Society for Neuroscience publishes works that advance
the understanding of the brain and nervous system.

Copyright © 2016 by the Society for Neuroscience

Published by the Society for Neuroscience
1121 14th Street, NW
Washington, DC 20005
www.sfn.org

All rights reserved. No part of this publication may be reproduced,
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without the prior permission of the Society for Neuroscience.

Library of Congress Control Number: 96070950

ISBN 978-0-916110-10-9

Printed in the United States of America

Contents

Previous Contributors

Preface to Volume 1

Preface to Volume 9

Cohen

Dudai

Fischbach

Grillner

Kaas

Kandel

Kopell

Livingstone

Rizzolatti

Robbins

Singer

Van Essen

Index of Names

Previous Contributors

Volume 1

Denise Albe-Fessard

Julius Axelrod

Peter O. Bishop

Theodore H. Bullock

Irving T. Diamond

Robert Galambos

Viktor Hamburger

Sir Alan L. Hodgkin

David H. Hubel

Herbert H. Jasper

Sir Bernard Katz

Seymour S. Kety

Benjamin Libet

Louis Sokoloff

James M. Sprague

Curt von Euler

John Z. Young

Volume 2

Lloyd Beidler

Arvid Carlsson

Donald Griffin

Roger Guillemin

Ray W. Guillery

Masao Ito

Martin Larrabee

Jerry Lettvin

Paul MacLean

Brenda Milner

Karl Pribram

Eugene Roberts

Gunther Stent

Volume 3

Morris H. Aprison

Brian B. Boycott

Vernon B. Brooks

Pierre Buser

Hsiang-Tung Chang

Claudio A. Cuello

Robert W. Doty

Bernice Grafstein

Ainsley Iggo

Jennifer Lund

Edith and Patrick McGeer

Edward R. Perl

Donald B. Tower

Patrick D. Wall

Wally Welker

Volume 4

Per Andersen

Mary Bartlett Bunge

Jan Bures

Jean Pierre G. Changeux

William Maxwell (Max) Cowan

John E. Dowling

Oleh Hornykiewicz

Andrew F. Huxley

JacSue Kehoe

Edward A. Kravitz

James L. McGaugh

Randolf Menzel

Mircea Steriade

Richard F. Thompson

Volume 5

Samuel H. Barondes

Joseph E. Bogen

Alan Cowey

David R. Curtis

Ennio De Renzi

John S. Edwards

Mitchell Glickstein

Carlton C. Hunt

Lynn T. Landmesser

Rodolfo R. Llinás

Alan Peters

Martin Raff

Wilfrid Rall

Mark R. Rosenzweig

Arnold Bernard Scheibel

Gerald Westheimer

Volume 6

Bernard W. Agranoff

Emilio Bizzi

Marian Cleeves Diamond

Charles G. Gross

Richard Held

Leslie L. Iversen

Masakazu Konishi

Lawrence Kruger

Susan E. Leeman

Vernon B. Mountcastle

Shigetada Nakanishi

Solomon H. Snyder

Nobuo Suga

Hans Thoenen

Volume 7

Floyd E. Bloom

Joaquín Fuster

Michael S. Gazzaniga

Bertil Hille

Ivan Izquierdo

Edward Jones

Krešimir Krnjević

Nicole M. Le Douarin

Terje Lømo

Michael M. Merzenich

John Wilson Moore

Robert Y. Moore

Michael I. Posner

Peter H. Schiller

Gordon M. Shepherd

Robert H. Wurtz

Volume 8

Huda Akil

Philippe Ascher

Giovanni Berlucchi

Lily Jan

Yuh-Nung Jan

Bruce Sherman McEwen

Frederick A. Miles

Peter M. Milner

Fernando Nottebohm

Tomaso A. Poggio

Marcus E. Raichle, Sr.

Pablo Rudomin

Anne Treisman

Stanley J. Watson, Jr.

Anne Buckingham Young

Preface to Volume 1

Before the Alfred P. Sloan Foundation series of books began to appear in 1979, the scientific autobiography was a largely unfamiliar genre. One recalls Cajal’s extraordinary Recollections of My Life, translated in English in 1937 and the little gem of autobiography written by Charles Darwin for his grandchildren in 1876. One supposes that this form of scientific writing is scarce because busy scientists would rather continue to work on scientific problems than to indulge in a retrospective exercise using a writing style that is usually outside their scope of experience. Yet, regardless of the nature of one’s own investigative works, the scientific enterprise describes a community of activity and thought in which all scientists share. Indeed, an understanding of the scientific enterprise should in the end be accessible to anyone because it is essentially a human endeavor, full of intensity, purpose, and drama that are universal to human experience.

While writing a full autobiographical text is a formidable undertaking, preparing an autobiographical chapter, which could appear with others in a volume, is perhaps less daunting work and is a project that senior scientists might even find tempting. Indeed, a venture of this kind within the discipline of psychology began in 1930 and is now in eight volumes (A History of Psychology in Autobiography). So it was that during my term as president of the Society for Neuroscience in 1993 to 1994, I developed the idea of collecting autobiographies from senior neuroscientists, who at this period in the history of our discipline are in fact pioneers of neuroscience. Neuroscience is quintessentially interdisciplinary, and careers in neuroscience come from several different cultures, including biology, psychology, and medicine. Accounts of scientific lives in neuroscience hold the promise of being informative and interesting, and they could be a source of inspiration to students. Moreover, personal narratives provide for scientists and nonscientists alike an insight into the nature of scientific work that is simply not available in ordinary scientific writing.

This volume does have a forerunner in neuroscience. In 1975, MIT Press published The Neurosciences: Paths of Discovery, a collection of 30 chapters in commemoration of F. O. Schmitt’s 70th birthday, edited by F. Worden, J. Swazey, and G. Adelman. The contributing neuroscientists, all leaders of their discipline, described the paths of discovery that they had followed in carrying on their work. While writing in the style of the conventional review article, some authors did include a good amount of anecdote, opinion, and personal reflection. A second, similar volume, The Neurosciences: Paths of Discovery II, edited by F. Samson and G. Adelman, appeared in 1992.

In any case, neuroscience writing that is deliberately and primarily autobiographical has not been collected before. This project, The History of Neuroscience in Autobiography, is the first major publishing venture by the Society for Neuroscience after The Journal of Neuroscience. The book project was prepared with the active cooperation of the Committee on the History of Neuroscience, which serves as an editorial board for the project. The first chairperson of the committee was Edward (Ted) Jones; its members were Albert Aguayo, Ted Melnechuk, Gordon Shepherd, and Ken Tyler. This group compiled the names and carried out the deliberations that led to the first round of invitations. In 1995 Larry Swanson succeeded Ted Jones as chair of the committee, and as we go to press with volume 1 the committee members are Albert Aguayo, Bernice Grafstein, Ted Melnechuk, Dale Purves, and Gordon Shepherd.

In the inaugural volume of the series, we are delighted to be able to present together 17 personal narratives by some of the true pioneers of modern neuroscience. The group includes four Nobel Laureates and 11 members or foreign associates of the National Academy of Sciences, USA. The contributors did their scientific work in the United States, Canada, England, Australia, France, and Sweden. It is difficult to imagine a finer group of scientists with which to inaugurate our autobiographical series. The autobiographical chapters that appear here are printed essentially as submitted by the authors, with only light technical editing. Accordingly, the chapters are the personal perspectives and viewpoints of the authors and do not reflect material or opinion from the Society for Neuroscience.

Preparation of this volume depended critically on the staff of the book’s publisher, the Society for Neuroscience. The correspondence, technical editing, cover design, printing, and marketing have all been coordinated by the Society’s central office, under the superb direction of Diane M. Sullenberger. I thank her and her assistants Stacie M. Lemick (publishing manager) and Danielle L. Culp (desktop publisher) for their dedicated and skillful work on this project, which was carried out in the midst of demands brought by the first in-house years of the Society’s Journal of Neuroscience. I also thank my dear friend Nancy Beang (executive director of the Society for Neuroscience) who from the beginning gave her full enthusiasm to this project.

Larry R. Squire
Del Mar, California
September 1996

Preface to Volume 9

This ninth volume of The History of Neuroscience in Autobiography includes 12 chapters by senior neuroscientists. Collectively, these chapters document the steep rise of a bold venture in biomedical research, as it played out in the late 20th century. Individually, they are treasures, for they are cast in that irresistible and uniquely human form of expression: the story. As such, they connect the dots along paths of scientific discovery, but they also convey the human elements behind those connections, the rich drama and comedy of interpersonal relationships, the sudden flashes of insight, the folly of hubris and the pain of missed opportunities, the beauty of new ideas and the raw excitement of discovery. These are stories populated by imposing and quirky characters, magnified by the lenses of memory and attention. There are tales of brilliance, fantasy, risk, sacrifice, triumph, and camaraderie, but the theme that binds every one of the chapters in this volume is success. Thus not only do these chapters entertain in the way that only good stories can, they also offer appealing models and nuanced lessons for success in the human side of science for the next generation of vanguards in our field.

In this new volume, Tom Albright joins Larry Squire in the role of coeditor. It was through Larry’s inspiration and farsighted vision that the series was founded over 20 years ago. Beginning with publication of the first volume in 1996, Larry’s passion for history and his devotion to neuroscience have yielded an expanding library of autobiographical chapters that, with this new volume, now numbers 130. There are many more great stories in the making, of course, as the field of neuroscience bounds ahead, and we look forward to curating them in these pages.

Volume 9 was prepared with the advice of the Publications Committee of the Society for Neuroscience, which serves as editorial board for the project. With input from the committee, from the Council of the Society for Neuroscience, and many others, names were compiled for this volume.

Beginning with volume 8 in this series, the Society for Neuroscience assumed full responsibility for the project. Volume 9 was produced under the capable direction of Suzanne Rosenzweig (director of scientific publications), with project management handled by Jackie Perry (senior publications manager). The contents of the volume will be posted on the Society’s Web site, under the “About SfN” menu tab (https://www.sfn.org/about/history-of-neuroscience), where one can also find the 118 autobiographical chapters that appeared in the first eight volumes. Copies of volume 9 will also be available for purchase. We hope readers will find volume 9 as interesting and useful as the earlier volumes.

Thomas D. Albright and Larry R. Squire
Del Mar, California
March 2016

David H. Cohen

BORN:

Springfield, Massachusetts

August 26, 1938

EDUCATION:

Harvard University, Cambridge, MA B.A. Magnum Cum Laude with Highest Honors (1960)

University of California, Berkeley, Ph.D. (1963)

UCLA, Brain Research Institute, NSF Postdoctoral Fellow (1963–1964)

APPOINTMENTS:

Assistant Professor of Physiology, Western Reserve University (1964–1968)

Associate Professor of Physiology, University of Virginia (1968–1971)

Professor of Physiology, University of Virginia (1971–1979)

Chairman, Neuroscience Program, University of Virginia (1975–1979)

Professor and Chairman, Department of Neurobiology, SUNY Stony Brook (1979–1986)

Vice President for Research and Dean of the Graduate School, Northwestern University (1986–1992)

Professor of Neurobiology, Northwestern University (1986–1995)

Provost, Northwestern University (1992–1995)

Vice President and Dean of the Faculty of Arts and Sciences, Columbia University (1995–2003)

Professor of Biological Sciences, Columbia University (1995–2008)

Professor of Neuroscience in Psychiatry, Columbia University (1995–2008)

Vice President and Dean of the Faculty Emeritus of Arts and Sciences, Columbia University (2008–Present)

Alan H. Kempner Professor Emeritus of Biological Sciences, Columbia University (2008–Present)

Professor Emeritus of Neuroscience in Psychiatry (2008–Present)

HONORS AND AWARDS (SELECTED):

NIH, NHLBI Research Career Development Award

Fellow, Academy of Behavioral Medicine Research

Fellow, Society for Behavioral Medicine

Fellow, American Association for the Advancement of Science

Distinguished Service Member, Association of American Medical Colleges

Distinguished Service Award, Association for Neuroscience Departments and Programs

President, Society for Neuroscience, 1981–1982

President, Association for Neuroscience Departments and Programs, 1981–1982

Chair, Association of American Medical Colleges, 1989–1990

Cohen spent the first half of his career developing a vertebrate model system for cellular studies of associative learning. He delineated a necessary and sufficient conditioned stimulus– conditioned response pathway, and unconditioned stimulus information likely converges on every relay of this pathway. This potentially enables training-induced plasticity throughout the pathway. In fact, cellular changes occur as peripherally as the lateral geniculate nucleus. These neurons receive unconditioned stimulus input via an inhibitory noradrenergic projection from locus coeruleus that is necessary for the learning-related discharge change. By no means a simple system, the identified pathways are reasonably well defined and the central processing time sufficiently short, 40–80 msec, that the system can be described as temporally compact.

Cohen left the laboratory in 1986 for university central administration, and much of the second half of his career has involved administrative activities engaging the sciences broadly, both through his university responsibilities as a senior administrator and through his service on the boards of such organizations as Argonne National Laboratory and the Fermi National Accelerator Laboratory. Throughout his career, Cohen has been deeply involved in the affairs of the Society for Neuroscience (from 1971 to the present), including eight years as an officer.

David H. Cohen

I have been intensely future oriented throughout my life, and only now in my mid-70s has the present become as preoccupying as the future. The past was never even a contender. An unintended consequence of this has been a relative inattentiveness to personal history and a general neglect of historical recordkeeping. I cannot always retrieve the years in which various events occurred and may have even lost some events entirely. Therefore, I ask your indulgence as I struggle to fill in blanks, glide over gaps, and hope not to make this brief history too egregiously revisionist.

Early Years

As long as I can recall I have been attracted to mathematics and science. This first expressed itself in any concrete fashion as an interest in chemistry around age 13, when I teamed up with a like-minded fellow down the block. We began assembling a chemistry lab in his attic, assisted by an uncle of mine, Philip P. Cohen, who was a distinguished biochemist at the University of Wisconsin and in the words of the National Academy “a pioneer in studies of transamination reactions and in the investigation of urea production.” He sent us CARE packages of lab equipment and generally cheered us on. This created some minor family friction, because he and my father, Nathan E. Cohen, a distinguished social scientist at Columbia University at the time, were fiercely competitive. My uncle’s generosity and encouragement were likely motivated in part to recruit me to “real science” and to spare me from the “soft social sciences.”

For a time, my friend and I mixed haphazardly following the muse of alchemy, occasionally stumbling across some rather impressive exothermic reactions. These occasions captured our attention and focused us on exploring how to amplify the intensity of these reactions. It was not long before we tripped over concepts such as valences and realized there was some meaningful theory and predictability in chemistry that we would be well advised to study. So we visited the high school chemistry teacher and asked to borrow a textbook, explaining that we were interested in understanding more about the nature of chemical bonds and reactions. He was generously encouraging, talked to us for a short while, and as we were leaving, textbook in hand, said, “It is such a delight to find two young fellows interested in more than making explosives.” We managed never to disabuse him of this undeserved noble view of us.

Come high school, retreating to an attic laboratory lost much of its luster, and my interests expanded from science and math to include technology and engineering, rounding it all out to STEM, an acronym that would not hit the streets until decades later. In real terms for me this involved transitioning from trying to make bigger bangs to trying to make faster cars. Throughout high school, I worked at a local auto repair shop, eventually becoming a credible mechanic. But the place was more than a simple repair shop. The folks there lived for more horsepower and speed. The measure of one’s worth was how fast you could get a car to go from zero to sixty. It was an innovative teaching experience for me. If we needed to make fuel-flow more efficient, we would argue for weeks about the optimal angle to grind and reseat the intake valves. If we increased the horsepower of an engine such that any standard clutch would regularly blow out, we would argue about what truck clutch springs should be used in rebuilding it. So, here I was back in the laboratory, but in a Texaco uniform and with grease under my nails.

Eventually it was college application time and my teacher in AP English counseled me to be sure that there was no grease on my applications. My first choice was Harvard, and to this day, I think the dean of admissions at Harvard who interviewed me saw the grease on my application as a plus. The thick letter from Harvard arrived in the mail, and at the dinner table that night my parents were elated. (Perhaps a bit of relevant background is that my father earned both his bachelor’s and doctoral degrees from Harvard and my mother her bachelor’s degree from Radcliffe.) I casually mentioned that my boss at the garage had nominated me for the new fuel injection school at General Motors and that I was weighing that against Harvard. I looked at my father who was rising out of his seat, I think still flexed at the knee. To this day that evening stands as the most compelling instance I have experienced of levitation. And so, on to Harvard.

College—Harvard University

I arrived in Cambridge with the intent of resurrecting my interest in chemistry. In fact, physical chemistry was where I wanted to be, because reductionism was deep in my DNA. Harvard assigned me an adviser who was a physical chemist housed in a basement office. I met with him a few times and, as superficial as it might sound, I simply did not want to be like this fellow. In retrospect, I find it embarrassing that I had the arrogance to make this fellow the avatar of physical chemistry. But I was 18 years old, not an excuse but a soft explanation.

So, I retreated to mathematics. This was emerging as my default mode and intellectual halfway house. As I wallowed in advanced calculus, partial differential equations, algebraic structures, complex variables, transfinite arithmetic, and so on, it became, clear to me that, although mathematics captivated me, it was not where I could spend my life. I recall a beautiful spring day in Cambridge when I sat for a final exam. The first question started, “Consider an n-dimensional unit hypersphere.” I was not really up for that at the moment and jumped to the second question that was in transfinite arithmetic: “Show that a cardinal infinity is equal to 2 raised to the power of a countable infinity.” I looked out the window at the sun and the newly blossoming trees and recollected the story in which Gertrude Stein was taking a course with William James. At the final exam, she was alleged to have written in her blue book, “Dear Professor James, this is simply one of those days I do not feel like taking an exam.” James was alleged to have replied, “Dear Miss Stein, I know just how you feel, A.” It seemed highly unlikely that dog would hunt for me. So I completed the exam and decided it was time again to regroup.

I began taking courses in probability and statistics, which introduced me to stochastic time series that in turn led me to econometrics. This, of course, alienated my advisor in the math department who felt I was compromising my intellectual purity and was being traitorous by not signing up for such courses as Quantum Theory and Lie Groups. I then found a welcoming home in the Department of Statistics, and I owe a deep debt of gratitude to Professor Frederick Mosteller, the departmental chair, for taking me on. This was an exciting period during which I was introduced to a number of extraordinary faculty and exciting research directions that took me on a journey through mathematical modeling. For example, I spent a semester tutorial working with the distinguished sociologist Professor Samuel Stouffer who was impressive in stifling his amusement when I approached him with the proposal that I take the semester to develop a formal model of societal power structures. I vaguely recollect his asking wryly if I felt this would really take the full semester. Then came my introduction to game and decision theory and the opportunity to read with Professor Duncan Luce, one of the driving forces in developing the area. This work prompted me to begin thinking about behavior itself and not simply how to formalize a set of given behavioral outcomes. From here, it was a natural transition to choice behavior and, while still deeply embedded in such concepts as Arrow’s impossibility theorem and Pareto optimality, I began to think ever more seriously about behavior.

At this same time, Professor Mosteller involved me as a research assistant in some projects deriving from a book he and Robert Bush had recently published entitled Stochastic Models for Learning (1955). Although this introduced me to modeling with difference equations and Monte Carlo methods for testing models, much more importantly, it also introduced me to learning behavior—a topic that would preoccupy me for many years. I had the memorable experience of spending a summer with NSF support working under the tutelage of Mosteller, Bush, and others, splitting our time between Cambridge and a rental house in Rockport, Massachusetts, that was a hotbed of analytic capability.

During this time I met a classmate at Harvard, Wayne Wickelgren, who was following a similar path to mine. Wickelgren was a fellow traveler who was anchored in mathematics but captivated by modeling of behavior. We teamed up and collaborated on various projects, eventually publishing two papers together based on work we completed as undergraduates. Mosteller, my advisor, also served as Wickelgren’s advisor, and he approved of and guided our undertaking a joint undergraduate honors thesis. This was an experimental study of human choice behavior and generated the first of our two undergraduate publications, “A Regression Analysis of Problem Solving in a Binary Choice Task” (Cohen and Wickelgren 1961).

This honors thesis was a watershed event in various ways. It solidified our interest in behavior, although somewhat differently for each of us. Wickelgren became enamored with the processes of human problem solving and migrated toward cognitive psychology. I became interested in learning behavior. We both cooled significantly on the prevailing modeling efforts. After running the experiments for our honors thesis and interacting with our experimental subjects, what became exceedingly clear is that our models paled in the face of the complexity of the ongoing behavior. Also, at the time, it was common practice for researchers in behavioral modeling to write ongoing white papers and circulate them among colleagues. I recall receiving one such white paper from an eminent colleague that was signed, “Sincerely yours in linearity.” Linear models, and all our models were indeed linear, simply were not going to cut it. In the modeling business, there often comes a time when one has to choose between the model and the real world. At a young age, I recall my father telling me that there are times in life to abandon your principles and do what is right. This was one of those moments.

Before moving on to the next phase of my professional life, I feel compelled to acknowledge how fortunate I was to have been an undergraduate at a time when one could follow whatever muse was intellectually captivating at the moment. It was a world of opportunity in which “creeping vocationalism” and “credential building” had not yet tainted the scene. I lament that this seems no longer so; what a tragic loss.

Graduate School—University of California, Berkeley

Wickelgren and I put the math behind us and decided we needed to learn about behavior. It seemed that the best way to do this was to go to a leading graduate program in psychology. We had made the decision to remain associated and headed together for the doctoral program in psychology at the University of California, Berkeley. Wickelgren caught me up in his fever of getting to independent research, unencumbered by advisors, as quickly as possible. After all, in the arrogance of youth, we were persuaded that our ideas, which were well out of the mainstream, were compelling and that advisors were barriers to creativity rather than helpful mentors. Operationally, this translated into getting through the PhD program as quickly as possible. We set the finish line at two to three years and began strategic and tactical brainstorming sessions to craft a plan for achieving this. Well, it succeeded. Wickelgren finished in two years and I finished in two and a half.

Let me offer one example of how this strategizing worked. The doctoral program at Berkeley had a challenging set of preliminary exams that generally took a few years to pass. One exam addressed content and consisted of a large number of multiple-choice questions that tested a daunting reading list of books and journal articles. The brute force approach would be to take a year or two (at the very least) to slog through this material, an unacceptably long time. Research on human memory had drawn a sharp distinction between recall and recognition memory. We hypothesized that, if the literature on recognition memory was indeed correct, we could just skim the background material, covering multiple books in a single evening. Then at exam time, for each question we would simply choose the answer that felt right, making no effort to decide whether it was correct or not. We assembled this large collection of materials, to my wife’s displeasure, stacked on our living room floor. We spent some weeks skimming through it all. It worked! Was there a cost to not having mastered all that material at the recall level? That did not concern me at the time and, in retrospect, I seriously doubt it.

Not to appear unduly competitive, I do feel the need to address why it took me six months longer than Wickelgren to finish my PhD. As I mentioned, our interests had begun to diverge. Wickelgren’s migrated toward human problem-solving behavior and mine toward learning. For my dissertation, I undertook a study of the decay of short-term memory for absolute brightness values in pigeons. Shortly after I began my experiments, the animal facility director expressed concern about whether the pigeons I was bringing into the animal facilities were free of ornithosis. I was tested for this infection and had a high titer. They would not let me bring in any more birds until I could assure them that they were free of ornithosis. It took me six months to resolve this issue. I located a veterinarian from the CDC working on psittacosis in parrots at a public health facility in San Francisco. We teamed up to develop a prophylactic regime for clearing pigeons of the rickettsia causing ornithosis by embedding chlortetracycline in the feed. So there I was, delayed by half a year, but still within the two- to three-year bogie and having generated my only publication in the Journal of the American Veterinary Medical Association (Arnstein et al. 1964).

The path of one’s life is in no small measure defined by presented opportunities. One such opportunity for me at this time was working in a lab on a floor amid biologists. A nearby biologist who was involved in comparative studies of the pineal gland saw my pigeons and asked whether he could have the glands of any animals I no longer needed. Wanting to be collegial, but having no idea how to remove the pineal gland, I said, of course, but in the interests of my time, I would appreciate his coming to get them. He did, leaving me with pigeon heads with partially opened skulls. Within fairly short order, I became proficient at removing the brains, and I began accumulating a number of these brains in jars of formalin. Anyone who has observed operant conditioning of pigeons must be impressed with what impressive learning machines they are. I kept staring at the bottles, wondering how that innocuous looking bit of tissue mediates that behavior.

And thus my passage. I was hooked on the challenge of understanding how the brain mediates the storage of information that enables learning. It was not really a passage into neuroscience, because no such field existed at the time. But it was clearly a passage into the anlage of neuroscience.

Postdoctoral—UCLA Brain Research Institute

As Wickelgren shifted his interests to human problem solving and ultimately headed off to a faculty position in the Department of Psychology at MIT, I explored how best to acquire the skills I would need to study the cellular mechanisms of learning. It was clear that committing to a traditional biological discipline was not the answer and that I needed to find an environment that would expose me to a broad array of disciplines in the context of research on the brain. One of the few places that fit this job description was only a few hundred miles south of me, the Brain Research Institute (BRI) at the University of California–Los Angeles (UCLA).

Rather than identifying a specific mentor and undertaking a defined research project, the more conventional postdoctoral experience, I sought the freedom to audit courses and wander from lab to lab, learning approaches, methods, and what a broad array of distinguished scientists considered to be the most important questions about the brain. I applied for an NSF postdoctoral fellowship, explaining in my application that I was migrating from psychology to a field that had not yet been defined and sought support for a study rather than a research postdoctoral. Happily, NSF bought the plan and I headed to UCLA. Sadly, I cannot imagine this happening today.

What an extraordinary time it was. I sat through neuroanatomy and neurophysiology with the first-year medical students. I learned single-cell recording, basic histological techniques, and animal surgery. The BRI had a rich fare of speakers from around the world, and I did not miss many. And, I did manage to complete and publish a small research project on the effects of lesions of the pigeon optic tectum on brightness discrimination learning (Cohen 1967b).

Among the most valuable products of this time was my ability to clarify my long-term research objective—to develop a vertebrate model system for studying changes that mediate associative learning. During this time, I settled on a model system approach and, consistent with my strong reductionist bias, committed to analysis at the single-cell level. As I look back on what the catalysts might have been for my defining this direction, I believe it derived from my background in mathematics and formal modeling. The BRI provided a fertile opportunity for conceptualizing it, and my experience there helped shape it into a biological narrative.

Simple systems such as the Aplysia (Kandel and Spencer 1968) in many ways were exceedingly compelling, and it seemed almost foolhardy to tackle the complexity of a vertebrate brain. It was not even clear at the time whether it would be possible, with the available methods, to map the relevant pathways for any learned response. That said, what drove my decision was a deep concern that simple systems were too simple behaviorally. Indeed, over the ensuing years, the struggle to demonstrate associative learning in Aplysia offered testimony to this concern. So intrepidly, perhaps a euphemism for naively, I forged on toward trying to develop an effective vertebrate model system for cellular analysis of associative learning (Cohen 1969).

Unbundling the Different Paths of My Career

Before describing that work, I need to address some organizational matters for this essay. My active research career spanned the years 1964 to 1986 at three venues—the Department of Physiology at Western Reserve (now Case Western Reserve) Medical School (1964–1968), the Department of Physiology at the University of Virginia Medical School (1968–1979), and the Department of Neurobiology and Behavior at the State University of New York (SUNY) at Stony Brook (1979–1986). Beginning in 1971, however, administrative activities began looming increasingly large in my life. A first phase involved activities related to the development of neuroscience as a field. These included neuroscience program development at the University of Virginia and Stony Brook (1971–1986) and, particularly prominently, broad and deep involvement with the SfN (1971–present). A second phase began at the close of my research activity in 1986, when I moved into central university administration and became increasingly involved in national activities, most often science related (1986–2008).

Research Years (1964–1986)

My program to develop a vertebrate model system for cellular studies of associative learning began in earnest when my postdoctoral ended and I moved to my first faculty position as an assistant professor in the Department of Physiology at Western Reserve University Medical School.

Developing the Behavioral Model

A first task was to select an experimental animal. Having worked with pigeons both as a graduate student and postdoctoral fellow, I had become impressed with how easily they could be trained in associative learning tasks. They were inexpensive, readily available, easily maintained, and easy to handle. From a behavioral perspective, this turned out to be a particularly fortuitous choice, as I will describe shortly, less so with respect to delineating the neural circuitry. I expected that to be quite challenging for any mammalian species, but it turned out to be particularly daunting for the pigeon because the avian neuroanatomical literature was so limited. There was also a price to be paid for working outside the mammalian mainstream. On the positive side of the ledger, it permitted ongoing contributions to comparative neurology, and I take great pride in my publications over the years in the Journal of Comparative Neurology. This also began a long-term association and friendship with Harvey Karten, the contemporary maven of avian neuroanatomy. Although we only occasionally published together (e.g., Cohen and Karten 1974), we maintained an ongoing dialogue about a broad range of topics in avian and evolutionary neurobiology.

The next task was to identify an appropriate behavioral paradigm. Constraints on the behavioral model were that it had to show robust associative learning that developed in a nonmoving animal in a single training session of at most a few hours. An obvious candidate was a classically conditioned autonomic response, and because heart rate is so easily measured and quantified, I began there. There was a significant literature on classical conditioning of heart rate in various mammalian species. The developmental time course and robustness of the conditioned response were attractive in some but not all mammals (e.g., the rat), but such conditioning had never been demonstrated in the pigeon. By 1966, I had developed a standardized training paradigm in which a 6-sec pulse of whole-field illumination, the conditioned stimulus (CS), was followed by a mild, 500-msec foot-shock, the unconditioned stimulus (US), which elicited cardioacceleration, the unconditioned response (UR). A conditioned cardioaccceleratory response (CR) of predictable dynamics begins developing within 10 light-shock pairings and is asymptotic by 30 pairings (Cohen and Durkovic 1966).

This work began defining three themes that carried throughout my research years. The dominant theme, of course, was pursuing a cellular analysis of associative learning. Both comparative neuroanatomy and neural control of the cardiovascular system became significant subsidiary themes. Although these subsidiary themes were of genuine interest to me, they also generated support for the laboratory during the long march to develop the model to the point at which single-cell studies could be undertaken. For example, neural control of the cardiovascular system enabled a successful application to the National Heart, Lung, and Blood Institute at NIH for a Research Career Development Award and, over the years, the laboratory generated a number of publications relating to neural control of the cardiovascular system (e.g., Macdonald and Cohen 1973; Cohen and Cabot 1979; Cabot and Cohen 1980; Cohen and Randall 1984).

Mapping the Circuitry

During my four years in Cleveland, I consolidated the behavioral model and began the daunting task of mapping the neural pathways involved in mediating the learned response. I approached this by heuristically defining four segments of the system: the visual pathways transmitting the CS; the somatosensory pathways transmitting the US; the descending pathways mediating expression of the CR; and the efferent pathways mediating the UR. I then began at the periphery of each segment and systematically mapped the pathways centrally using multiple techniques. It was assumed that such an analysis of the input and output segments of the system would lead to sites of convergence of the CS and US pathways, as well as to their sites of coupling with the CR.

This mapping program was pursued vigorously until I left the lab in 1986 and, over this period, I did in fact succeed in gaining a first approximation to a necessary and sufficient pathway from the eye to the heart (Cohen 1980, 1985). A number of students contributed significantly to this effort: John Cabot, Thomas Duff, Russell Durkovic, Paul Gamlin, Charles Gibbs, Michael Gold, Robert Leonard, Robert Macdonald, Lawrence Pitts, Theresa Ritchie, Adrian Schnall, James Schwaber, Doris Trauner, and John Wall.

With respect to transmission of CS information, it involves three ascending parallel pathways: a thalamofugal pathway homologous to the mammalian geniculo-striate system and two tectofugal pathways perhaps homologous to mammalian tecto-thalamo-extrastriate pathways. Each of these three pathways can transmit effective, although not necessarily redundant, CS information, and it is only with their combined interruption that formation of the CR is precluded. A number of studies from 1967 onward were necessary to define these CS pathways (e.g., Cohen 1967a; Cohen and Trauner 1969).

To characterize the descending pathways mediating expression of the CR, I began at the final common pathway, the sympathetic and vagal motoneurons. We initially showed that the response, at least within the 6-sec conditioned stimulus period, is mediated entirely by the extrinsic cardiac nerves; there is no hormonal component. Although the vagus nerve mediates the shortest latency component of the CR, the major contribution is mediated by the sympathetic cardiac innervation (Cohen and Pitts 1968; Cohen 1974a).

Given a description of the final common path, we launched a comprehensive study to identify the central pathways that control heart rate and blood pressure, assuming that some subset of these would converge on the cardiac motoneurons to mediate the CR (Macdonald and Cohen 1973). We ultimately identified a descending system in which electrical stimulation elicits striking pressor-accelerator responses and lesions prevent expression of the CR (e.g., Cohen 1975; Cohen and Macdonald 1976; Cohen and Goff 1978a). The most rostral component of this pathway is the avian amygdalar homologue, which is the most cardioactive structure of the avian telencephalon. There is then a well-defined amygdalar projection to the posteromedial hypothalamus in which a pathway originates that traverses the ventromedial brainstem at mesencephalic and rostral pontine levels. In the caudal pons it shifts to a ventrolateral position that is maintained through the medulla. At medullary levels, fibers project dorsomedially from the pathway to access the dorsal motor nucleus of the vagus, while the spinal continuation of the pathway occupies a position in the lateral funiculus and ultimately accesses the sympathetic preganglionic cardiac neurons through one or more spinal interneurons.

Given that the CS pathways ascend to the telencephalon and that the CR pathway involves the amygdala, it seemed reasonable to hypothesize that the relevant visual areas of the telencephalon influence the amygdala through intratelencephalic circuitry. An extensive series of anatomical experiments identified intrinsic telencephalic cell groups and their connections that could serve this function (Ritchie and Cohen 1977, 1979). These cell groups, including a critical subnucleus of the amygdala, are all responsive to varying degrees to whole-field illumination (the CS), and preliminary behavioral experiments suggested the necessity of this circuitry for acquisition of the CR.

Rather early in the program we described the peripheral components of the US and found that activation of A-delta and C fibers is required to elicit a CR (Leonard and Cohen 1975c). Subsequently, we completed a cytoarchitectonic analysis of the pigeon spinal cord, described the patterns of dorsal root termination, established some of the properties of the intraspinal circuitry by which the US influences sympathetic postganglionic neurons, and generated preliminary data implicating the dorsolateral funiculus in the transmission centrally of the US (Leonard and Cohen 1975a, 1975b, 1975c).

At this point, we had begun to appreciate that most, if not all, central structures along the CS–CR pathways receive US input. Given this understanding, we made the tactical decision to shift our focus from trying to map the US pathway from the periphery centrally to mapping it back from the nuclei along the CS–CR pathway. A particularly compelling example of the merits of this approach will be described shortly.

Specifying the pathways that mediate the cardioacceleratory to the US was of low priority, and this response is almost certainly quite diffuse and can be mediated at many levels, including spinally. Consequently, we did not make a systematic effort to delineate this segment of the system.

Temporal Properties of the Information Flow

The CR has a latency of approximately 1 sec and persists for 6 sec (Cohen and Goff 1978b). The central processing time for this response, however, need not be of the same order of magnitude. Characterizing the discharge properties of the cardiac motoneurons during the conditioned response allows specifying that response in a neurophysiological time domain that excludes delays at the motor periphery. Determining the temporal properties of the retinal response to the CS then permits a reasonably precise estimate of central processing time. That estimate, in turn, establishes the temporal boundary conditions for interpreting neurophysiological data from central structures.

The sympathetic cardiac postganglionic neurons respond weakly to the visual stimulus before training. The latency of this orienting response is approximately 100 msec, and it consists of a short burst of action potentials followed by a brief period of depressed discharge before a return to maintained activity levels. This response habituates rapidly. With CS–US pairing, the probability of occurrence of this phasic response and its duration increases rapidly. An important feature of this CS-evoked sympathetic discharge is that it consists almost exclusively of a transient response at CS onset with a latency of approximately 100 msec and a duration of 300–400 msec. Thus, the central processing time for the 6-sec behavioral conditioned response does not exceed 400 msec, indicating a highly nonlinear input–output relation between the sympathetic postganglionic innervation and the heart (Cohen 1982, 1985).

The cardiac neurons in the dorsal motor nucleus of the vagus also respond to the CS before training, but with decreased discharge. Because the vagal cardiac innervation is inhibitory, this contributes to the CR. Like the sympathetic response, the vagal response has a prominent phasic component, with a more modest tonic component lasting 110 msec. Associative training enhances the magnitude of this decreased discharge, as well as shortening its latency to 60–80 msec at asymptotic performance (Gold and Cohen 1981, 1984).

At the input to the system, retinal ganglion cells respond to whole-field illumination as a rather homogenous population, bursting briefly at light onset and largely ceasing activity during the remainder of the sustained illumination. This “on” burst has a minimal latency of 18 msec and a maximum duration of 80 msec (Duff and Cohen 1975). These response properties are not affected by associative training (Wild and Cohen 1985).

Calculating the differences between the modes of the response histograms of the retinal ganglion cells and the cardiac motoneurons gives 105 msec for the central processing time for the vagal component of the CR and 135 msec for the sympathetic component. The minimal central processing times for the vagal and sympathetic components are approximately 40 msec and 80 msec, respectively. This significantly delimits the system and, although certainly not a “simple system,” it might be described as a “temporally compact system” (Cohen 1982, 1984).

Sites of Neuronal Modification—the CS Pathways

So, some 15 years after the initiation of the program to develop a model system, it had advanced sufficiently to permit cellular study of potential sites of plasticity. An obvious starting point was the CS pathways and, beginning at the periphery, we first showed that neither the CS-evoked nor maintained activity of the retinal ganglion cells change as a function of conditioning (Wild and Cohen 1985).

We then focused on the most prominent of the three ascending pathways transmitting CS information: the retino-tecto-rotundo-ectostriatal pathway, and initially studied its telencephalic target, the ectostriatum. If these neurons were invariant with training, we could infer that the subtelecephalic components of the pathway also would be invariant. Certain classes of ectostriatal neurons clearly showed modification of their CS-evoked discharge during conditioning. An examination of the thalamic relay of this pathway, the nucleus rotundus, similarly demonstrated classes of neurons whose discharge changed as a function of associative training (Wall et al. 1985).

This raised the possibility of training-related plasticity as peripherally as the first central synapses of the retinal ganglion cells. Given the structural complexity of the avian optic tectum, we turned our attention to the thalamofugal pathway, the avian homologue of the mammalian geniculostriate system. Studying these retinorecipient neurons permitted both assessment of training-induced plasticity in a second of the three involved ascending visual pathways and determination of whether such change occurs as peripherally as the first central synapse of this visual pathway. The results clearly showed robust training-induced changes in the avian equivalent of the dorsal lateral geniculate nucleus (LGN) (Gibbs et al. 1986). There were no changes in maintained activity, and only the short latency phasic response showed modification. The short latency and duration of the modified discharge make it highly unlikely that it is driven by feedback from more central structures. At this point, we felt confident in concluding that at least two of the three visual CS pathways undergo associative modification and that this modification can occur as peripherally as the retinorecipient neurons.

The modifiable geniculate neurons respond initially to both the CS and US, demonstrating the expected need for convergence of these two inputs for associative learning. The associative training paradigm then enhances the initial CS-evoked discharge of the modifiable neurons, whereas in a nonassociative control paradigm, this discharge habituates. The discharge enhancement is largely restricted to the short latency, transient visual response, which is consistent with the pattern of training-related discharge changes observed in the cardiac motoneurons. Thus, the modifiable neurons simply seem to do more of what they initially do in response to the visual stimulus, and the time course of this discharge modification over training parallels that of the motoneuronal discharge changes.

CS–US convergence is necessary for associative modification, but it is not sufficient. Modifiability seems to depend on the nature of a neuron’s response to the US. Only LGN neurons whose discharge decreases in response to the US show associative modification. Neurons that are either unresponsive to or excited by the US show discharge attenuation under either associative or nonassociative paradigms. Thus, the properties of the US input are more critical in determining a neuron’s modifiability than the properties of the CS input. Modifiable LGN cells can show either increased or decreased discharge in response to the CS, and therefore the direction of the CS-evoked and US-evoked discharges need not be the same in the modifiable cells.

The obvious next step was to investigate the source of the US input to the LGN, and a series of neuroanatomical and neurophysiological experiments implicated a projection from the locus coeruleus (Cohen et al. 1982; Gibbs et al. 1983; Broyles and Cohen 1985; Elmslie and Cohen 1990). Histofluorescence and immunohistochemistry clearly demonstrated the presence of norepinephrine and serotonin in LGN, and iontophoresis of norepinephrine can inhibit the firing of LGN neurons. Recording from cells in locus coeruleus indicated that a substantial proportion are responsive to the US at latencies consistent with relaying timely US information to the LGN. Furthermore, electrical stimulation of locus coeruleus can decrease the discharge of LGN neurons, and interruption of the coeruleo-geniculate projection largely eliminates the population of LGN neurons showing decreased discharge to the US. Under these conditions, such neurons are no longer modifiable by conditioning. Finally, electrical stimulation of locus coeruleus can serve as an effective US. Consequently, it seems reasonable to tentatively conclude that the coeruleo-geniculate projection is both necessary and sufficient for relaying effective US information for associative modification of LGN neurons.

Brief Overview and Forks in the Road

It was now the mid-1980s, and the state of play was as follows: We had a highly effective behavioral model and had specified a necessary and sufficient CS–CR pathway, which in some segments such as the visual system involved parallel pathways. We had good reason to suspect that US information converges on every relay along this CS–CR pathway, although the source of that input need not necessarily be the same for different levels of the pathway. This would suggest the potential for training-induced plasticity at all relays along the pathway, giving an anatomically localized system with widely distributed sites of plasticity. Furthermore, this system, although by no means simple, is “temporally compact,” such that it may well be possible, admittedly with challenging effort, to ultimately describe the input–output relations at each relay of the system.

In pursuing the most peripheral site of plasticity, a somewhat unexpected finding was that clear training-induced change occurs in the retinorecipient neurons of the thalamus, the avian lateral geniculate homologue. Equally surprising was that the necessary and sufficient US input to the geniculate is via a projection from the locus coeruleus. This was one major fork in the road at this time.

I say it was a fork because this potentially could have taken the lab in the very different direction of focusing on an in vitro model with a slice preparation, using electrical stimulation of the optic nerve as the CS and iontophoresis of norepinephrine as the US. At the same time, I was reluctant to abandon such other possible directions as gaining an understanding of the role of such structures as the amygdala (Cohen 1975). To pursue the many opportunities would have meant a substantial expansion of the laboratory, an unattractive prospect as I had always preferred a modestly sized enterprise.

I never resolved this dilemma because of another entirely unexpected fork in the road, the prospect of moving into university central administration. I will tell that story a bit later.

Society for Neuroscience (1970–Death Do Us Part)

Permit me to backtrack now to 1970 when my involvement with the SfN began, an involvement that continues to this day. The Society has had an extraordinary impact on the development of neuroscience as a field. Early on after the start of my professional career, it was clear to me that, to play off Pirandello, I was a neuroscientist in search of a field. Thus, when the fledgling Society was hatched, there was no question that I would be willing to commit deeply to working for its success. Indeed, I traded significant potential research time for this endeavor and have never regretted that decision. My involvement with the Society has been one of the most rewarding experiences of my career, and I would like to think that I contributed materially to the development of this truly uncommon organization.

I have organized this section by functional activities of the Society that I had a significant hand in developing, and to the extent possible, I have tried to order these chronologically. A first period, the pre-officer period was 1970–1975. I had the honor to be elected secretary in 1975 and to serve in that position until 1980 when I was elected president. I then served as president-elect, president, and past-president until 1983. This defines the officer period of 1975–1983. The post-officer period that began in 1983 continues to the present.

Pre-Officer Period (1970–1975)

During this period, I was involved with the Society primarily through its chapter structure. In 1968, I left Western Reserve to accept a position in the Department of Physiology at the University of Virginia (UVa) School of Medicine as an Associate Professor. At that time, UVa Medical School had received substantial federal funding to invest in building its basic science departments. It was importing whole departments, and I was part of the wave migrating from the Department of Physiology at Western Reserve. Western Reserve émigrés also populated the Department of Pharmacology, while the revitalized Departments of Biochemistry and Microbiology came from Johns Hopkins.

Not long after my relocation to UVa, I learned about the existence of the SfN, a newly formed organization defined by an organ rather than by function or methodology as were the traditional disciplines of anatomy, biochemistry, pharmacology, and physiology. I cannot recall how I first learned of the Society, but I do recall that I resonated immediately to the concept. At the time, I was already a member of the American Association of Anatomists and the American Physiological Society and, in addition to attending the annual meetings of these organizations, I would less regularly attend meetings of various behavioral and pharmacological associations. This was necessary to cover the span of the multidisciplinary needs for my research program. The Society was clearly an enterprise I needed to become involved with and give my all to support.

Early on, the Society developed a local chapter structure, an insightful decision, as it created local receptor sites for institutional program development. I took advantage of that to establish a chapter at UVa in 1970, I believe one of the earliest chapters of the Society. In 1971, I was invited to serve on the Society’s Committee on Chapters, which I then chaired in 1974–1975. While on this committee, I approached the Grass Foundation, which already supported the Grass Lecture, seeking support for a traveling scientist program that would cover the costs of invited speakers to visit chapters. The objectives were to strengthen the chapters locally by enabling a major event to coalesce local neuroscientists, to incentivize chapter development, and generally to make the Society more attractive to its evolving constituency. The Grass Foundation encouraged me to submit a proposal. I did, it was successful, and the program launched in 1972. I directed it until 1975, when I was elected secretary of the Society. (Ironically, many years later in 2005 I joined the board of the Grass Foundation, and during the economic downturn a few years after found myself in the uncomfortable position of listening to discussions about whether the annual grant to the Society for the Grass Traveling Lecture Program should be reduced, if not eliminated. Appropriately, I had no alternative but to recuse myself.)

Officer Period (1975–1983)

My involvement with the SfN expanded explosively during this period, and I take great pride in having played an instrumental role in the expansion of the Society’s mission to encompass various new and critical areas. It was during this time that the Society adopted advocacy as central to its mission, and advocacy was one of the critical stimuli for our committing to an ongoing effort to communicate to the public. The Society took its first step to becoming an international organization during this period. It undertook its first long-term strategic planning effort, and it was during these years that external events thrust the Society into the vigorous defense of the role of animals in research. All of these areas are now structurally embedded in the organization and are fundamental elements of its mission.

Advocacy and Public Information

On being elected secretary, my involvement with the Society broadened and deepened. I became a member of Council, serving from 1975 to 1983. As the growth of the Society was becoming a national phenomenon, it increasingly was called upon by various organizations to join in advocacy efforts, and it was not long before this was incorporated into the mission of the Society. I represented the Society in most of these early relationships, such as with the National Committee on Research in Neurological and Communicative Disorders and the Coalition for Health Funding. The Society’s involvement in advocacy was formalized in 1977 with the establishment of the Government and Public Affairs Committee, which I started with Floyd Bloom. I chaired this committee for many years. Also, beyond acting as liaison with other advocacy groups, I regularly wrote for the Neuroscience Newsletter about the funding environment, provided congressional testimony, met with senators and representatives who sat on key committees, and maintained ongoing contact with the leadership of our principle funding agencies.

I do need to digress to share with you one of my favorite anecdotes of these advocacy years, a situation that was both amusing and disconcerting. During the Carter administration I managed to schedule a meeting with an individual rather high in the executive branch. I made some introductory remarks about neuroscience and its funding needs. Following that, he asked whether I was aware that Rosalyn Carter had an interest in mental health. I responded that, yes, we were aware of that and were deeply grateful for her interest. He then asked whether I also knew of her interest in learning disabilities. I said, no, I did not, and he followed that by asking whether learning disabilities had anything to do with the brain. That left me momentarily speechless and, on recovering, the only response I could muster was, “Sir could you possibly suggest an alternate organ?”

This experience with advocacy offered significant civics lessons with respect to how Washington works (or does not), including the role of lobbying. One of my most important takeaway lessons, beginning with the previous anecdote, was the monumental task we confronted to educate both our elected officials and the public about brain research. Congressmen continually reinforced this message, and still do, telling us to get out there at the local level. Many others in the Society understood this need for informing the public and this, like advocacy, was incorporated into the mission of the Society and catalyzed the establishment of the Public Information Committee. I served on this committee as a member beginning in 1983.

One of the early efforts in this context was an effort to establish connections with leading science journalists. We organized a meeting at Airlie Conference Center in Warrenton, Virginia (I do not recall the year), in which a group of neuroscientists and distinguished science journalists spent a few days together getting to know each other and exploring how we might more productively interact. I suspect the neuroscientists learned considerably more than the attending journalists. I was disabused of my assumption that science writers were failed scientists. On the contrary, I learned they are talented and accomplished reporters who could just as adeptly be covering the crime desk or foreign affairs. In the spirit of full disclosure, I put my sister, Susan Cohen, in that category. We also learned that attempting to convince a journalist to include the salient historical background and key scientists enabling any discovery they were reporting on was not a battle we were likely to win, any more than making the case for caveats in reporting a result. It was in this context that we learned the frequent lament of journalists that they wanted to meet a one-handed scientist who does not tell them, “on the other hand.” Their goal was to get their article on the front page, and one-handed scientists were simply not going to capture their attention. All this said, my sense was that we walked away from that meeting wiser about the media and having established substantial good will with the attending journalists.

Perhaps our most important advocacy partner was the Association of American Medical Colleges (AAMC). At the time, the AAMC was the biggest game in town in advocating for support of medical research. Our first formal contact with the organization was in 1978 when we were invited to join the Association’s Council of Academic Societies. I served as the Society’s representative and, in 1984, was elected chair of the Council. Beyond serving as the Society’s point of contact with the AAMC, out of personal interests deriving from my positions on medical school faculties, I became deeply involved in AAMC activities, serving on its various committees; ultimately, I was elected chair of the AAMC in 1988.

Going Global

The seeds of international neuroscience were clearly evident in the establishment of the International Brain Research Organization (IBRO), incorporated in Canada in 1961. Indeed, IBRO was seminal in establishing early on an international network of neuroscientists and initiating important activities, including international congresses.

In its early years, the Society was appropriately focused domestically, but it was not long before it began to look beyond U.S. borders. It could hardly do otherwise, as it was becoming clear that the Annual Meeting of the Society, from its inception in 1970, increasingly was attracting foreign attendance and was becoming the dominant neuroscience meeting globally. As of 2016, I believe, approximately 40 percent of the Society’s membership is foreign.

During my officer years, the first non-U.S. chapters in Canada and Mexico were chartered. I was particularly involved in the establishment of the Mexican chapter, and I developed personal relationships with the Mexican neuroscientists leading its development. I was also involved in the Society’s establishing formal relations with IBRO. I served as the liaison to the IBRO Central Council from 1978 to 1982 and served on the U.S. National Committee for IBRO of the National Academy of Sciences from 1980 to 1986.

The exciting growth of the field during this time was penetrating a number of countries, as it had the United States, and neuroscience organizations were blooming globally. To get some sense of what was happening internationally and on behalf of the Society to express solidarity with these developing enterprises, as president-elect, I convened the presidents of the various national neuroscience societies in Malaga in 1982 and again, as president, in Paris in 1983. Also, during my presidential year, I visited various countries to offer encouragement for national neuroscience society development and to offer what consultative advice I could.

Strategic Planning

The explosive growth of the Society and its expanding menu of activities had a Wild West character as I entered my presidential year. The reactive nature of our growth stimulated me to initiate a long-range planning effort, not to control our trajectory but rather to get some sense of priorities for our ongoing activities and to identify other projects and areas in which we should be engaging. I appointed an ad hoc committee of “tribal elders” to look into our future. It was a rather informal exercise, different from the stylized strategic planning exercises of today. The enthusiasm of the ad hoc committee I believe signaled a collective sense of our having reached a milestone in the development of the Society. Although I cannot assess the impact of the ad hoc committee’s report, I have been told that subsequent planning exercises have validated its findings and recommendations.

Animals in Research

As I indicated earlier, much of our activity in governing the Society in these, its late teenage years, was heavily reactive. That was certainly the case for our initial involvement in the issues of animals in research. Some of you may recall the Ed Taub case, in which People for the Ethical Treatment of Animals, still a fledgling organization, infiltrated his laboratory and released films allegedly documenting mistreatment of research primates. This broke in the press during the annual meeting where I was assuming the presidency of the Society. The membership was outraged and demanded that the Society defend Taub. This was a classic instance of the adage, “where you stand depends upon where you sit.” As a colleague, I was prepared to go to the barricades for Taub, but as president of the Society, I had no choice but to hold back and tell the membership that we needed facts before we could take a public position. This was the shot heard round the vivarium that embedded us deeply as advocates for the use of animals in research, a cause that has become deeply institutionalized in the Society.

Concluding Comments on the Officer Years

Over this period, I spent a significant amount of time each week on Society activities, beyond the more formal responsibilities of an officer or as a member of standing committees. For example, I chaired the Grass Lecture Selection Committee for five years, sat on the Gerard Prize Selection Committee, served on the Subcommittee on By-Laws, and was the liaison to a number of organizations both domestic and international. Additionally, I spent many hours on the phone each week with the executive director of the Society, Nancy Beang, and with the other officers. Also, with the growing recognition of neuroscience and of the Society as the dominant professional organization of this explosively emerging field, I was asked to serve on what seemed like countless advisory committees for NIH, NSF, the Department of Defense, and the National Academies, as well as being invited by numerous institutions to consult on how they should move forward in their local development of neuroscience.

It was a great honor to be elected to these offices. It put me at the center of the Society’s governance during one of the most exciting periods of the organization’s development and of the emergence of the field as an integrated discipline. I had the extraordinary privilege of being in a leadership position as the Society grew into adulthood, broadened its missions, and gained enviable recognition nationally and internationally.

Post-Officer Period (1983–Present)

My involvement with the Society following my officer years focused largely on its financial affairs. As an officer, I served ex officio on the Finance Committee from 1976 through 1982. At the time I was elected president, the financial state of the Society was sound, if not thriving. I took it as a serious responsibility of my office to look toward ensuring the organization’s longterm financial stability. It seemed to me that, beyond responsible management and governance, this demanded focusing on two objectives: developing diverse revenue sources and building a financial reserve. Too many of our fellow societies were overly dependent on one or at most two dominant revenue sources, such as dues or publications, and almost none had developed a strategy for establishing a significant financial reserve.

We clearly had a healthy start with respect to revenue channels. Membership was growing substantially each year, and it had become evident that foreign membership was becoming a significant unanticipated revenue source. The annual meeting was generating sizable surplus revenue annually because the meeting was well managed and had become a “must attend” rather than a “nice to attend” event both domestically and internationally. This of course generated strong exhibitor revenue. The journal recently had been launched and represented yet another potential revenue channel for the future.

With respect to building a financial reserve, I cannot recall our cash situation at the time. If memory serves it was perhaps $2 million plus parked in a mattress. So I began to consider ways we could deploy these funds more productively to launch a reserve fund. We began by engaging an investment advisor and adding annual surpluses into an investment pool. Before long, it became clear we needed a better structure than a single advisor informally dealing with a few of us. So, I drafted an investment policy, and in 2002, we constituted an Investment Committee and engaged a custodian to manage our accounts and advise the committee. I undertook the responsibility of chairing the committee and early on recognized the need to bring on some members who were investment professionals. I had relocated to Columbia University in 1995 and by 2002 had built a rolodex of Manhattan-based financial people who could assist us in assembling a powerful advisory structure. Since then, we have enjoyed the benefits of having on the committee at any given time one or more truly impressive investment professionals. I chaired the committee from its inception until 2011, and I am highly gratified that we now have a reserve exceeding $50 million (not including the significant equity in our building) that has had a solid annual return on investment—adding yet another revenue source.

I again served on the Finance Committee from 2000 to 2006 and continued ex officio until 2011 in my capacity as chair of the Investment Committee, giving me in aggregate 17 years on the committee. Over these years, we have developed an extraordinarily productive relationship between the Investment Committee, Finance Committee, and the Council with respect to how best to ensure the financial stability of the Society. This is testimony in my estimation to the impressively thoughtful and effective governance of the Society over the years by its Council and elected officers.

The finance story does not end here. When the Society constructed its own building, I was asked to serve on the Building Committee. This was in 2003, and my role on the committee primarily focused on the building’s financing. We were fortunate in getting gold-plated bank ratings, in no small measure because of our financial reserve, and this gave us exceedingly favorable financing. So, with annual dues, annual meeting revenue, journal revenue, investment revenue, and then real estate revenue, we are enviably diversified. As I write this, that looms large as our environment becomes increasingly challenging financially.

And, my story with the Society does not quite end yet, although my window into the Society now sadly narrows to the Investment Committee on which I continue to sit as vice chair.

Institutional Program Development (1971–1986)

As the Society was undergoing its extraordinary evolution, exciting developments also were being realized locally at members’ institutions. These were the venues of the actual research and training that represented the “on the ground” development of our emerging interdisciplinary field of neuroscience.

The UVa chapter of the Society that I initiated in 1970 flourished, as did neuroscience at UVa. John Jane, the chair of Neurosurgery, a strong advocate for basic neuroscience and a dear friend, was an essential colleague in this development. Neuroscience flourished sufficiently that in 1975 we established a formal, degree-awarding program in neuroscience that I chaired until 1979 when I relocated to SUNY Stony Brook. Mounting a new degree program at UVa, as at most public universities, required state approval that in turn required a convincing statement of need. Successfully addressing the question of need was, indeed, an interesting and highly productive exercise that catalyzed some of my evolving views of the field and stood me in good stead in advising colleagues at other universities on program development, in my leadership roles in the Society, and in our advocacy efforts in Washington, DC.

My first direct involvement in any formal entity that recognized our emerging field occurred in these years, the early 1970s. This was serving on the NSF’s Panel for Neurobiology from its inception in 1972 until 1975. I believe this grant review panel was the first formal federal acknowledgment of neuroscience as a field. Jim Brown from NSF was responsible for making this happen and for recruiting our merry band that included, among others, Gary Lynch, John Hildebrand, Jeff McKelvy, and later Lorne Mendell. NIH reviewed brain science proposals at that time primarily through disciplinary committees, such as the Neurology A and B Study Sections. I served on the Neurology A Study Section from 1977 to 1987, chairing it from 1983 to 1987.

What lured me away from UVa was the proverbial offer that could not be refused from SUNY Stony Brook. The offer was to develop a full-service Department of Neurobiology and Behavior that, if memory serves, would have about 20 full-time faculty, primarily new hires. The committed space, start-up resources, departmental budget, and graduate student support were beyond generous. The department was responsible for teaching undergraduates, medical students, and graduate students. Although not formally in the medical school, we had close ties and, as the department developed, there were an increasing number of joint appointments with medical school departments. For example, although my primary appointment was in the Department of Neurobiology and Behavior, I also held appointments in both the Department of Physiology and the Department of Anatomy.

The development of interdisciplinary training programs in neuroscience was accelerating, but few of these programs had yet transformed structurally into departments. It was exciting to lead the development of one of the first departments of neuroscience in the country, and with 20 or so dedicated faculty, it was indeed a substantial department. Recruiting was relatively easy, given the concentrated presence of neuroscience colleagues and the ample space and start-up resources of the department. The department grew and flourished. Early senior faculty included Harvey Karten, Murray Sherman, Lorne Mendell, Jeff McKelvy, and Paul Adams. All newly recruited faculty secured substantial grant support, and it was not long before our graduate program competed successfully for an NIH training grant. We then moved into the rarefied atmosphere of Hughes and MacArthur awards. Meanwhile, with all the recruiting dinners, I gained 10–15 pounds.

From my experience in program building at UVa and department building at Stony Brook, I was becoming increasingly involved with neuroscience education both at the ground level at home and in responding to requests for advice and consulting from colleagues at various universities. The absence of a forum or organization to assist emerging programs to develop and to facilitate communication among them became acute. Education was not really on the Society’s agenda in its early years. Given the growth velocity of the Society, it simply did not have the bandwidth to stretch its missions even further at that time. I was familiar with the organization of chairs of other medical school disciplines, such as the chairs of physiology departments, and I became convinced that a similar structure might well serve neuroscience program directors and departmental chairs.

This was 1980, and I had just been elected president of the Society. At the annual meeting in 1981, I convened an informal meeting of a group of directors of neuroscience programs to get a sense of their views about launching a chairs-type organization. The responses were mixed but on balance constituted a go-ahead in my view. Thus was born the Association for Neuroscience Departments and Programs (ANDP). I served as its first president in 1981–1982 and as past-president in 1982–1983. Joe Coulter was an essential collaborator in launching this effort. Validating the organization has been its sustainability, indeed significant growth, over many years until it was formally incorporated into the Society in recent years, giving the Society a firm presence in neuroscience education.

Post-Neuroscience Career (1986–2008)

My time at Stony Brook, 1979–1986, was a special time in many respects. Beyond building one of the first neuroscience departments, being elected president of the Society, founding the ANDP, and enjoying one of my most productive periods scientifically, I married Anne Remmes, a neurologist I met at Stony Brook, had a fourth child and gained a stepdaughter to bring us to a total of five, all of whom lived with us in a house we bought that was built in 1750. It was indeed a frothy time. But what caught me by surprise were pressures that were not immediately apparent and began to steer my life along a rather new course, one different from the traditional academic life.

The first of these pressures was an offer to become the director of the National Institute of Neurological Disorders at NIH. I was seriously tempted by the offer, but it simply was not the right time of my life to move. Anne and I were trying to integrate families, and I felt it was premature to leave the department I had committed to build. I began to sense that this offer signaled something about possible new, unexpected directions, but this path still felt reasonably close to my home base of neuroscience. I could understand that I met the science test and had gained experience with advocacy groups, had some experience on the Hill, and had had deep involvement with NIH. Thus, although I sensed this offer might mean more, I had not yet appreciated that I was on a path leading to a rather radical change in my life.

Not long after I received the offer from NIH, I began receiving occasional feelers about senior administrative positions at universities. I had never aspired to be a university senior administration and was quite content with my life at Stony Brook. One prospect did catch my attention, however, vice president for research and dean of the graduate school at Northwestern University. Neuroscience, defined by an organ, is an amalgamation of many fields. It was not a large intellectual leap to imagine playing a role in overseeing and cultivating an even broader array of scientific disciplines and catalyzing cross-disciplinary efforts. There was an appeal to viewing science more broadly from a higher altitude.

I agreed to a visit and was impressed immediately by four things: the unexploited scientific potential at Northwestern, the structure of the position that implied it could indeed have a high impact, the richness of the scientific environment in the Chicago area, and the president of the university—Arnold Weber. The search was on a fast track, and I visited again in two weeks. By then it had become clear that the demands of the position simply would not permit operating a laboratory and, in fact, Weber made this quite explicit. First, I was surprised I would even consider this. I had just had my principal grant renewed for five years, and my research program was at a significant inflection point. I did not have the luxury of agonizing over the decision because the search was on such a fast track. I honestly cannot say where I would have come out if I had had more time to consider. But the position was intriguing, and I took the leap.

Did I have subsequent regrets about abandoning the model system when it had just reached such a potentially productive stage? Aside from an occasional pang when talking to old colleagues, I really did not with one exception: no one was able to pick up the baton of the model system. I have wondered at times to what extent the choice of a nonmammalian vertebrate was an almost insurmountable disincentive. Beyond this, my life at the time became increasingly relentless between the demands of my university position and a full dance card of growing outside responsibilities that I describe shortly. I must admit, however, that as I write this autobiography and recount my research life, I have had some sharper than usual pangs.

In my first six years at Northwestern, 1986–1992, I was embedded in educating myself about a broad range of sciences and vigorously promoting science at the university. The research volume in dollars at Northwestern tripled during these six years. Significantly contributing to this growth were interdisciplinary research efforts through centers, some of which involved collaborations with other universities. For example, we competed successfully for an NSF Science and Technology Center in Materials Sciences in collaboration with the University of Chicago and the University of Illinois. We also were awarded an NSF Science and Technology grant for a Circadian Rhythms Center in collaboration with UVa. Another initiative was to bring focus to and advance what had been a low-key Technology Transfer Office. This was an enormously instructive and exceedingly satisfying time for me, as well as being a highly productive time for the university.

During this same period, requests to serve on an array of scientific boards filled my dance card to overflowing. I joined the Life Sciences Research Advisory Board of the Air Force Office of Scientific Research, serving until 1991. I served on the board of Argonne National Laboratory, one of the large general purpose laboratories of the Department of Energy from 1986 to 1994, and I was privileged to chair the Scientific and Technical Advisory Committee of that board from 1988 to 1994. This committee was responsible for in-depth reviews of all programs at the laboratory. During my tenure as chair, the Advanced Photon Source was constructed at Argonne, a major national facility of broad benefit to science and in particular to structural biology.

This kind of activity became epidemic, and in 1987, I was invited to join the board of the Fermi National Accelerator Laboratory, a special purpose Department of Energy Laboratory and, until the Large Hadron Collider at CERN went online in 2008, the most powerful accelerator in the world. I served until 1995 and chaired the Administrative Committee of the Board from 1993 to 1995. This role immersed me in high-energy physics and cosmology, and as the only nonphysicist on the board, I must admit to feeling at moments like I was having an out-of-body experience. This feeling reached a peak when for a brief time I served on the oversight committee for superconducting magnet development for the Superconducting Super Collider. Additionally, I sat on the Executive Committee of the Scientific Advisory Committee of the Governor of Illinois from 1989 to 1995.

Between my role at Northwestern in broadly facilitating research and these outside responsibilities, I underwent 6–10 years of “total STEM immersion.” I deeply value that experience of viewing science from 30,000 feet. To this day, I can understand at least three research articles in each weekly issue of Science.

In 1992, the provost at Northwestern stepped down and I was asked to fill that position. On arriving at my office at 7:30 a.m. on my first day, there were already two phone messages. One was from the general counsel of the university and the other from the football coach. It was immediately clear that my intellectual life was going to move from foreground to background. Indeed, my first administrative act was to sign off on a policy banning rollerblading in university buildings. So much for the life of the mind.

My administrative experiences up until this time, from departmental chair at Stony Brook to vice president for research at Northwestern, had substantially broadened and deepened my exposure to science and developed my skills in research administration. On becoming provost in 1992 and going forward, I began to acquire rather different skill sets. These skills are perhaps best described as general management and budget skills and at Northwestern I was trained by a master, President Arnold Weber. He is the toughest and most effective manager I have ever encountered. An MIT-trained economist, Weber had served as a deputy director of the federal Office of Management and Budget under George Schultz, chancellor of the University of Colorado system, and as director on many Fortune 500 boards. One particular testimonial has stayed with me, a comment made by one of our trustees at Northwestern, a Fortune 500 CEO. He said, “Weber could run anything, including World War III.”

In parallel with my emerging academic management skills and likely because of them, I found myself being increasingly exposed to business, first through my activities directing Northwestern’s Technology Transfer Office and then with enterprises outside of the university. In 1990, I was asked to serve on the board of Zenith Electronics and continued in this post as director until 1995 when LG Electronics acquired Zenith. I have been serving on boards of private and public companies ever since.

When Weber retired from the presidency of Northwestern in 1994, I decided it was time to explore new directions. As a sitting provost at a major research university, it was not a surprise to be invited to look at various university presidencies. The problem here was being offered presidencies I did not want and not being offered presidencies I did want. Also, given my service as chair of the AAMC and other activities in academic medicine, it also was not a surprise to be invited to look at medical school deanships. After exploring two such possibilities, I decided this was not a direction I wanted to pursue.

What did come as a surprise, however, were contacts from outside academe. One direction that perhaps should not have been unexpected, given my scientific background, management experience, and growing involvement with business, were inquiries about CEO positions at start-up biotech companies. Two other offers in particular stick with me because they seemed rather discontinuous with my background. One was finding myself on the short list for the secretary of the Smithsonian. The more deeply I explored that prospect, the more exciting it became and had I been offered the position I would have accepted. The other was even further afield. It was a phone call asking would I be willing to be a candidate for the presidency of the Federal Reserve Bank of Chicago. My initial response was to tell the gentleman on the phone that he had the wrong David Cohen. (I assumed that somewhere in the country there was a David Cohen who might be qualified to head a Federal Reserve Bank.) He asked if I were the provost at Northwestern. I said, yes, but I was a biologist and, while I would enjoy sitting on the Federal Open Market Committee setting interest rates, I had no idea how to clear checks. He said what the bank currently needed was a strong manager, and I now apparently enjoyed that reputation. The lesson for me was that I had unknowingly earned my way into a labor pool of “freerange chickens” and was fair game for possibilities I never had imagined.

At the end of the day, I decided two things with respect to my next career move. I belonged at a university and I wanted to be deeply embedded in the academic action in a senior operating position. I did not want to spend my days (and evenings) fund raising and attending grip-and-grin events. About this time I was asked by Columbia University to consider the position of vice president and dean of the faculty for Arts and Sciences. It is difficult to describe the position because it defies all principles of sound management. It is probably closest in structure to the dean of the faculty at Harvard, but with a somewhat expanded portfolio. All of the Arts and Sciences chairs were direct reports, as were the deans of Columbia College, the Graduate School, the School of General Studies, Continuing Education, the School of International and Public Affairs, and the School of the Arts. And, somewhere in the range of 30–35 centers and institutes were also in the portfolio. On paper, this gave approximately 65 direct reports. One could not be more involved in the day-to-day academic action. The vice president for arts and sciences was also a member of the president’s cabinet, giving broad exposure to university affairs. Finally, it was an opportunity to return to Manhattan, the mother country for me. So, I relocated to Columbia in 1995.

Even though administration at Columbia was a body contact sport and the job was relentless, I stayed with it for eight years, significantly outlasting the tenures of previous incumbents. I recall at the end of my first Arts and Sciences faculty meeting declaring that I would not return for another such meeting until I had a dais that covered my entire body. I retired from this administrative position in 2003 on turning 65. Those eight years were exceedingly exciting and satisfying with respect to enhancing many of the 26 departments in the Arts and Sciences. Many of these departments were highly ranked on my arrival at Columbia, and we managed to bring almost all into the top ranks through an innovative and highly rigorous process of program review. At the same time, we improved faculty salaries and eliminated a longstanding structural deficit, balancing the Arts and Sciences budget for the first time in more than a decade.

It is difficult to describe how intellectually stimulating it was to be so deeply involved with the broad array of Arts and Sciences departments, many of which were among the best in the world. We also substantially strengthened the School of the Arts and connected it to the undergraduates. It was a priceless education. And, I was hardly isolated from neuroscience, given the depth of neuroscience faculty at Columbia, including four who had been or would become presidents of the Society—Eric Kandel, Gerry Fischbach, Mickey Goldberg, and Carol Mason.

I returned to the faculty in 2003, but I had accrued sufficient leave to almost carry me to my full retirement from the university in 2008 at age 70. (Columbia has an extraordinarily generous leave policy that I critically looked at early on when planning how to balance the budget. That look lasted about 500 msec when I quickly realized there was not enough political capital on the entire planet to survive touching that third rail.) During this five-year period, I became increasingly involved in the business of education. I joined the boards of various companies involved in education-related enterprises and became an advising partner in a private equity enterprise involved in education. This carried me into my retirement life.

Retirement

I have now been retired from Columbia for seven years. During that time, I have continued to serve on boards, not all of which are related to education. Over time, however, the number of boards I serve on is steadily declining. I do continue to serve on the Investment Committee of the Society, and I try to attend as many of the past-president lunches at the annual meeting as I can. Until rather recently, the seating arrangement at these lunches had been chronological, based on the year of your presidency. When some of us more elderly presidents pointed out that each year we were getting closer to the end of the table, SfN compassionately moved to open seating. That removed a disincentive to attending the lunches. I do remain deeply interested in the affairs of the Society. It has been a truly significant part of my life.

A main event of my current life is serving pro bono as provost of a fully online, tuition-free university, the University of the People. This nonprofit university was established in 2009 with the mission of offering access to affordable, quality degree-granting programs online to any qualified student. I joined the institution soon after its launch. We were accredited in 2014 and currently have approximately 2,000 students from more than 150 countries. Since receiving accreditation, the university is vigorously ramping up it enrollment and expanding its degree-granting programs. This all keeps me as busy as I wish to be, because I have every intention of fully enjoying my now rural life on our property that sits at the eastern border of the Hudson Valley and the western border of the Southern Berkshires.

Conclusion

I appreciate that this autobiography has been a bit atypical, if not disjointed, as neuroscience was the dominant theme of only the first half of my professional career, and this is a series dedicated to the history of neuroscience. On the other hand, had I restricted this to only that period, my autobiography would have ended at age 48 and that seemed rather peculiar. Hopefully, the second half of my career, although not bearing directly on the history of the field, might be of some interest as a case study of a neuroscientist’s evolution to platforms that view science from an increasing altitude. After all, science did loom large in the second half of my career, but from a different perspective than the lab bench.

Throughout, however, the SfN has continued to be woven into the fabric of my life. I feel we came of age of together as neuroscience established itself as a field. It has been extraordinarily rewarding to have deeply experienced this period in the history of science and, hopefully, to have made some contribution to it. As part of this, I want to take this opportunity to say how privileged I have been to have worked closely with all three executive directors of the Society. In the beginning was Marjorie Wilson. Were we blessed in having her. Wilson was responsible for steering us and launching us on our incredible growth path. She was indeed an uncommon woman. Wilson was succeeded on her retirement by Nancy Beang. Beang skillfully brought us through our adolescent years and into adulthood, providing essential support throughout my years as an officer. And then there is Marty Sagese who has impressively professionalized the Society, a critical need as we became an 800-pound organization. Indeed, I believe no scientific society is better managed or governed than the SfN.

To close, in 1993, I was invited to deliver the keynote address at the Annual Meeting of the Association of Neuroscience Departments and Programs, an organization I had founded some 10 years earlier. In preparing my remarks for that address, it occurred to me that a simple acronym, DRG, wove through life as a changing metaphor. In my student years it stood for dorsal root ganglion. Then, as I was launching my laboratory its meaning shifted to the Division of Research Grants at the NIH. As I became deeply involved with the AAMC in the 1980s and engaged with broad issues in academic medicine, including reimbursement for services, it transformed to Diagnostic Related Groups. On moving to Columbia in the 1990s and adding the humanities and social sciences to my portfolio, DRG came to signify the budget code for the Department of Religion. That was as far as I took the metaphor at the time of that keynote address. Now, as I become longer in tooth, this metaphor continues by fully cycling back to its first incarnation, dorsal root ganglion, as I become more and more preoccupied with the expected aches and pains of aging. Since that begins to sound a trifle whiny, I will quit here—but not without saying it has been a great run. And I would leave you with two bits of gratuitous advice that have stood me in good stead throughout my career. Make your mistakes slowly and never forget the whimsy of it all.

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Yadin Dudai

BORN:

Tel-Aviv, Israel

December 8, 1944

EDUCATION:

Hebrew University, Jerusalem, Israel, BSc with distinction, Biochemistry, Genetics (1969)

Weizmann Institute of Science, Rehovot, Israel, PhD, Biophysics (1974)

APPOINTMENTS:

Research Fellow, California Institute of Technology, Pasadena, CA (1974–1976)

Scientist, Weizmann Institute of Science (1974–1977)

Senior Scientist, Weizmann Institute of Science (1977–1980)

Associate Professor, Weizmann Institute of Science (1980–1988)

Professor, Sara and Michael Sela Chair in Neurobiology, Weizmann Institute (1988–)

Albert and Blanche Willner Family Global Distinguished Professor of Neural Science, New York University (2008–)

HONORS AND AWARDS (SELECTED):

The J.F. Kennedy Prize, 1974

The Glicksman Award, 1983

Fogarty Scholar in Residence, National Institutes of Health, 1991–1995

Annual Distinguished Lecture, University of Edinburgh College of Medicine, 1998

Public Lecture Series, College de France, Paris, 2002

D.O. Hebb Lecture, McGill University, 2003

The Annual Volker-Henn Lecture, University of Zurich, 2005

The Eduardo de Robertis Lecture, Argentina, 2007

The Annual Carl P. Duncan Lecture, Northwestern University, 2011

Honorary Member, Argentinian Society for Neuroscience, 2012

Fellow, American Association for the Advancement of Science, 2012

Fellow, Association of Psychological Science (APS), Washington, DC, 2012

Fondation IPSEN Neuronal Plasticity Prize, 2013

Member, European Molecular Biology Organization, 2014

Member, Israel National Academy of Sciences and Humanities, 2014

The Annual Picower Lecture, MIT, Cambridge, MA, 2015

Yadin Dudai explored neurobiological mechanisms of single-experience memory. He was in the team that discovered the first memory mutants of Drosophila, providing the proof of concept for the molecular neurogenetic analysis of memory. He then discovered that the mutations affected memory rather than encoding and described consolidation and roles of the cAMP cascade in cellular and behavioral plasticity in the fruit fly. He developed a multilevel approach to investigating memory in the behaving rat brain, using conditioned taste aversion as a model, and identified posttranslational modifications in receptors and signal transduction cascades during the encoding and consolidation of memory in the mammalian cortex. He also identified behavioral and brain processes of memory extinction and reconsolidation and their competition over behavioral control, and proposed boundary conditions and models of reconsolidation of long-term memory (including the dominant trace hypothesis and the lingering consolidation hypothesis). He developed protocols for analyzing realistic episodic memory in the human brain and described mnemonic roles of the hippocampus in the first seconds after experiencing an event and in integrating new information, including social influence that distorts memory.

Yadin Dudai

Students of memory are rather suspicious of the veracity of recollections. Yet although flashbulb memories are not spared the distortion of time and use (Christianson 1989), the fact that the recollected rare moment has emotional uniqueness is seldom doubted. Sometime in high school, in the 11th grade (or was it the 12th?), in a biology lesson, the same teacher that so often kicked me out of the class and swore loudly to God that nothing would ever come out of me, caused me to experience a miniepiphany and start a lifelong love affair with biology.

For more than 50 years I have never reconstructed the details of that event. Only the emotional gist remained. In preparation for this essay, I started a small detective investigation, guided by fragments of reminiscences: it was botany, it was evolution, it was unrelated ends suddenly falling into place to create an unexpected plot. I located an old botany textbook (Harder et al. 1965), bought a new one (Mauseth 2014), followed by still another one on evolution (Willis and McElwain 2014). It was like sailing to an abandoned personal Ithaca. Soon, I reached the conclusion that the flashbulb moment was that in which I realized that a flowering plant hides within itself another, miniature organism; the two protagonists in this story are the same encountered independently much earlier in evolution in green algae, embodying the alternation of haploid and diploid generations typical of plants. Nature has concealed one creature inside the other. This was an amazing nature-made narrative, providing the restless teenager with a startling example of evolution and experience of the sublime. Decades later, was I re-enthralled? Admittedly, less so. First times are difficult to reenact. In the search for the evasive memory, I also was gratified to rewitness how much the life sciences have changed. The older textbook had no molecular biology whatsoever.

The reader who has made it to this point in the essay might be lured into thinking that my journey into science followed naturally. This, however, was not the case. Life had surprises.

Tel-Aviv, on the Mediterranean

I was born on December 8, 1944, in Tel-Aviv, a bustling city that was expanding rapidly on the sandstones of the Mediterranean beach north of Jaffa. I grew up as the youngest son in a posttraumatic family. My parents’ big families were murdered by the Nazis and their collaborators in Lithuania and Poland in 1941–1943. My father, Aharon-Zvi, and my mother, Batya, immigrated to Palestine shortly before World War II. They never again saw those left behind. Both were from a Lithuanian shtetl in which Hebrew culture flourished and the dream of returning to the land of Israel was kindled for generations. Years later, while preparing a family book for my grandchildren, I took a DNA test and realized that the origin of our ancestry is indeed in the eastern Mediterranean basin. And if the shock of the holocaust was not enough, my elder half-brother was killed in Israel’s War of Independence. Ongoing bereavement was a fact of life.

My early years were spent in times of war. Unfortunately, wars kept intruding into my life since then. Snipers from Jaffa used to fire on our house. On one occasion bullets landed in my bed, in my absence. I do seem to recall a snapshot of bullet holes in the wall; this recollection does raise questions about childhood amnesia or about reconstructive memories. That war ended, I went to a religiously oriented school, moved to a secular school, and then spent memorable years at a high school in Tel-Aviv. If grades are the criteria, I was far from being a good student, except in composition, and my mother had to come to school quite often to hear from the principal that I was terribly disruptive. I was socially constructive, headed the students’ council, contributed to the school newspaper, and organized parties. I was not engaged too much in contemplating the future. Some days, I considered becoming a doctor, but then I watched a movie in which a young physician spends his days pampering newborn bottoms with talc, and my enthusiasm dwindled. Despite my attraction to biology, I was not sure it was a future. I considered seriously, in fact, becoming a professional journalist.

This decision materialized more quickly than expected. During the summer break after the school year I found work as a switchboard operator at the leading Israeli daily, Yediot Ahronot, to earn pocket money. This was an old-type switchboard in which the lines had to be connected manually to close the circuit. It was a hot stuffy basement of an old building. All this led me to experience a behavioral paradigm that I was to encounter years later in science: fear conditioning. The unconditioned stimulus was the shock delivered through my sweating fingers each time I closed the circuit. The conditioned stimulus was the ring signifying the request for calls. The number of callers, some mumbling unintelligibly, seemed to be directly proportional to the frequency of shock. Late at night, rats crossed the room, making the situation even worse.

I was rescued by the political cartoonist Ranan Lurie, who wandered downstairs out of curiosity. A short conversation was initiated, I gave an affirmative answer to his question as to whether I could write, and composed a short item (signed “special correspondent”) on the health risk of eating overcooked meat (about which I had read somewhere before; Polish food was always overcooked). This piece was published and attracted the attention of the omnipotent editor, Dov Yudkovsky, who transferred me to the news desk, where I found myself converting boring texts written by confused correspondents into terse statements and catchy titles. Soon I found myself arriving at the news desk daily before dawn, struggling with the racing clock to crank out headlines as part of a small team of editors all of whom were much older than me. The disciplinary experience of those predawn routines served me well in later years. Yudkovsky, the editor whom everybody feared, also appointed me as his personal assistant, exposing me at that early age to the political and social intricacies of Israel. Many years later, he invited me to say a few words at a public ceremony honoring him on the occasion of his 80th birthday. I thanked him for his role in my life. He started his speech by thanking me for not accepting his advice to pursue a career in journalism. Traces of his childhood dreams to gain a formal education, shattered in the extermination camps in which he had strived to survive as a lonely child, surfaced in his speech.

Wars, Peace, and in Between

Being young in my class, I was given the opportunity to enroll for a year in Tel-Aviv University immediately after graduating from high school and before the compulsory service in the Israeli Army. In parallel to gaining experience in journalism, I studied philosophy and history. When the time finally came, the army decided that my experience would be of some use as a combat correspondent. I became the chief combat correspondent of the army weekly magazine. Given the lack of electronic media, that magazine was in fact the major communication channel of the army and often the government. This meant, on the one hand, joining units in the field and becoming embedded in commando raids across enemy lines, and on the other, spending time with the high command and sometimes with the prime minister. Looking back, I think that those years endowed me with some sense of proportion, traces of a capacity to distinguish the critical from the less so, and a better appreciation of the complexity of human behavior. It also made me get rid of any fear of authority. This went well with my innate chutzpah. Furthermore, witnessing intimate moments in the life of a nation imprinted me strongly on my homeland.

Toward the end of my army service, I was summoned to the office of the chief of the intelligence services. He offered me an immediate shortcut to a special officer course, promising a fast career track. This was one of the toughest decisions of my life. After a sleepless night, I declined. I felt I needed a more systematic education, and that it should be done now, before falling into the muddy pond of international affairs, or never. I also declined offers from newspapers. The inherent superficiality of journalism was always in the back of my mind. Over the years, I did remain occasionally engaged in state and in public affairs. These chapters are not covered here.

In one of the last months of my army service, while in a jeep approaching the gate of an army base, the driver and I noticed two girls in military uniform attempting to hitchhike to the closest city. We stopped. One of them was Rina Hon. About a year later, we married and she has been my partner ever since. Her wisdom and loving influence cannot be overstated. Some good things do come out of the army. Rina and I were already together when I had to leave on an army-related mission to Europe only to return shortly before the Six-Day War, in which I participated, as did other Israelis of my generation.

I then found my way back into the university and this time decided to give biology a try. I graduated with distinction from the Hebrew University in Jerusalem, majoring in biochemistry and genetics, with supplements in modern history. My attraction to the humanities kept kicking in. In fact, the first job offer I ever got in academia was to serve as research assistant in modern history. I was kicked out of the room of the history department chair when I said that I couldn’t accommodate the itinerary because it conflicted with my biochemistry lab assignments.

At that time, Rina and I moved to Jerusalem, and already had our daughter, Orit. Our son, Rani, was born a few years later, after another fierce war, the Yom Kippur War, which I barely survived.

Weizmann Institute of Science: The Tale of an Enzyme with a Tail

It was my experience in journalism that brought me to the Weizmann Institute of Science. While a student at the Hebrew University, I supplemented our income by working as an editor in a Hebrew popular science magazine, whose editorial offices were conveniently located in Jerusalem. The chief scientific advisor of that magazine was a professor of biochemistry at the Weizmann Institute, Nathan Sharon. Sharon asked me about my plans, I replied that they included MSc studies in genetics at the Hebrew University, and he commented that although this option would be brilliant, he would still arrange for me to visit the Weizmann Institute and meet with Professor Ephraim Katchalski (Katzir), chair of the Department of Biophysics. I had heard beforehand about the excellence of the Weizmann Institute, and knew who Katzir was, but the real-life encounter made a strong impression. The milieu was more research oriented than at the Hebrew University, and Katzir greeted me as though I was already in. He told me that he was usually quite busy and suggested that although he would still be officially in the picture, I should select a younger faculty to mentor me in the lab. He introduced me to Israel Silman, just back from his postdoc training in the United States. Following that visit, I decided to join the Weizmann Institute. Silman (known as Sili to his friends), a brilliant biochemist, spoke fast and wrote in miniscule indistinguishable ink specks, and the first expertise I had to acquire in the lab was to understand what he really wanted.

I took several courses in physical chemistry, including advanced math, statistical thermodynamics, and quantum physics, to ensure that I had the proper quantitative background. I have hardly used these subjects since, but am grateful to the teaching committee of the Feinberg Graduate School of the Weizmann Institute for making me take these courses. Among others, they have proven to be an effective long-term preventive medicine against intimidation by talks in computational neuroscience. As to the lab, we decided that I would join a long-term project concerning the structure and function of the nicotinic acetylcholine receptor from the electric organ of the electric eel. Because another student, Nurit Kalderon, was doing exploratory experiments along these lines, we thought that I should first engage in an interim project that was supposed to take a few weeks only: purification of the enzyme acetylcholinesterase (AChE) from that same tissue, with the goal of later crystalizing it. The major role of this enzyme, one of the fastest in nature, is to hydrolyze the neurotransmitter acetylcholine, which plays a critical role in the neuromuscular junction and the brain. AChE is the target of many poisons, including nerve gases and insecticides, as well as, more recently, drugs to alleviate symptoms of the early stages of dementia.

What was supposed to be an interim project took years and became my thesis topic, later to be pursued by generations of students in Silman’s lab. We thought it was a short-term project because a report in the literature claimed to have already purified and crystalized the enzyme. This report may have been premature. Furthermore, little was known at that time about the biochemistry of the cell membrane, let alone about the integration of enzymes and receptors into the membrane. I therefore embarked on a new approach, affinity chromatography. One of the founding fathers of this method, Professor Meir Wilchek, was down the corridor. The idea was to couple an enzyme or receptor inhibitor to an insoluble resin, apply to the conjugated resin a preparation such as a tissue homogenate containing the target protein, wash to elute the molecules that are not retarded by the inhibitor, and then elute the target protein specifically with a soluble inhibitor. We coupled inhibitors of AChE to a resin, applied homogenates prepared from the electric organ tissue, washed out the unrelated proteins, and then eluted the enzyme specifically by applying a solution containing another powerful AChE inhibitor. As with many things in science, God is in the details: I had to struggle for months to find the right conditions. At first, we were able to purify an AChE form that sedimented as an 11S particle on a sucrose gradient, present in a proteolytic digest of the homogenate (Kalderon et al. 1970, Dudai and Silman 1971, Dudai et al. 1972a). We then moved on to a stronger inhibitor and were able to purify on the affinity column heavier, native, nondigested forms of the enzyme, of 14S and 18S size (Dudai et al. 1972b). I proceeded to further separate the enzyme forms by sucrose gradients, and then subjected them to analysis in an analytical ultracentrifuge (to determine the molecular weight) and the electron microscope (to determine the shape; Dudai et al. 1973). The molecular weights ranged from about 335KD (11S) to 750KD (14S) and 1100KD (18S). They seemed therefore to represent multiples of a basic entity.

The surprise came with the electron micrographs of the heavier, native forms of the enzyme. They unveiled a head, consisting of a large number of subunits, and an elongated tail; the 11S was a tetramer devoid of a tail. This finding was so unexpected that I first thought I had purified some miniphage contaminant, and I was in fact later relieved when I learned that similar structures were observed in parallel in the laboratory of a French colleague. This was the first time that I encountered the Janus face of competition in science. On the one hand, it kindles the anxiety associated with the primitive drive to win the race. On the other, traces of stoicism can convert it into a reassuring reward if it confirms one’s own findings. These findings opened a new era in the study of AChE; the tail was later proven to be of a collagenous nature and served to anchor the enzyme in the synaptic cleft. In the decades since then, the study of AChE from various sources has flourished tremendously (Dvir et al. 2010), but one thing remains: it is still a tale of an enzyme with a tail.

The surprising findings concerning AChE compensated for hard and often boring work. I keep telling my students that the ability to withstand delayed gratification is essential for a scientific career. This conclusion came from those long weeks of boredom washing columns in cold rooms or in front of the giant analytical ultracentrifuge. I also discovered that I am not a one-method person, and am happy to learn any method that fits my ongoing goal and abandon that method equally happily when it doesn’t fit anymore. My later career proved that I am also not a singleexperimental preparation person. The questions and concepts seem to excite me more.

Silman was a great mentor. Wise, stimulating, highly knowledgeable, always available to listen and help, and, on top of it all, open minded. And as for Katzir, we in fact worked together a lot and became quite close, but this had little to do with my thesis. He was extensively involved in state affairs and schlepped me in. He was elected the president of the State of Israel in 1973 and requested that I serve as a special assistant to the president on some matters. I found myself spending many hours, often on short notice, at the president’s office in Jerusalem. My life adjusted literally to a 24/7 schedule.

In the meantime, as I was contemplating my future, my department chair, Professor Uri Littauer, arranged for the president of the Weizmann Institute, the physicist Professor Israel Dostrovsky (the father of Jonathan Dostrovsky from the now classic O’Keefe and Dostrovsky 1971), to offer me a position before I left. Dostrovsky had one condition, I should never go into politics. He previously had served as head of the Israeli Atomic Energy Commission, and his extensive interaction with politicians conditioned him to spare me the experience. This was an easy promise to keep.

Fig. 1.  Tough decisions. The J.F. Kennedy award ceremony at the Weizmann Institute, toward the end of my PhD thesis, with Prime Minister Yitzhak Rabin (shaking hands), and Professor Israel Dostrovsky, then the president of the Weizmann Institute (to his right). Becoming immersed early in life in professional journalism and in a hectic compulsory army service, rendered early career decisions somewhat more difficult. The conflicting advice I got didn’t make it easier. For example, Rabin, whom I came to know in the army, told me shortly before he became the prime minister that in his view the “university of real life” is much more interesting than life in academia (on his second term as prime minister, however, he became an avid supporter of science and technology at large). Probably sensing my hesitation, Dostrovsky made the offer that I join the Weizmann faculty contingent on my promise that I never would go into politics.

Caltech: A dunce Is Born

I first saw Seymour Benzer when he gave a talk at the Weizmann Institute on the neurogenetic dissection of behavior in the fruit fly, Drosophila melanogaster. I came out of the talk somewhat disappointed because the speaker presented no mechanisms. To a young biophysicist and biochemist, this was blasphemy. It took time for the ingenuity of Benzer’s approach to dawn on me. In the months thereafter, in a mostly implicit process, I realized that here is a minimalist, boldly reductionist approach to complex problems. Though fresh in neuroscience, this was the same approach that led to smashing success in the dissection of genetics and metabolic pathways in lower organisms. Benzer’s brilliant studies on the dissection of the RII locus in the bacteriophage T4 were breakthroughs in our understanding of the structure and function of the gene and have become classic textbook material (Benzer 1962).

During that period, I was still engrossed in an incessant internal discourse on whether I really wished to commit myself to a lifelong scientific career. I enjoyed the action, milieu, and intellectual adventures, but also missed the bustling life outside the bubble. I ultimately made a decision: I would apply for a single postdoctoral position only, and if not accepted, would reevaluate whether the scientific commitment indeed fitted me. Benzer’s approach looked more and more appealing and a bit mysterious. I thought that one could apply it to an enticing problem, namely, identifying genes that make people smarter. The possibility cannot be excluded that this was an urge implicitly kindled in me during my earlier nonscientific careers. In any event, I wrote Benzer a letter, stating my wish to join his lab and work on smart mutants. Within a few weeks (remember, no Internet yet), a reply arrived. Benzer said that I probably understand that it is much easier to find stupid rather than smart individuals, and furthermore, work on learning and memory in Drosophila and a search for stupid mutants already had begun in his group by Chip (William) Quinn. If I wished to join this effort, I should request two scientists to write letters of recommendation. I reached the conclusion that looking for stupid mutants is not a bad starting point, and asked Silman and Katzir to send the letters. Shortly afterward, the logo of the California Institute of Technology (Caltech) reigned again on the corner of the almost transparent airmail envelope waiting for me in the departmental mail box. The response said, “I have now received the letter from Professor Katchalski-Katzir and have learned that he was elected the president of the State of Israel, so you should keep his signature because it will be worth lots of money. However, would you please send me a letter from somebody who really knows what you are doing?”

I cherished this no-nonsense reply, asked for another letter of recommendation, and shortly afterward was invited to join the Benzer lab. The door to the unique world of fly genetics in Caltech was now open. But life, again, had its surprises. A terrible war erupted in October 1973, and my departure suddenly appeared to be an unrealistic dream. Benzer was considerate enough to write that my position was secured and that this should be the least of my worries at those difficult times. I switched from thinking about science to thinking about survival, found myself in some unbelievable situations, and unfortunately, as with almost all my colleagues, lost friends to the cruelty of war.

I was able to join Benzer’s group in Caltech in October 1974. A few weeks before that I participated in the fly course in Cold Spring Harbor and acquired some basic skills in fly work. My encounters with coursemates and the teaching staff were encouraging and heartwarming, and these were a harbinger of the impressions and esprit de corps that I was to later encounter in the fly community. I arrived in Pasadena alone, assisted by the hospitality of Danny Michaelson—at that time, a postdoc with Mike Raftery and later to become an expert on Alzheimer in Tel-Aviv University and a lifelong friend—and waited for my family to join. I then became immersed in fly neurogenetics and behavior. Letters from Katzir kept arriving from time to time, alerting me to the fact that the situation in the Middle East was much less favorable than in the fly world.

I consider Caltech to be my true scientific alma mater. Although I spent less than two years there, its scientific influence could not be overstated. Much has been written about Benzer and his fly group (e.g., Dudai 2008). The place epitomized the way I thought science should be conducted—that is, with originality, seriousness, drive, and persistence, yet without losing sparks of modesty, and engulfed with collegiality and joie de vivre. On the one hand, we mastered every trick of fly genetics and behavior, and on the other, we could spend hours stuffing flies into an empty orange just to be able to release them in class to make undergrads remember forever their first encounter with the fruit fly. Caltech also encouraged development of bullshit detectors, a useful mental device that unfortunately is not used sufficiently in current public relations–driven scientific culture. Nobody claimed they made breakthroughs daily, although some did achieve many. Max Delbruck, Ed Lewis, Richard Feynman, and other scientific legends were around, expressing keen interest and, from time to time, volunteering idiosyncratic advice on science and life. Daily lunch meetings were a mix of discussions of the latest restaurant experience along with recent advances, or setbacks, in our projects. So different from some current attempts to convert neuroscience into corporate-culture science.

When I arrived, Quinn already had left and Duncan Byers was engaged in the memory mutant search in his kind, thoughtful, melancholic manner. Quinn had developed the first successful memory assay of Drosophila, based on olfactory avoidance or fear conditioning. The assay worked well only on fly populations, whereas memory conventionally was expected to be tested in individuals; in Drosophila, however, this was not a problem, because we could breed fly populations in which individuals were genetically identical. Stampede effects notwithstanding, we could heuristically consider the behavioral test of a population of 40 flies as an approximation of 40 tests of a single fly. The idea was to mutate flies under conditions that result in only one to a few mutations per chromosome and to take advantage of the fact that a normal male carries only one X chromosome. Therefore, iso-X fly progeny will display single-mutational events on the X. Mutagenesis was done by feeding flies with ethyl methanesulfonate. The progeny populations were then each subjected to memory tests on the fear-conditioning paradigm, which we kept improving.

Looking back, this was a daring, risky project: we were able to generate and test only a few hundreds lines in the course of a year, and each line had to be tested several times to allow sufficient statistical power to deem that a mutational event indeed impairs behavioral plasticity. One of my scientific grandfathers, Professor David Nchmansohn from Columbia University who pioneered research on the biochemistry of the cholinergic synapse, once told me that science depends on three Gs: geduld, geld, and gluck (German for patience, money, and luck). Although I didn’t completely agree with him—imagination and a pinch of anarchy were missing from the list—gluck we surely had. Mutant lines 38 and 276 repeatedly were showing signs of stupidity. By that time, I was already practically navigating the pace of the team project, spending days in small darkened rooms testing one fly line after another for memory and carrying out control tests for sensorymotor thresholds on candidate dumb flies.

Fig. 2.  Happy discoveries. Celebrating dunce, the first Drosophila memory mutant, in Caltech. From left to right, upper row: Yuh-Nung Jan, the author, Chip Quinn, Bill Harris; bottom row: Duncan Byers, dunce, Seymour Benzer. Years later, upon seeing this picture, some noted that this might have been not only the proof of concept of neurogenetics of memory but also of the effectiveness of trans-species reverse genetics.

The single-gene neurogenetic dissection approach was not without its loud adversaries, among them classic population geneticists, who favored multiple trait selection and achieved only little in elucidating mechanisms, and behavioral biologists, some of whom doubted the ability of Drosophila to learn at all. One day somebody brought to the lab the front page of a local newspaper, stating that “Flies are stupid but dolphins use sonar.” Benzer was more affected by the opposition then we were, and uncharacteristically needed our explicit support. Maybe he felt confident in molecular genetics but less so in behavior. Another day, a television team came to the lab to produce a movie on fly behavior. The heat from their lamp killed the fly they filmed, but for them it didn’t make a difference.

The putative mutant lines were both defective in performance on the conditioning test despite displaying otherwise-normal sensorimotor behavior. We proceeded on the first line, and after convincing ourselves that we had something real, dubbed it dunce (dnc; Dudai et al. 1976), aptly commemorating the 16th-century theologian John Duns Scotus, whose followers were ridiculed by contemporary humanists as enemies of learning. The other line was also a dnc allele. I characterized the behavior of these and other lines of flies, including many existing mutants (Dudai 1977). We tried in parallel to get some hints on potential biochemical defects in the mutants, using pharmacology. Together with Yuh-Nung Jan, we discovered that feeding wild-type flies caffeine, a cyclic-AMP phosphodiesterase (cAMP PDE) inhibitor, makes them dunce-like. This was merely a hint, however. Direct evidence that dunce was a mutation in an isoform of cAMP-PDE came only later in the collaborative work of Byers, Ron Davis, and John Kiger (Byers et al. 1981). Interestingly, mutations in the same gene were identified in three different screens: for learning deficits, for female sterility, and for activity of the cAMP cascade. In fact, line 38 (dnc1) reduced the fecundity of females to about 50 percent and line 276 (dnc2) to only 2 percent. Clearly, although the mutations had a relatively specific effect on behavioral plasticity, they also affected other biological processes. But we were looking for clues about the mechanisms of memory, and here they were.

At about the same time, I also found that Drosophila memory consolidates—that is, it undergoes a transient maturation process after which it becomes resistant to amnesic agents. This was important because it showed that the memory we are dealing with is similar in a basic property to memory described in mammals. The trick was to identify the proper nontoxic amnesic agent that could work fast and reproducibly. It was cooling. Placing the flies briefly in a plastic tube in an ice bucket was sufficient to anesthetize them, and recovery was rapid as well. This was a clear Caltech influence: look for the simplest solution. Cooling immediately after training, but not a few minutes later, erased subsequent memory—a clear proof of consolidation. What happened when I shared my finding in the daily lunch meeting was typical of the Benzer lab. Benzer reacted softly: this is an important finding. Quinn (then in Princeton) just shared with me this morning that he found the same thing. Why don’t you both get on the phone and publish together? I flew to Princeton, we coauthored a note to Nature, the only manuscript in my career that was accepted without even a single comment from the editor (Quinn and Dudai 1976). No scoopophobia (Dudai 2002a) in the small fly community those days.

Starting My Own Lab at the Weizmann Institute

Both Benzer and I agreed that although it would be fun to continue, I had achieved my planned goals and the time had come for me to start my own lab. It was also time for Rina, who studied literature at UCLA, to return to her work and studies in Israel. Two years away from home, as much as we enjoyed them, seemed enough to us. We hence returned to Rehovot, not before stopping on the way for two months in Utrecht, Holland, for me to gain experience in rat neuroanatomy, neurohormones, and behavior in the Rudolf Magnus Institute of Pharmacology, under the guidance of Professor David de Wied and with the generous help of Willem Gispen. I wanted to keep my future options open and familiarize myself with the most common memory model in neurobiology those days. This indeed came in handy years later.

I established the first Drosophila lab at the Weizmann and proceeded to analyze in fine detail the behavior of the learning mutants (Dudai 1979, 1983), to investigate receptors and their signal transduction cascades in the fly brain, and to identify their contribution to behavior and behavioral plasticity (Dudai and Zvi 1982, 1984a, 1984b; Uzzan and Dudai 1982). I should note that at first it was not easy to convince my colleagues at Weizmann that flies are real animals, and as a back up, I hired a PhD student to do some rat neuroreceptor work so that we could walk down the corridor with rat cages to show that we were also serious scientists. (That project triggered in fact a set of informative studies on the role of neurotransmitter receptors in the brain of the rat; e.g., Ben-Barak and Dudai 1979, 1980.) I remember that on one international site visit an eminent biochemist from the West Coast came to my lab and upon seeing the milk bottles with the fruit flies jumping inside, asked why I wasn’t waiting for them to grow bigger. The research on Drosophila, however, soon provided intriguing results and the attitude of the milieu changed. First, I discovered that dnc, and another mutation isolated in the laboratory of Quinn, rutabaga (rut), are in fact memory mutants and not learning mutants: they perform reasonably well in the memory test immediately after training, but their memory decays rapidly (Dudai 1983). This was important, because, together with our earlier findings on memory consolidation, it showed that the memory can be dissected into subprocesses, rendering it more likely that specific mutations will affect different memory processes and thus allow mechanistic dissection of the memory machinery step by step. Second, we found that rut is also mutated in a component of the cAMP cascade, this time in a subtype of the enzyme that generates cAMP, adenylyl cyclase (Dudai et al. 1983, 1985; Dudai and Zvi 1984a, 1984b, 1985). Quinn’s lab also reported that rut is defective in adenylyl cyclase (Livingstone et al. 1984). Third, we described the biochemistry of multiple components of the cAMP cascade in wild-type and mutant Drosophila and their role in behavior (Buxbaum and Dudai 1987, 1988, 1989a; Orgad et al. 1989), and a data-driven kinetic model was proposed to explain how persistent activation of a component in this cascade, the cAMP-dependent protein kinase, may subserve long-term plasticity (Buxbaum 1989b). This model fit the concept that memory could be encoded by molecular switches based on the operation of protein kinases (Crick 1984; Lisman 1994).

The implication of the cAMP cascade in Drosophila memory also triggered a collaboration (and a long-term friendship) with Eric Kandel and Jimmy Schwartz at Columbia University, the shrine of Aplysia memory. I spent a sabbatical there in 1982, which also was used to familiarize myself with new developments in molecular biology, with the kind advice of Richard Scheller and Tom Maniatis, across the street from the Kandel and Schwartz labs. To convert theory into skill, I took part in cloning the Aplysia calmodulin gene. Kandel and I and our teams became particularly interested in the role of the Ca2+/calmodulin-sensitive form of adenylyl cyclase (Ca2+/CaMAC) as a coincidence detector that subserves stimuli associations in conditioning (Eliot et al. 1989; Yovell et al. 1992). I was particularly intrigued at that time by the possibility of identifying properties of Ca2+/CaMAC that might explain elementary operations of biological learning machines (Dudai 1985).

The question underlying this interest is fundamental to this day: can behavioral properties be inferred from molecular properties? A tenet of the reductionist approach is that molecular and cellular properties can explain systems and behavioral properties (for an opposite view, that higher, more global levels are agnostic to the inner working of lower levels, see Laughlin and Pines 2000). For example, those who advocate long-term potentiation (LTP) as a cellular device of memory argue that LTP subserves memory not only because in some cases LTP has been shown to correlate or interact with memory performance, but also because the cellular model shows properties similar to those of memory, such as associativity and persistence (Dudai 2002a). In this case, we specifically wanted to test whether the properties of Ca2+/CaMAC can account for properties of memory performance. Our idea was that the enzyme is a coincidence detector on which the molecular representation of the conditioned stimulus (CS) and the unconditioned stimulus (US) converge. On the basis of findings from the gill and siphon withdrawal reflex in Aplysia, in our model, Ca2+ was considered to be the cellular representation of the CS, and the transmitter serotonin was considered to be the cellular representation of the US. Classical conditioning is successful when the CS starts before the US. We therefore hypothesized that optimal activation of the enzyme requires Ca2+ to precede serotonin by a fraction of a second. Together with my student Yoram Yovell and with Tom Abrams, we built what then was considered to be the ultimate reductionist dream machine: an apparatus for a continuous assay of Ca2+/CaMAC in response to transient pulses of Ca2+ and transmitter (Yovell et al. 1987). We used this system to quantify in detail the kinetics of Ca2+/CaMAC and its interaction with key cellular cations, and the potential relevance to plasticity (Yovell et al. 1987, 1992). This system was later used to show that in Aplysia Ca2+/CaMAC peak activation occurs when Ca2+ precedes the transmitter pulse (Yovell and Abrams 1992).

Two caveats are noteworthy, however. First, many macromolecular entities, ranging from receptors and channels to transcription factors and promoters, can be considered to be coincidence detectors (Dudai 2002a). If Ca2+/CaMAC indeed implements a basic property of biological memory machines, it is only a single token in the type of molecular devices that the nervous system uses to embody temporal associations in behavioral and developmental plasticity. Second, even more important, should one expect the properties of a molecule to mimic the properties of behavior, or, in other words, the properties of the whole to be identical to the properties of one or more of its components? This, in fact, is not remote from the homunculus fallacy (Dudai 2002a): the belief that a diminutive system resembles the bigger system in which it resides and reads information and commands action within that bigger system. This is not a satisfactory explanation because it is a slippery slope to the assumption of homunculi (or turtles) all the way down. These issues prompted me to pay increasing attention to the distinction between neuronal plasticity and memory, which the contemporary molecular and cellular literature sometimes blurred. I will return to this fundamental distinction in the following. In the meantime, suffice it to say that in my internal mental discourse, I considered the molecular underpinnings of neuronal plasticity as the elementary nuts and bolts that permit and constrain the encoding of information in the higher system level and, as such, indeed can display some basic properties that also are expressed at the higher level, whereas memory is the specific content embodied in and expressed by the higher level and therefore cannot be reduced to molecular devices. The study of neuronal plasticity therefore is not identical with the study of memory and is not expected to unveil homunculi that have the same knowledge as their intelligent host.

Conceptual unrest notwithstanding, all in all, the experimental work in the fruit fly did proceed nicely (Dudai 1988). However, even in our successful neuronal plasticity playground, we did not identify a dihydromemorase or data-convertase. Rather, we identified gene products that are variants of molecular building blocks used by nature for many processes, including elementary neuronal function and development, and furthermore, that are not necessarily exclusive to the nervous system. The conclusion was in line with the idea, consonant with aforementioned remarks, that to account for specificity of information, one must consider how neurons are interconnected, and hence the study of memory should involve an identification of the circuits that subserve a specific behavior. This was easier said than done. The Aplysia people did achieve this, but they lacked the powerful tools of genetics, and this is what the Drosophila community was still missing in those early days. The methods available were not yet suitable for dissecting identified circuits in the central nervous system of the fly. I am not a method-oriented person and furthermore the resources available to me at that time did not make the development of novel imaging and physiology techniques a realistic goal. Initial attempts to convince a colleague, whose expertise was imaging, to devote some energy to development of methods in Drosophila were unproductive.

The solution we found, together with my student Gabrial Corfas, was to turn to the peripheral nervous system. We thought that if the work on Aplysia was so successful in dissecting a sensory-to-motor reflex, why shouldn’t we try to follow the same line of thought in the behaving fly. We developed for that purpose a “cleaning reflex” paradigm, based on the observation that upon tactile stimulation of its thoracic bristles, the fly cleans, with a patterned set of leg movements, the field covered by the stimulated bristles. We found that this reflex can undergo habituation and dishabituation. Single sensory neurons that mediate the input and the output and motor neurons that mediate the behavioral output are identifiable. Therefore, the system is useful for exploring the effects of single-gene mutations on behavioral and developmental plasticity in a prewired system. Most promising, we found that a memory mutant showed abnormally short-lived habituation.

Gabriel was able to record from the mechanosensory neuron and identify sensory adaptation and fatigue as physiological correlates of the behavior. Both dnc and rut altered the kinetics of the sensory fatigue. This was the first time that the effect of memory mutations was identified on the functional properties of an identified neuron that subserves a modifiable behavior in Drosophila. The results also indicated that the memory mutations affect fundamental neuronal plasticity properties and that the relation between the molecular defects and memory would not be straightforward: whereas both dnc and rut impaired classical conditioning in what seemed to be a similar way, they displayed opposite effects on sensory fatigue. We also found that the fine morphology of the identified mechanosensory neuron is abnormal in both dnc and rut, with an abnormally large number of side branches and varicosities, which were identified as potential synaptic sites. This showed that the mutations in the cAMP cascade play a role in shaping neuronal connectivity and link behavioral and developmental plasticity (Corfas and Dudai 1989, 1990a, 1990b, 1991).

This preparation probably could have sufficed to nourish scribomania from our lab until retirement. But the big question (what is the proper way to tackle the machinery of memory?) kept bothering me. Does a peripheral neuron in the fly satisfy my urge to understand memory? Again, do I make the proper distinction between neuronal plasticity and memory? What is the way to identify the correspondence rules between the two, assuming that indeed neuronal plasticity is the engine of behaviorally expressed memory?

At about the same time, I reached another conclusion, known probably to many, that the most powerful (and admittedly painful) way to master a field and reassess one’s own knowledge, worldview, and aims is to write a book on the topic. I also realized that despite the availability of excellent books on memory, none, to the best of my knowledge, provided a multilevel integration of the contemporary neurobiology of memory. The result was The Neurobiology of Memory. Concepts, Findings, Trends (Dudai 1989). This monograph was not only an integrative précis of the field as I saw it but also a statement: if you study only molecules or synapses or even neurons in isolation, you are bound to study plasticity. Memory is about a change in specific behaviorally related content embodied in activity states and patterns of in situ systems; it is about the change occurring with experience in internal representations, that is, models of the world encoded and computed in neuronal space. Plasticity mechanisms modify (or preserve) the representations, but the content is provided by the circuit functioning in the specific neuronal context in the behaving brain. Hence, my conclusion: go to the brain, young man.

But which brain? It is of note that the methodology for studying the fly brain was at that time much less developed than that required for exploring the mammalian brain. I had to make the decision on whether I next devote years to the development and compilation of the suitable methodologies, and I decided against it. I felt that I might for years distance myself from the study of memory per se and likely would end up with a description of a modifiable reflex, which is great but less to my personal liking. I also felt that it was about time to start dealing with a brain that is more similar to our own. Flies are beautiful, but they think and speak flyish. Even Benzer used to say that he studies the fly brain only to model the human brain, although at a later stage, he commented that after acquiring more experience with people, he reached the conclusion that the human brain is a model for the fly brain.

On Béarnaise Sauce and Rats

At that time, most of the knowledge on the biological underpinnings of human memory still was based on pathology, inferring function from dysfunction; noninvasive methods with a reasonable spatiotemporal resolution to study a healthy brain were lacking. I wanted to work on a normal brain. I was not personally comfortable with working on primates (I did travel to NIMH, to Mort Mishkin’s lab, to get the flavor), not to mention that molecular tools, which were one of my entry points, were practically a no-go in primates. This restricted the choice to rodents. My engagement in the study of Drosophila had led me from the outset to focus on the encoding and consolidation of information acquired in one-shot experiences in naturalistic conditions. I was looking for a system that could allow me to pursue this line of investigation.

One candidate stood out: conditioned taste aversion (CTA; Garcia et al. 1968, Bures et al. 1998). This is the learned association of taste with visceral distress. Farmers know well that animals tend to avoid poisonous bait if they survive their first encounter with it. Humans are more familiar with the version in which consumption of spoiled falafel or Béarnaise sauce induces long-lasting specific avoidance of the foodstuff (this is why CTA is also dubbed the Béarnaise sauce effect). Amazingly, a phenomenon considered as obvious by the layperson was rejected for years by editors of scientific journals, because it didn’t fit all the rules expected from conventional classical conditioning (efficient associativity of diverse types of stimuli, brief interstimulus interval; Garcia 1977). CTA was easy to achieve in the rat by pairing a novel taste solution with subsequent transient malaise induced by intraperitoneal injection of lithium chloride. Quite a lot was learned over the years on the behavioral phenomenon and on some brain correlates (Bures et al. 1998). Mechanistic analysis, targeting identified brain areas with molecular and cellular tools, was lacking, however. Furthermore, from reading the literature, it became clear that a neocortical area (in the insular cortex) was suspected to be involved. Taken together, this appeared as a suitable candidate for multilevel integrative dissection of the mechanisms of learning and memory in the mammalian cortex. We could benefit from much previous knowledge on the one hand, but add novel approaches and a fresh mechanistic view on the other.

Before long, along with my students Kobi Rosenblum and Noam Meiri, we showed that the insular cortex not only is involved but also is a major site of consolidation of both the taste memory and its associative trace (Rosenblum et al. 1993). This finding paved the road to work conducted over several years during which time we identified behavioral and brain mechanisms of memory formation and storage of taste and CTA, focusing on the insular cortex and in some experiments on the amygdala. This effort involved many in our group (e.g., Lamprecht et al. 1995, 1997; Rosenblum et al. 1995, 1996, 1997; Lamprecht and Dudai 1996; Naor and Dudai 1996; Berman et al. 1998, 2000, 2003; Berman and Dudai 2001; Bahar et al. 2003, 2004a, 2004b; Desmedt et al. 2003; Eisenberg et al. 2003; Guitton and Dudai 2004; Kobilo et al. 2007; Shema et al. 2007, 2009, 2011; Guitton et al. 2008). Overall, we combined behavioral analysis, biochemistry and molecular biology, pharmacology, neuroanatomy, and some electrophysiology. This is not a review of the field, yet a few findings are worth noting en passant. Among them are the following discoveries: (1) the tyrosine phosphorylation of the 2B subunit of the N-methyl-D-aspartate receptor (NR2B) is involved in initiating memory in neocortex; (2) the mitogen-activated protein kinases (MAPs) ERK1/2, and their downstream substrate ELK1 are instrumental in downstream signaling in memory formation; (3) the stimulus-induced transcription factor cAMP response element-binding protein (CREB), previously identified to play a key role in neuronal plasticity in invertebrates, plays a similar role in the mammalian brain; (4) the molecular and circuit mechanisms of learning a new item are different from those of learning new things about a familiar item; (5) encoding of novelty of an item requires a cholinergic signal in cortex; and (6) memory extinction, that is, learning that an association is not relevant any more, is not a unitary processes, but rather the sum total of multiple processes, some of which conflict with each other in their effect on behavior. This, by the way, was a conclusion I reached over the years: whenever you detect a behavioral phenomenon, analysis will expose richer subprocesses, sometimes competing with each other, and these subprocesses can be used to manipulate the outcome of the system (another example is noted in the following section).

In the earlier Drosophila days, we were toying with the idea of using genetics to enhance memory. Soon after we described the role of tyrosine phosphorylation of NR2B in neocortical memory in the behaving rat, Joe Tsien, then at Stanford, reported a transgenic mouse overexpressing NR2B with enhanced learning and memory (Tang et al. 1999). This achievement resulted, as expected, not only in a high-profile publication but also in catchy headlines in the lay press. Enters pleiotropy: again, as with the fly mutants, the effect on memory was not on memory only—in this case, unfortunately, it was accompanied by a decreased threshold for pain (Wei et al. 2001). This echoed not only Benzer’s skepticism concerning the ability of neurogenetics to increase wisdom but also a moral committed to my memory during religious elementary school: “he that increaseth knowledge increaseth sorrow” (Ecclesiastes 18:1). In Hebrew, it sounds even better, as “sorrow” in the original is in fact “pain.” Whether this is a universal maxim is still for science to find out, but the possibility that we may pay a dear price if we ever seriously attempt to genetically enhance our species’ biological memory should be kept in mind.

Many of these findings identified nuts and bolts of memory consolidation, that is, the transformation of the trace over time from an early, malleable form, to a mature, more firm form (Dudai 1996, 2002b, 2004, 2012; Dudai and Morris 2000). My interest in consolidation goes back to the Drosophila days. Note, however, that despite my long-term investment, I never discarded the possibility that consolidation is not a “natural kind” (Quine 1970), but rather it is a convenient way to classify a set of phenomena because it makes it easier for us to construe what we think the brain does with the learned information. The question of natural vs. anthropo-created types kept occupying me throughout my career, and will resurface below. Furthermore, in its original form, the consolidation hypothesis presumed that it occurs just once per memory item, but much evidence has accumulated that this is not the case and that items in long-term memory (LTM) can “reconsolidate” after their reactivation.

“Reconsolidation” was first proposed in the 1960s (Misanin 1968), subsequently practically muted by the zeitgeist (Sara 2000), and then boldly revitalized by Nader (Nader et al. 2000). Our work on the consolidation and later extinction of CTA fed into the debate and provided some insights. We were able to dissociate brain mechanisms that contribute to consolidation and reconsolidation (Bahar et al. 2004a). Most notably, we found that in memory retrieval, among the multiple associations invoked by the available cues, the association that comes to control (dominate) behavior is paradoxically the one that becomes more sensitive to interference in the hypothetical process of reconsolidation, which results in diminishing subsequent memory (Eisenberg et al. 2003). I was particularly gratified to learn that Joe LeDoux, a leader in memory research who is also a gifted musician, wrote a song about our dominant trace model for his rock band, The Amygdaloids (http://www.amygdaloids.com/?page_id=463); only that in the song, the dominant trace is never erased, in real life it is. Another type of collaborative work with another dear friend, Richard Morris, on spatial memory in the rat, led to the conclusion that for reconsolidation to take place at all, something new must be present in the retrieval situation, so that an encoding state is engaged (Morris et al. 2006).

These and additional findings (e.g., Eisenberg and Dudai 2004) led us to conclude that as opposed to synaptic or cellular consolidation, which is universal and reported in every system and paradigm of LTM, reconsolidation takes place only under certain boundary conditions. One of these is the strength of the trace (“dominant traces” tend to reconsolidate); another is the need for something new to appear in the retrieval situation (“encoding mode”); still another is probably the age of the memory (old memories tend to reconsolidate less). It became evident that reconsolidation, extinction, and memory updating all interact with each other, raising again the issue of the natural kind. For the brain, all these phenomena may reflect a continuum of computations, sometimes competing, performed in the postactivation state (Dudai 2007). These findings also have resulted in the hypothesis that what we identify as reconsolidation is in fact an additional phase in consolidation, that itself consolidates (the lingering consolidation hypothesis, see Dudai and Eisenberg 2004). The idea was that a major function of consolidation is to form retrieval links rather than reinforce the core representation itself and that this consolidation lingers much longer than previously thought.

A common method to identify consolidation is to use agents that block memory only within a limited time window after encoding. But what happens if an agent is found to block memory long after consolidation is assumed to be over? This is what happened with the zeta inhibitory peptide (ZIP), the pseudosubstrate of the enzyme protein kinase M zeta (PKMζ), a member of the family of protein kinase C proteins. Following the findings of Todd Sacktor on the ability of ZIP to erase LTP and memory in the rat hippocampus (Pastalkova 2006), we found that ZIP blocks long, even very long (several months), CTA memory in the neocortex, which is considered the ultimate repository of many types of memory in the mammalian brain (Shema et al. 2007, 2009). These results were astonishing, as this was the first case of an agent that specifically could erase consolidated memory in the absence of the need to reactivate the memory (i.e., not by blocking reconsolidation). This was taken to suggest that the activity of PKMζ is critical in maintaining LTM. Being quite experienced in enzyme biochemistry, however, the use of an inhibitor to conclude that the assumed target is involved appeared somewhat risky. Therefore, we used genetics and discovered that overexpression of PKMζ enhances LTM performance long after encoding, whereas overexpression of a dominant negative form of the gene blocks LTM (Shema et al. 2011). The former result was particularly intriguing: how could an “old” memory be enhanced by an enzyme? The jury is out on the role of PKMζ in maintenance of LTM (Sacktor and Fenton 2012; Volk et al. 2013). As these lines are being written, we are struggling in our lab, together with our colleague Menahem Segal, to understand what ZIP really is doing at the cellular level, and we have some doubts as to whether its amazing effects on memory are a consequence, or only a consequence, of the inhibition of PKMζ (Sadeh et al. 2015). Having said that, studies from several labs continue to indicate a role for PKMζ in memory (Hardt et al. 2013; Xue et al. 2015). Stories in science are never as simple as they may look at a first glance, and this only renders them even more interesting.

In the meantime, upon entering mammalian brain projects, my research group has largely diversified. The background of my students and postdocs now ranged from psychology to molecular biology and computer sciences. This diversity also reflects the general increasing interest of smart students in the brain sciences. I realized that for them to interact efficiently, furthermore to navigate in the field more productively, they needed to become more familiar with basic notions and concepts about memory and to learn to speak a common language. I embarked on what turned out to be the most demanding and difficult project that I have ever done: write a book that defines, gives the historical and conceptual framework, and discusses more than 130 keywords and concepts that I wished my students to know (Dudai 2002a). In fact, this was akin to writing more than 130 books. The entries ranged from a priori to zeitgeist, with representation of multiple levels of analyses and subdisciplines. There were extra terms related to the culture of science, scoopophobia being but one example.

The investigation of reconsolidation, extinction, or use-dependent updating of memory raises fundamental questions concerning the relevance of memory to reality. If the trace metamorphoses with use, what is the relevance of the expressed representation to the original event? These issues naturally are better studied in humans. Furthermore, functional imaging methods had been developed that rendered the noninvasive study of the human brain more accessible. The opportunity for me to use these methods came soon.

Human Correct and Erroneous Recollections

In 2004, the Center for Neural Science at New York University offered me a position as Global Distinguished Professor of Neural Science (later to become the Albert and Blanche Willner Family Global Distinguished Professor of Neural Science). This post allowed me to become integrated in the research and academic life of the outstanding New York University (NYU) neuroscience community, yet still retain my position at the Weizmann Institute and avoid the need to relocate from Israel. Since then NYU has become my second home, and I am grateful to my colleagues there for their friendship, wisdom, insight, and support, particularly to Joe LeDoux and Tony Movshon. NYU has a cutting-edge center for human brain imaging and memory, and it is there that I was trained in human fMRI and in the adaptation of human memory protocols to the scanner. In parallel, at the Weizmann, while still pursuing at full speed our work on single-shot learning in the rat neocortex, I started to develop memory protocols to quantify episodic memory in humans under naturalistic conditions. The human episodic memory literature was remarkably rich and deep, but much of the work had been conducted along the Ebbinghausian tradition of using artificial stimuli and associations. I wanted to go into real-life memory, as I firmly believe that the brain, that of humans as well as that of other species, operates differently in natural contexts than when facing artificial and often admittedly boring stimuli.

Fig. 3.  Cross-level integration. My interest in cross-level translation of concepts, processes and mechanisms of memory in general and of the encoding and consolidation of one-shot real-life experiences in particular, was a driving force in gradually shifting my lab from studying the fly brain to exploring the human brain. In a recent version of my research team, only one student is still using molecular biology in the rat brain, whereas the others combine their training in psychology, biology, neuroimaging, and computer science to study the encoding and time- and use-dependent transformation of human episodic memory. From left to right, standing, are Micah Edelson, Noa Sadeh, Ella Bar, Noga Cohen, Meytar Zemer, the author, Uri Korisky, Neetai Eshel; and seated are Catarina Raposo (a student in another group, adopted by us given that she married Micah), Maya Shemesh, Aya Ben-Yakov, and Liat Pell.

The idea was to use narrative movies to simulate episodic experience. Movies are amenable for use as stimuli in the scanner, and they can be tailored in content and length to the requirement of different encoding and retrieval situations. Movies have been used by Uri Hasson at Weizmann to study visual perception and develop novel fMRI analysis methods. Because we wanted our participants to be able to face novel situations in a natural context, one of the first actions we took was to produce movies of our own. A team in our lab, with the assistance of a few cinema studies students, produced many hours of documentaries, centering on the life of an Israeli student. On top of the fun, the advantage was that the movies were filmed in Hebrew, and whereas commercial movies avoid boring the viewer, we wanted to achieve the opposite, to mimic the style of most real-life routine situations. The first movie that we used in the scanner, however, was a rather tedious episode from an English-speaking sitcom unlikely to have been seen by students and more suitable to be used at NYU because of the language and the context.

We started sailing into the marvelous world of human episodic memory (Tulving 1983; Squire et al. 2004), amazed to discover how well participants remember incidental, useless events, and realizing the important role of social information (and its brain underpinnings) in encoding realistic episodic memory. Analysis of the behavioral and brain mechanisms of the formation and the transformation of episodic memory started in collaboration with colleagues at NYU (Furman et al. 2007; Hasson et al. 2008) and proceeded in parallel as well as independently in Rehovot (Mendelsohn et al. 2009, 2010). We found that the episodic trace is transformed over weeks and months into a semantic form, in which the neocortex supports context-poor recollections in the absence of significant hippocampal involvement; however, if contextrich, vivid recollections still surface even after months, they still are associated with hippocampal activity. The role of hippocampus in storing LTM is hence task dependent (Dudai 2012). Furthermore, we found that over weeks and months, the brain shifts into a parsimonious neural mode in recollecting the event, leading us to suggest that metabolic frugality was a driving force in shaping systems consolidation (Furman et al. 2012).

Selected elements of the rich behavioral repertoire of humans was translated in our work into a set of encoding, consolidation, and reconsolidation projects, including another collaboration with NYU, on encoding and memory following insight, which by definition, is a one-shot task (Ludmer et al. 2011). Some of the projects were clearly unconventional. We used hypnosis in the scanner to identify brain circuits that inhibit the expression of episodic traces (Mendelsohn et al. 2008). We also used a large live snake to create a paradigm for rapid switching between fear and courage in the scanner to identify rapid alternations in dominant traces in retrieval (see trace dominance earlier and Nili et al. 2010). Work in the lab was really fun, with those still pursuing memory in the rat brain enjoying the movies created by their peers studying memory in the human brain.

Personal Memory, and That of the Other

In recent years, my work has shifted increasingly to focus on behavioral and brain mechanisms of the consolidation of human episodic memory. Much of the more recent work has been devoted to two topics. The first topic of interest examined the first seconds of realistic episodic memory and the triggering of consolidation (Ben-Yakov and Dudai 2011; Ben-Yakov et al. 2013, 2014; see also review in Cohen et al. 2015). In other words, what happens in the brain in the “big bang” of memory, those first seconds that influence the fate of memory in the years thereafter? Here, using brief movie clips as memoranda, we discovered that the hippocampus seems to wait for a few seconds, possibly until the episode makes sense, before initiating consolidation. We also found memory-related involvement of the striatum in these critical seconds, a region so far mostly considered as supporting nondeclarative memory. Indeed, this brings up again the issue of natural kinds: we are used to classifying memory into declarative and nondeclarative, yet it is unclear whether those are natural kinds in the brain, or whether the brain recruits computational modules as the situation demands without necessarily honoring our taxonomy. We also found a way to dissociate the contribution of the hippocampus to encoding and retrieval in a single experience, because in real life, even novel experiences have familiar elements, and hence rarely, if at all, do we encode without retrieving at the same time. Again, two competing computational modes, probably reflecting pattern separation and pattern completion, in response to the same event.

The second topic of interest looked at the degree of resemblance of the retrieved information to the original event. We developed paradigms to manipulate realistic memory (Ludmer et al. 2014) and discovered that the computational strategy recruited by the hippocampus depends on the internal state of the participant, whether naïve or distrustful at the start. We also delved into the behavioral and brain mechanisms that mediate the remarkable distortion of an individual’s memory engendered by social conformity (Edelson et al. 2011, 2014, 2015). We found that engagement of the amygdala and amygdala-hippocampal functional connectivity at the time of potential social influence predicts subsequent memory distortion. Furthermore, only part of the distortion can be reversed, via engagement of frontal areas, when the social pressure is lifted. We also identified the role of oxytocinergic neuromodulation in this social distortion of memory. Given that humans are social animals, it is important to understand that a significant part of what we believe we know, in fact, is a product of the amalgamation of the views and memories of others. Personal memory hence may be considered conceptually as a node in a distributed memory space that transcends the personal. This may provide us with a phylogenetic advantage in that, on the one hand, accumulated information can be fitted to the real-time requirements of the locale, but on the other, the capacity and availability of information markedly exceeds the capacity and life span of the individual.

On Drives and the Taxonomy and Frequency of Discoveries

I started my independent research in studying the memory of flies, with the loudly declared and only loosely believed assumption that this ultimately would contribute from the bottom up to the dissection of brain mechanisms of human memory, and decades later, I have found myself dealing directly with human memory. During this period, the neuroscience of memory has advanced tremendously (Dudai and Morris 2013; Kandel et al. 2014) to include novel stunning methods, as well as brilliant ideas for how to use them. The pace of data accumulation is almost unbelievable. It would have been difficult, if not impossible, to write now my 1989 monograph, at least not without leaving out most of the findings and concentrating on only a few big questions.

This conclusion reflects two developments. First, in my view, it is impossible for a single individual to genuinely master all or even most of the knowledge in their discipline, unless the definition of discipline becomes narrower at an alarming pace. Did I say “master”? Even seriously keeping up with the literature becomes impossible, and the most we can do is file some of the relevant papers under “to read,” primarily as a defense mechanism to pacify the revolting professional conscience. Second, and even more profoundly, it is highly questionable whether we still can grasp the full picture of our discipline, let alone comprehend it. This task seems to far exceed the capability of a single brain. And what is the meaning of comprehension or understanding in science? Recently, I devoted a special topic seminar series at NYU to the question of “what is the meaning of ‘understanding’ in the brain sciences?” The participants, including seasoned experimentalists and modelers, tended to agree that understanding requires a mental model that combines both mathematics and intuition. Even if we feed the mammoth amount of data that we collect into a computer, we may get some solutions and generalizations, deus ex machina, but the epistemic opacity of the nonlinear, multidimensional computations done on the computer may hinder not only the joy of personal discovery but also the ability to intuitively grasp what is going on (Dudai and Everts 2014). In other words, the neuroscience ahead of us presents the newcomer to the field with cognitive and emotional demands and personal expectations that are different from those that many of the authors in this volume were facing at the beginning of their careers. One possibility is that neuroscience needs increasingly more phenomenologists, as in theoretical physics, in which experts try to dissociate themselves from collecting data and only think big. The rise of computational neuroscience signals that this is a useful direction for the discipline. This direction requires many biologists to reconsider the attitude that whoever doesn’t produce data is a different species, and for some computational neuroscientists to reassess their belief that seriously consulting the biological data is a superfluous luxury.

Our knowledge about mechanisms is now orders of magnitude more extensive and richer and more exciting than it was 25 years ago. The deeper we go, however, the more we may have to reassess some basic assumptions. Consider just one example: is synaptic plasticity indeed the engine of memory storage, or only of its encoding or expression? My own stand on the big questions is that because memory is the study of experience-dependent alteration in information, to understand it, we need to understand the brain code of internal representations, including the “machine language” and its computations. The $64,000 question (devaluation notwithstanding) is inseparable from the central question in brain research in general: what language(s) does the brain speak, and what does it compute in this language? I also believe that this search must involve concerted efforts of many subdisciplines of neuroscience to ensure that pretty models are reflecting what the brain really does and that pretty experiments do not lure us away from feasible models.

In my career thus far, I have sacrificed a few persistent long-term reductionist excursions into molecular mechanisms, using disciplines in which I was trained formally, in favor of behavioral, brain, and more recently, social mechanisms, delving into formal disciplines that were initially more of a terra incognita for me. What navigated these decisions? Recollection is mental time travel into the past, whereas reality is concrete traveling, guided by implicit or explicit mental time traveling into the future. Although postfactum interpretations may not necessarily reflect the critical factor in realtime decisions, they sometimes make sense as more integrative information becomes transparent to the narrator. I am tempted to take on two examples. Why did I decide to apply for only one postdoc position, contemplating reconsideration of my career if the application proved unsuccessful? I may have navigated myself into a test, to see whether the unknown institution that I identified as top-notch accepted me. It was not lack of confidence; it was a reality check. I recommend idiosyncratic reality checks to my students when they finish their thesis and consider a career. I was also attracted by the unknown—neurogenetic dissection à la Benzer was almost the furthest possible from my thesis topic. I am unabashedly inclined to become increasingly bored by paths I traverse. This terrible trait is consistent with my tendency to slowly deviate from the molecular level of analysis. And, on top of it all, I became explicitly and increasingly aware over the years that the drive to understand humans is for me stronger than the drive to understand flies and rodents.

In the career path that we select, we also are driven by interim rewards. How frequently do they arrive? I am not talking about the routine ones, like enjoying a clean electrophoretogram, nice behavioral data, a convincing functional image or a clear-cut statistical significance. I also am not talking about acceptance of a paper for publication in a high-profile journal. I am talking about what we deem as major findings, the adult equivalent of that mini-epiphany that I experienced in the understanding of evolution in high school. How frequent do these findings occur? I tried to estimate and counted seven or eight in my career. They are hidden in the previous text and in my list of publications. This means that I ended with, more or less, one private aha moment every five years or so. As I’ve said, to be a scientist, you must prepare for delayed gratification.

Epilogue: On Reminiscence Bumps

Upon rereading this essay, I note that in terms of space I did cover the various chapters in my scientific career reasonably proportionally, but the early chapters may seem a bit more colorful. This is the reminiscence bump: the tendency of older adults to have increased recollection, in terms of details and emotions, for events that occurred during their adolescence and early adulthood (Berntsen and Rubin 2002; not to be confused with the sense of well-being that increases after age 50, Stone et al. 2010). Hence, even in writing one’s scientific autobiography, one may find oneself either confirming or refuting a scientific model. The aforementioned observation should not belittle the color and emotions of the later chapters of my life. It is only that some of the later events, exciting as they were, lacked the kick of novelty, some became skills and habits, and still others had to do with more time allotted to administration rather than to real science. But one type of reward is sometimes replaced by another. At the Weizmann Institute, I was dean of the Faculty of Biology for six years and chair of the Department of Neurobiology and of the brain research centers for another six years. When I was appointed dean, Benzer dropped me a note, claiming that I should have followed the advice of his colleague, Max Delbruck, to fail on one’s first administrative assignment. Science administration does have its own merit, though. My main job was to recruit new faculty that are more knowledgeable than I am. I see them now in labs, corridors, and seminar rooms. In the endless expedition cycles of the scientific culture, their personal chapters are now consolidating.

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Gerald D. Fischbach

BORN:

New Rochelle, New York

November 15, 1938

EDUCATION:

Colgate University, Hamilton, NY, B.A. (1960)

Cornell University, Ithaca, NY, M.D. (1965)

APPOINTMENTS:

Senior Surgeon, National Institute of Neurological Diseases and Stroke (1966–1969)

Staff Fellow, National Institute of Child Health (1969–1973)

Associate Professor of Pharmacology, Harvard University (1973–1978)

Professor of Pharmacology, Harvard University (1978–1981)

Edison Professor of Neurobiology and Chair, Department of Anatomy and Neurobiology, Washington University of St. Louis (1981–1990)

President, Society for Neuroscience (1983–1984)

Nathan Marsh Pusey Professor of Neurobiology and Chair, Department of Neurobiology, Harvard Medical School (1990–1998)

Non-resident Fellow of the Salk Institute (1990–2010)

Director, National Institute of Neurological Disorders and Stroke (1998–2001)

Executive Vice President Health Sciences and Dean, Columbia University (2001–2006)

Director, Simons Foundation Autism Research Initiative (2006–2013)

Chief Scientist and Fellow, Simons Foundation (2013–current)

HONORS AND AWARDS (SELECTED):

Mathilde Solowey Award in Neurosciences, NIH, 1975

Honorary M.A. Harvard University, 1978

W. Alden Spencer Award, Columbia University, 1981

President, Society for Neuroscience, 1983

Member, National Academy of Sciences, 1984

Member, American Academy of Arts and Sciences, 1988

Member, Institute of Medicine, 1990

Member, European Academy of Sciences and Art, 1991

The Foundation Ipsen Neuronal Plasticity Prize, 1998

Member, American Philosophical Society, 2003

Honorary Doctor of Science, Colgate University, 2003

Honorary Doctor of Philosophy, Hallym University, South Korea, 2008

Fellow, American Association for the Advancement of Science, 2008

Honorary Doctor of Science, Washington University in St. Louis, 2015

Gerald Fischbach has studied the formation and maintenance of chemical synapses throughout his career. He pioneered the development and use of dissociated nerve cell cultures to study the physiology, morphology, and biochemistry of developing nerve-muscle and interneuronal synapses. He found that at the neuromuscular junction, synaptic transmission begins immediately after a motor axon growth cone contacts a naïve muscle cell, but maturation of this prototypic synapse continues for weeks thereafter. The early appearance and regulation of glutamate and GABA receptors in spinal cord and hippocampal neurons and the modulation of voltage-gated calcium channels in developing neurons was studied as well. Neuregulin, a protein purified from brain tissue based on its ability to promote the accumulation of acetylcholine receptors at nerve-muscle synapses, recently has been implicated in the developing central nervous system and in certain neuropsychiatric disorders. Fischbach is widely recognized as a scientific leader, possessing a deep understanding of the normal and disordered brain. He has served in leadership roles at three universities, at the National Institutes of Health, and at the Simons Foundation. He has helped transform neuroscience in several areas of study, and he has influenced the careers of many scientists throughout this country and abroad.

Gerald D. Fischbach

My long-term interest in neuroscience has been the formation, function, and plasticity of synapses. Most often my research has involved the neuromuscular junction (nmj), the synapse formed by spinal motor neurons on skeletal muscle fibers. Beyond the nerve-muscle synapse, I have studied synapses formed between neurons dissociated from the central nervous system (CNS) and from peripheral ganglia.

What follows is a brief summary of selected findings from my laboratory over the course of the past half-century. This is not an exhaustive review of my work or of the field at the time the work was conducted, or of the current literature. But this memoir is but a start.

The recitation of experiments is not strictly in chronological order. Techniques emerge at different times, personal matters intervene, and some projects proceed more rapidly than others. Rather, I have presented experiments in a more coherent way as they appear to me today.

An important part of my life in science has been the administrative responsibilities that I have held. One might consider these duties as burdensome distractions, but I learned a great deal from each experience. I came to consider science administration, with the possibility of inspiring others, as science on a meaningful level.

One advantage of the nmj is that we know its “purpose”: sufficient transmitter acetylcholine (ACh) must be released from the nerve terminals to activate a sufficient number of ACh receptors (AChRs) in the postsynaptic membrane to trigger an inward current sufficient to depolarize the membrane past threshold and trigger a muscle contraction. The postsynaptic membrane at the nmj contains a high density of AChRs. This remarkable specialization became a main focus of my work.

Another advantage of the nmj is the remarkable legacy left by Bernard Katz, Stephen Kuffler, John Eccles, and many others. My generation benefited from their studies of synaptic transmission extending from the dawn of microelectrode physiology to current giga-seal single-channel recordings. The case can be made that most of what we now know about chemical synapses in the brain was either first or best described at the nmj.

Early Personal History

My first four years were spent in Brooklyn, but I grew up in Mount Vernon, New York, a comfortable suburb squeezed between the Bronx and wealthier sections of Westchester County. My parents were children of Jewish immigrants who arrived from Russia, Romania, and Austria. My mother was a graduate of Hunter College. Her warm, outgoing nature helped her succeed as a leader of Jewish communities, and as a real estate broker in a competitive market.

My father was a lawyer educated at Columbia University and Brooklyn Law School. He was a demanding intellectual, proud of his encyclopedic knowledge of many, somewhat irrelevant, topics. One of his joys was to complete the Sunday New York Times crossword puzzle, which he often did in less than an hour. My sister Joan and I tolerated his incessant challenging questions and high expectations. I regret that I did not appreciate him when I could. He had a debilitating neurological disorder characterized by muscle wasting and an intention tremor. As I matured in college and medical school, he had difficulties with his law practice that embarrassed him and presented a further block to our communication. I have kept several of his books and continue to be impressed with the diversity of his interests.

Joan, four years my senior, pursued various careers, including occupational therapy and, like my mother, real estate sales. She moved to Denver 40 years ago, and we grew apart. This emotional distance, thankfully, has been reduced in recent years. Joan cared for both my mother as her memory failed, and my father as his neurological deficits progressed.

The 1940s and 1950s in Mount Vernon are a blur to me, as they are to many who grew up in that era. We were innocents who managed to ignore the gloom of the Cold War, the legacy of the holocaust, racial segregation, and the threat to civil liberties. I was a good, but not exceptional student in high school.

I left Mount Vernon in 1956 to attend Colgate University on a New York State Regents Scholarship. This small stipend of $2,500 covered tuition at that time. It was at that small liberal arts college in the beautiful Chenango Valley in upstate New York that I developed a deep self-confidence and began to enjoy academic pursuits.

I became a freshman dorm advisor in my second year, helping new students about my own age adjust to academic and social challenges. This early experience played a role in the satisfaction I derived from organizing diverse groups in academia as a student, lab chief, department chair, institute director, and dean. I excelled academically at Colgate, graduating magna cum laude with high honors in mathematics and chemistry and was accepted early decision at Cornell Medical College with new scholarship support from New York state.

Cornell University Medical Center (1960–1965)

The Cornell medical faculty was excellent at that time with Vincent du Vigneaud who isolated and sequenced oxytocin, Harold Woolf, Fred Plum, and Jerome Posner working in my areas of interest.

Marriage

I met Ruth Zeitlin in 1960 during our first weeks at Cornell, and my life changed forever. Ruth had begun a three-year program at the Cornell University–New York Hospital School of Nursing after completing two years at Mount Holyoke College. We moved imperceptibly from acquaintances, to study partners, to close friends, to an engaged couple. We married in 1962 despite warnings from our parents that we were acting precipitously. What if Ruth became pregnant? We assured them of our maturity in such matters and then proceeded to have two wonderful children in the next two years. Elissa was born in 1963 and Peter in 1965. We lived in a small, fifth-floor walk-up for two years. Mark and Neal, our unsuspected twins, were born three years later when we lived in Bethesda, Maryland. Perhaps because of our early indiscretion, we now have 12 wonderful grandchildren. These events were and remain the most important of my life. We still celebrate the union of four wonderful families: Wolsk, Zeitlin, Fischbach, and Coopersmith. Three years ago, we purchased the home in Purdys, New York, once owned by Ruth’s parents, where we were married in 1962.

Despite the challenges of raising four children and attending to a needy husband frequently on the move to different parts of the country, Ruth forged a remarkable career creating important programs at Washington University, Harvard, the NIH, and Columbia University, completing a PhD in medical sociology and a graduate degree in psychiatric epidemiology along the way. Her enduring interest has been in the field of bioethics. She created and has served as director of Centers of Bioethics at Washington University and at Columbia. Ruth gave me the courage to take a leave of absence from medical school to pursue laboratory research and to make every subsequent move over the years.

I tolerated much of the memorization required in medical school at that time because the subjects were interesting. But rote learning was a far cry from the independent honors work I completed at Colgate, and I was soon bored. One lab exercise stands out in my mind. We were charged with recording the resting membrane potential of frog Sartorius muscles. I recorded a value of −90 mV, the highest value in the class, probably aided by a tip potential of a poorly constructed microelectrode. In any case, the rush of success reinforced my urge to break out, and with Ruth’s encouragement, I decided to take a year off from medical school to learn electrophysiology. Few students took this option in 1962.

I spent the year in the Department of Pharmacology. Walter Riker, the empathetic chair, provided me with a room of my own, equipment, and an interesting question: Does ACh, the transmitter of excitation from motor axons to postsynaptic muscle fibers also exert actions on presynaptic motor nerve terminals? I was on my own, an independence that gave me the opportunity to study the literature of synaptic physiology and the electronics required for intracellular microelectrode recording. Meetings with Ernie Amatniak, Harry Grundfest’s former technician, at his company Bioelectrics, taught me a great deal about high-input-impedance unity gain amplifiers.

I was proud that my work on quantal release of ACh from motor nerve terminals treated with an anticholinesterase was awarded the Harold G. Woolf Prize at Cornell. Less important was the rejection of my singleauthored manuscript by Science magazine. I had the bug, and I wanted to continue in neuroscience research. An important conversation with Eric Kandel, a cousin by marriage, convinced me to apply to the Laboratory of Neurophysiology at NIH for further training. Kandel had recently completed a successful tour in that laboratory where his groundbreaking work with Alden Spencer on the hippocampus shaped his long-term interest in synaptic plasticity and memory. Kandel and I began a conversation about neuroscience that has lasted, on and off, for 50 years. I was accepted for a position at the NIH in the Laboratory of Neurophysiology directed, at the time, by Wade Marshall. Phil Nelson directed the Spinal Cord Secton of the lab, the unit to which I applied.

There were no openings for one year, so I accepted a medical internship at the University of Washington Medical Center (UWMC) in Seattle. The UWMC was growing rapidly in 1965. There was great expertise in infectious disease, led by Robert Petersdorf, the chair of medicine; in renal disease with the first kidney transplant; and in neuroscience. Bertil Hille and Charles Stevens were members of the Physiology Department, and I naively thought I would have plenty of time to meet and perhaps work with them during the year. Seattle was a welcome change for Ruth and for me. We loved to camp, hike, and ski, and we still describe a beautiful day in the East as a “Seattle day.”

I enjoyed the internship experience, and I was good at it. Secure in clinical medicine, I planned to return to New York City for advanced training in neurology with Fred Plum and Jerry Posner at Cornell after I served time in the Public Health Service at the NIH. It took me several years to turn away from this plan.

An important event that reinforced my decision to join the Public Health Service without delay was a telegram from my draft board requesting that I report within three days for duty in Vietnam. Ruth called to inform me of this request at 3:00 a.m. while I was working at the hospital. The “doctors draft” during the Vietnam War was indeed a significant factor in creating the superb community of young biomedical scientists at NIH during those years.

National Institutes of Health (1966–1973)

In 1966, the NIH sat in a bucolic, wooded campus of more than 300 acres in Bethesda, Maryland. The Laboratory of Neurophysiology spanned the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH), a wonderful precedent that is echoed in the new intramural John Porter Neuroscience Center that brings together scientists from several institutes. Senior investigators, including Phil Nelson, Karl Frank, Mike Fuortes, Ed Evarts, Will Rall, Ichi Tasaki, Walter Freygang, Milt Bridgman, and Marshall Nirenberg, interacted seamlessly with more junior scientists, including Bob Burke, Bob Wurtz, Dennis Baylor, Mahlon DeLong, Tom Thatch, Al Gilman, John Heuser, Tom Reese, and Stan Rappoport. I was welcomed into the midst of this extraordinary community. They offered an exciting, often iconoclastic, outlook on important problems in brain science and shared a great passion for research that shaped my life in science.

These early years at the NIH continued my march toward independence. The scientists were friends and mentors for each other. But in the main, I was on my own with ample resources and enough time to think about the questions I asked and to explore new techniques. I realize in writing this memoir that nearly all of my subsequent ideas and experiments can be traced back to this extended postdoctoral experience in Bethesda.

Use and Disuse at the nmj

My first experiments at the NIH, undertaken with Norman Robbins, focused on effects of use (exercise) and disuse (immobilization) on the contractile properties and synaptic function of skeletal muscle fibers. We took use and disuse as a better model for “experience” or “learning” than was denervation, a popular paradigm at the time. Robbins was more experienced in the lab than me, having studied trophic interactions at Rockefeller University with Benice Grafstein and Paul Weiss, but he treated me as an equal partner from the start.

Postural muscles such as the soleus in the calf are tonically active, and their twitch time is slow. When the hind limbs of rats were immobilized, the pattern of activity, measured with indwelling electromyography (EMG) electrodes, changed from low-frequency tonic activity to high-frequency bursts characteristic of fast-twitch muscles. Immobilized, tonic muscles developed faster contraction times, higher tetanic fusion frequencies, and lower twitch–tetanus ratios. The discovery that properties of innervated muscle fibers were not fixed was a revelation. As a model for the brain, it emphasized the role of experience in molding the properties of target cells.

The pattern of motor neuron activity also altered the distribution of AChRs in the muscle membrane as measured by iontophoretic application of ACh. This was the beginning of my interest in AChR regulation by impulse activity or by neurotrophic influences.

Beyond our immersion in medical science, the NIH group was socially and politically active. Robbins introduced me to a challenging brand of political activism, a lifelong commitment of his. Remarkably, it was possible to pursue one’s conscience at the NIH in the late 1960s and early 1970s. I joined the Physicians for Social Responsibility, participated in demonstrations at the NIH and at the capital, and appeared on television talk shows. Ruth joined Bella Absug’s Mothers Strike for Peace. On one occasion, they tried to surround the Capitol building in a human chain. Our daughter, Elissa, who was seven at the time, remembers fearing her arms were being pulled from their sockets as the line was stretched. How different is the situation today.

Leap into Cell Culture

After a productive collaboration with Robbins, I wanted to develop a preparation in which I could observe the sequence of events during nerve-muscle synapse formation in real time. Cultures of dissociated cells offered many advantages, including direct visualization of fine neurites in unfixed preparations by phase contrast or interference contrast microscopy, and precise control of the microenvironment of the developing cells. Looking ahead, I realized that sparse cell cultures would provide convenient assays for studies of known neurotrophic factors and for purification of new ones.

From the start, my intent was to prepare co-cultures of motor neurons and muscle cells, but I cut my cell culture teeth working with muscle cells grown alone. The electrical properties of excitable cell membranes are exquisitely sensitive, and they seemed like a good bioassay for health in vitro. I was lucky enough to meet Mark Nameroff then at the Walter Reed Hospital. Nameroff was a student of Howard Holtzer, one of the pioneers in studies of myogenesis.

We plated myoblasts dissociated from chick pectoral muscles cells in Nameroff’s lab. After the mononucleated myoblasts settled on the collagencoated tissue culture dishes and had begun to fuse to form multinucleated myotubes, I drove them to my electrophysiological rig at the NIH in a lidded container wedged upright on the floor of my Ford station wagon. The loss of CO₂ was not severe, provided the traffic was light, and the cells did not complain loudly.

We estimated membrane resistivity and capacitance by solving the second-order partial-differential cable equation assuming that the myotubes were closed-end cylinders. I was happy and relieved to find that the membrane resistivity, 2,000 ohms cm2, and the specific capacitance, 1 μF/cm2 were comparable to values of muscle fibers in vivo. Cultured myotubes cells were “tight” rather than leaky sacks.

Wilfred Rall recently had published his multicompartmental model of branched motor neuron dendrites as equivalent cylinders that revolutionized our thinking about dendritic arbors. Rall was a great help to me as I modeled branched myotubes to determine their specific membrane properties. The classical papers of Rushton on the cable properties of nerve axons were also a great help.

The resting membrane potential of myoblasts and young myotubes was low, but it increased with time in culture, and the cells developed overshooting action potentials. Many fibers twitched vigorously and many exhibited spontaneous tetanic contractions. I believe that this study was the first quantitative description of development of electrical excitability in vitro of any cell type.

Tom Smith loaned me my first inverted microscope. After I pledged to care for it with my life, I picked up the heavy Zeiss scope by the arched neck and watched, helplessly, as the heavy, dependent optics rolled off the rack and pinion and fell to the cement floor. I was forgiven by Smith, always the generous scholar, and we soon collaborated on studies of spherical “myoballs” created by treatment of the cylindrical myotubes with colchicine. We used this preparation to measure voltage-gated Na, Ca, and Cl currents under voltage clamp conditions.

Nerve-Muscle Synapses Form In Vitro

I moved on to co-cultures of dissociated spinal cord and muscle. My first publication described the fact that nerve-muscle synapses, in fact, do form in sparse cell culture. This was revolutionary at the time. I vividly recall the thrill I felt sitting alone in my small, dark physiology room listening to the hum of vacuum tube amplifiers and staring at the glow of the oscilloscope screen when the first synaptic potentials appeared. The excitement and beauty of the moment are with me today.

My resolve to return to medicine was shaken, but the decision was drawn out. I enjoyed working with patients, and in later years, I returned to clinically relevant problems. Our parents had experienced the Great Depression and saw a more secure future for us in clinical practice. They were concerned, but they did not apply pressure. As always, Ruth urged me to think about the moment and to emphasize the positive. We bought and renovated an old Sears Roebuck–designed house in Potomac, Maryland, mowed two of our four acres, boarded horses, raised white leghorn chickens (hatched, inadvertently, in my lab incubator), and continued to focus on our ever more active kids.

Earlier in the year, I agreed to substitute for K. Frank as the project officer on a PL 480 grant to Kamal and Susheel Sharma in the Department of Physiology of the new St. John’s Medical College in Bangalore, India. Before leaving, I wrote a “brief report,” as science papers were called at the time, and mailed it off to Science. I heard nothing about the paper while we spent four months in India. When I returned to the NIH, I found the manuscript on my desk returned for “inadequate postage.” When I recovered, I added a few stamps, and sent it off again. The paper was accepted by return mail.

Bangalore was an interesting, transforming experience for us all. I went to work every day at the medical school and at the nearby Raman Institute, Ruth worked in the hospital, and Peter and Elissa attended local schools and made friends. The tapping of the night watchman’s stick on the path outside of our apartment to chase cobras into their nests, and Ruth’s warning not to slam the refrigerator door and disturb the sediment in our water jugs, remain in our thoughts. But that is another essay. Mark and Neal, who were two years old at the time, waited for us at home in the loving arms of their grandparents.

On our return from India, I began immediately to expand the work on nerve-muscle synapse formation in vitro. I was joined by Stephen Cohen, then a medical student at Georgetown University. We further simplified the neuron-muscle cultures by eliminating fibroblasts, which in some situations are unwelcome “contaminants.” Even the finest neurites could then be visualized and followed over long distances as they contacted nearby and more distant myotubes. Our preplating technique followed by treatment with antimitotic agents resulted in essentially “pure” nerve-muscle co-cultures, and many labs adopted this strategy.

The mean quantum content of evoked epps and the mean mepp frequency were low at nerve-muscle synapses identified between 4–25 days of co-culture, and many muscle fibers were innervated by more than one axon and at more than one site. Moreover, synaptic potentials decayed slowly, and they were not further prolonged by physostigmine, implying the absence of acetylcholinesterase (AChE). This conclusion was confirmed in subsequent experiments with Lee Rubin at Harvard by focal extracellular recording of slow synaptic currents and by the absence of staining for AChE reaction product. AChE does not appear when the cells are grown in the presence of blocking concentration of curare or local anesthetics. AChR clusters do appear under the same conditions. Thus, AChE appears at developing junctions later than the initial accumulation of AChRs, and it appears to depend on the level of nerve-muscle activity.

Three questions raised in these early experiments remain unanswered to this day. First, direct electrical coupling between synaptically connected motor neurons–myotube pairs was observed on several occasions. Do such contacts play a role in the initial stages of synapse formation? Second, a degree of specificity in nerve-muscle synapse formation was evident. Not every contact between a competent cholinergic neurite and a receptive myotube resulted in a functional synapse. What is missing at nonfunctional contacts? Third, why is the appearance of AChE at synapses delayed?

Most important for my future work was the observation that regions of high AChR density, 5–20 × background levels were identified on innervated myotubes by focal ACh micro-iontophoresis. In the first experiments, we knew the muscle fibers were innervated, but the precise relation between such hot spots and the overlying neurites was not determined. This was accomplished in subsequent experiments by focal extracellular stimulation and recording. The same estimate of synaptic–extrasynaptic AChR density ratio was obtained by 125I-αBTX autoradiography. AChR clusters were identified by electron microscopy (EM) after labeling with ferritin-coupled αBTX and by the appearance of intramembrane particle clusters in freeze fracture EM images at physiologically identified hot spots.

To our great surprise, we found similar ACh hot spots on uninnervated myotubes. This finding raised the important question whether neurite associated hot spots were induced or sought out by the incoming motor axon. Subsequent experiments at Harvard showed that neurite-associated receptor patches were induced by motor axons. Moreover, we found that new synaptic ACh aggregates contained newly synthesized receptors.

The extrasynaptic “background” ACh sensitivity on innervated muscle cells was essentially the same as that on uninnervated myotubes even after two weeks of co-culture. It took muscle activity—either spontaneous or driven by direct electrical stimulation—to lower sensitivity. Synaptic AChR clusters remain under these conditions, underscoring our belief that the nerve terminal must exert an influence to preserve synaptic receptors. Accumulation of AChRs at developing nmjs in vivo also occurs in the face of increasing muscle activity. It was natural to think of a locally acting trophic influence of nerve on muscle, a thought that occupied me over the next decade.

Many AChR aggregates on innervated and uninnervated myotubes were located immediately adjacent to muscle nuclei. This was an early hint that synaptic receptors were newly synthesized molecules. Jumping ahead in this narrative several years, additional evidence for the appearance of new AChRs came from measurements of AChR subunit mRNAs and from differential labeling of preexisting and newly inserted receptors. Fluorescence photobleaching recovery (FPR) measurements with Janet Dubinsky and Elliot Elson at Washington University showed that new AChRs were inserted centrally within receptor patches under neurites and not solely around the perimeter of such densely packed receptor clusters.

There was much to learn about neurons dissociated from embryonic spinal cord, brain, and peripheral ganglia. Neurons dissociated from E4–E7 spinal cords matured rapidly in sparse cell cultures. They generated action potentials and formed both excitatory and inhibitory chemical synapses with one another. Marc Dichter, newly arrived from New York University and his studies of epilepsy with Alden Spencer, was a great help in these early experiments. Subsequent studies of glutamate and GABA-mediated synapses and modulation of voltage-gated Ca channels were conducted at Harvard and Washington University.

Harvard (1973–1980)

I missed the breadth of a university environment and I enjoyed teaching, so despite all of the advantages of the NIH, after eight years, and much thought, I accepted a position in the Department of Pharmacology at Harvard Medical School. Irving Goldberg, a biochemist interested in antibiotics, was the chair. He had recruited a small but excellent faculty. The department had a distinguished history. Otto Krayer, the previous chair, came to this country after he was banned from all German universities for refusing to occupy a professorship from which a Jew was forced to resign on ethnic grounds. Krayer had perfected the heart-lung preparation for his own studies, and he built a department with expertise in cardiovascular pharmacology, addiction research, calcium metabolism, pharmacokinetics, and neuroscience. Indeed, Steve Kuffler moved to Harvard to join Krayer’s department in 1960 and was soon joined there by David Hubel, Torsten Weisel, Ed Furshpan, David Potter, and Ed Kravitz. This group split off five years later to form the Department of Neurobiology.

Krayer was disappointed with Harvard because of this split and other decisions that adversely affected the department that he had built over many years. He left Harvard and did not return until 1978 when Bernard Katz delivered the first Otto Krayer Lecture.

Kuffler was an important influence in my decision to move to Harvard. We first met at an SfN meeting in 1972, and we remained friends until his untimely death in 1981. Tennis, the Marine Biological Lab, and the nmj were our enduring shared interests. Kuffler had a genius for identifying simple preparations that allowed application of elegant techniques to answer important questions in synaptic biology. I was influenced by his work on the microphysiology and anatomy of the nmj. He was interested in our work on synapse formation in vitro. I also was influenced by the ongoing studies of Edwin Furshpan, David Potter, Story Landis, and Paul Patterson on the fate of autonomic ganglion neurons in sparse cell culture. They showed that the tissue culture environment influenced the transmitter synthesized by these neural crest derivatives. This remarkable, unexpected finding expanded our view of plasticity in developing neurons.

Among my first impressions of Harvard Medical School was the elegance of the Quadrangle, bordered by four classic marble research buildings with the elevated administration building at one end overlooking a spot of green in the midst of semi-urban Boston. Countway Library, a symbol of history and tradition in biomedical science, stood off to one side. Harvard University together with its affiliated hospitals was and remains to be one of the premier medical communities in the world.

We lived in Brookline in a handsome three-story house that Ruth discovered en route to the airport after a long day of house hunting. A large yard was great for the kids especially during the blizzard of 1978, when they constructed igloos (with my prize set of chisels) and small ski jumps. Our nearest neighbors, the Stroms and O’Briens, also members of the Harvard faculty, became close friends. Sinai Temple, a small congregation at Coolidge Corner, offered a meaningful experience at that time in our lives.

Jonathan Cohen joined the Department in 1975. Cohen came from the Institut Pasteur where he worked with Jean-Pierre Changeaux on Torpedo nicotinic AChRs and associated proteins. We met in 1972 during a biophysics summer school in Erice, Sicily. He remembers presentations by Bernard Katz, Rene Couteaux, and me (fine company) and thought it would be nice to collaborate. We did collaborate, eventually, on rapid Na flux measurements in cultured myotubes, and, years later, on the localization of neuregulin receptors at the nmj. Richard Zigmond arrived in 1975 from Les Iversen’s lab where he began his important work on tyrosine hydroxylase and catecholamines. Cohen, Zigmond, and I formed the core of our neuropharmacology group.

We organized the neuropharmacology part of the Medical Pharmacology Course. Others involved in that important course included Doug Waud, Peter Dews, Bill Morse, Roger Kelleher, Peter Goldman, Bob Rando, and Irv Goldberg. Waud’s emphasis on quantitative drug–receptor interactions, his encyclopedic knowledge of drugs, and his deep skepticism of the pharmaceutical industry were inspiring to students and to me. We also taught neuropharmacology to graduate students, and undergraduates at Harvard College.

During this period, Harvard was among the leaders in reform of the medical curriculum, determined to reduce the tedium of rote learning and to provide more opportunity for hands-on research experiences for students. In addition, four societies were created to bring together students at different stages of their education to share experiences and explore subjects of common interest, including current topics in biomedical science, along with a strong dose of medical history. I enjoyed and contributed to all aspects of these education reforms, and I became the founding master of the Fuller Albright Society.

Pharmacology was close, but not too close, to the Department of Neurobiology. I was welcomed in neurobiology activities, and I taught a course on developmental neurobiology with Patterson for six years. These facts are worth mention, as neurobiology did not welcome many outsiders in their crowded seminar room. Was this only a matter of space? In any case, such isolation eventually worked to their detriment. After Kuffler died and Torsten moved to New York City, the department stagnated. When I returned (from Washington University) in 1990 to chair the department, they had offered only one promotion to tenure in 26 years.

The Marine Biology Laboratory

Kravitz invited me to teach in the neurobiology course at the Marine Biological Laboratory (MBL) in Woods Hole, a job I loved and that became a major influence on my career and our family over the next 20 years. I shared responsibilities for the development section of the course with Story Landis. The talented students included undergraduates, postdoctoral fellows, junior faculty, and full professors seeking new approaches to their own studies. Students and faculty initiated much original research during the course. Softball, tennis, and swimming were mixed with four-hour lectures and late nights in the lab.

We lived in a small, rented MBL cottage each summer that was packed with our kids and their friends; our dog, cat, and fish; and with visiting cousins and grandparents. After five years, we bought a small house nearby and, then in 1982, after moving to St. Louis, we bought a home on a point of land jutting out into Buzzards Bay. Over the years, we renovated and rerenovated this house. It was a family project with major input from Mark, our architect son, and Elissa, our interior designer daughter. It was Ruth’s vision that brought us to this beautiful location, where we lived for the next 30 summers and where we gathered for family vacations and long weekends during the winter. It was her landscaping genius that made our Penzance Point home the most loved and valuable property that we have owned.

Nerve-Muscle Synapse Formation (continued)

Work on the formation of nerve-muscle synapses continued with the help of talented students and postdoctoral fellows. Our lab meetings were full of data and excitement. We demonstrated that AChRs were clustered precisely at newly formed synapses by focal extracellular recording and stimulation, but we still did not know whether competent axons sought out preexisting clusters or induced new ones. We approached this question by first increasing the likelihood of identifying competent axons before and after they formed functional contacts. The most successful procedure was to add small fragments of E4 ventral horn tissue to preplated myotubes. This maximized the number of cholinergic axons in the outgrowth zone and the rapid formation of nerve-muscle synapses close to the explant.

The next step was to follow growth cones as they contacted and innervated myotubes. Eric Frank developed a semi-automated mapping protocol in which the iontophoretic electrode tip was photographed immediately after the optimal response was obtained at each site. In this way up to 50 sites could be mapped at one sitting, and the same site could be relocated hour after hour and day after day. Hot spots were mapped with a resolution of less than 5 microns. The answer was clear. New AChR clusters appeared at new synapses. Noncontacted clusters near a developing synapse often disappeared with the onset of synaptic transmission. Perhaps the fluidity of the membrane in the vicinity of the synapse is altered. An increase in AChR mobility near growth cones was, in fact, found some years later by fluorescence photobleaching recovery experiments at Washington University in collaboration with Janet Dubinsky and Eliot Elson.

Uninnervated as well as innervated muscle cells near the explant contained more membrane AChRs and many more AChR clusters than did uninnervated muscle cells located farther away in the same culture dish. These powerful images added to our conviction that AChR-inducing substances emanating from the spinal cord tissue were at work.

Immobilization of AChRs within clusters does occur. Indeed, aggregation of preexisting surface at newly formed Xenopus neurite–myocyte contacts was demonstrated by Monroe Cohen, and by other workers in mammalian co-cultures. We found that newly synthesized receptors in chick and mammalian myotubes contribute to new clusters as well. They are distributed throughout the cluster from the start rather than aggregated around the edges.

When is a growth cone “competent” to form a synapse? We evoked the release of ACh from growth cones by focal depolarization within minutes of contact with a myotube. We found that growth cones can release ACh even before muscle contact. A novel “patch-sniff” bioassay was developed in which an outside–out patch of AChR-rich muscle membrane was placed adjacent to a growth cone as it emerged from the cell body and migrated over the tissue culture surface. When the neuron was stimated, a shower of channel openings was evident.

Transmitter release occurs early, but the entire process of synapse formation is a drawn-out affair. In the first weeks after birth, the mean quantal content of evoked endplate potentials increases dramatically, the mean AChR channel conductance increases, the mean channel open time decreases, and the half-life of AChRs in the surface membrane increases from less than 24 hours to more than one week.

Steve Schuetze in my lab initiated studies of ACh channel conductance and mean channel open time and metabolic stability of synaptic and extrasynaptic receptors in vitro and in vivo. He found that the mean channel open time of AChRs on chick and rat myotubes was 4 msec compared with 1.5 msec at mature endplates. The channel properties at rat junctions changed during the first week after birth. And the half-life of receptors in the surface membrane increased dramatically from 18 hours to several days. The properties of chick receptors did not change over the same time course. I believe that the ease of working with dissociated muscle cells and neurons in cell culture facilitated the entry of many scientists to the patch clamp industry.

Schuetze, an extraordinary student and scholar and friend, was tragically killed in a bicycling accident years after he left my lab while on vacation from Columbia University with his wife and friends.

The Search for an Acetylcholine Receptor-Inducing Activity

We began the search for an acetylcholine receptor-inducing activity (ARIA). A plunge into biochemistry was the obvious next step. Tom Jessell, newly arrived from studies with Leslie Iversen, was important in these early experiments. Jessell was fearless and enthusiastic, and his broad critical knowledge of biology was as remarkable then as it is today.

Together with Ruth Siegal, we found that saline extracts of embryonic chicken brains increased the total number of AChRs and the number of receptor clusters on cultured chick myotubes. The activity was destroyed by trypsin, and it was selective in that overall protein synthesis was not changed. A similar activity was secreted into the medium by cultured spinal cord cells. We presumed, of course, we had the factor responsible for inducing synaptic AChR clusters in these extracts. We made regular trips to a slaughterhouse in South Boston, put on boots, and collected heads falling from slaughtered chickens. Fortunately, we soon discovered a source of dissected and frozen chick brains.

While at Harvard, we refined the bioassay and applied several new purification steps. Myoblasts were plated in 96 well plates so each point could be measured in quadruplicate. The rate of appearance of new 125I-BTX binding sites was measured after blocking all surface sites with unlabeled BTX. Precise dose response curves then could be constructed, which showed a marked increase in the rate of AChR incorporation with no change in the rate of degradation. A large percentage of the receptor-inducing activity was soluble in 2 percent trifluoroacetic acid (TFA) and was further purified by reverse-phase high-pressure liquid chromatography. Susan Leeman was a great help at this stage as she shared her expertise and reagents for peptide– protein purification.

Efforts at purification were continued at Washington University. A 42 kD glycoprotein, purified 1.5 million fold, was effective at 10−9 M concentrations. We named this protein ARIA, for its acetylcholine receptorinducing activity. Ted Usdin, an MD/PhD student, deserves great credit for developing and perfecting several new (to us) biochemical steps in this series of experiments.

Final purification of ARIA and isolation of a full-length cDNA was published in 1993 after I returned to Harvard. Doug Falls, David Harris, and Ken Rosen, postdoctoral fellows at the time, played key roles in this effort. The cDNA showed that the purified 42 kD ARIA was the extracellular domain of a large transmembrane precursor protein. The extracellular domain contained an Ig-like domain and a 55 amino acid EGF-like domain that we showed was the active part of the molecule in inducing AChR synthesis. Was this the low-molecular-weight activity detected in our first attempts at purification 10 years earlier? We subsequently found that pro-ARIA is cleaved near the cell membrane and the extracellular fragment binds to heparin sulfate proteoglycans in the extracellular space, probably via the Ig domain.

It was immediately obvious that chick ARIA is homologous to the rat Neu differentiation factor and human heregulin, ligands for the family of erbB receptor tyrosine kinases. Recombinant ARIA, in fact, did induce tyrosine phosphorylation of a 185 kD muscle protein. ARIA is also homologous to glial growth factor (GGF), a protein that was also purified and sequenced at about the same time based on its ability to stimulate the proliferation of Schwann cells. The science community adopted the name “Neuregulin” (NRG) for this family of proteins. Subsequent work at Washington University, Harvard, the NIH, and Columbia addressed the mechanism of action of Neuregulin (NRG), its likely relevance at the nmj, and its actions in the brain.

Neurotransmitter Receptors in Spinal Cord and Sensory Neurons

During this time at Harvard, we also investigated the GABA responses of spinal cord neurons, GABA-mediated synaptic potentials, and the modulation of submaximal GABA responses by benzodiazepines. Denis Choi and David Farb took the lead in this series of experiments. We discovered that submaximal GABA currents were enhanced by chlordiazepoxide, an allosteric modulation of GABA receptors that had not been described previously. We suggested that such an action might account for the anti-anxiety properties of benzodiazepines, soon to become the most commonly prescribed drugs in America, but were criticized by reviewers because there was no evidence that chickens experienced anxiety.

Kathy Dunlap, Alcmene Chalazonitis, and Ann Mudge studied dorsal root ganglion (DRG) neurons. Thanks to NGF and high K, these cells survive well in sparse cell cultures. Kathy explored the Ca component of DRG action potentials. GABA, noradrenaline (NA), and serotonin (5-HT) all decreased the Ca2+ component of the soma spike, which pointed to roles in presynaptic inhibition. Enkephalin also inhibited the DRG Ca spike. This inhibition was accompanied by a decrease in substance P release, consistent with modulation of nociceptive inputs at the spinal cord level. Richard Tsien had studied modulation of Ca currents in cardiac muscle, but our work was among the first to demonstrate modulation of voltage-gated ion channels by neurotransmitters in neurons. This was indeed a productive period in my lab.

Washington University (1980–1990)

After 15 years of intense focus in my own lab, I had begun to think about a wider sphere of responsibility when I was offered the opportunity to chair the Department of Anatomy and Neurobiology at Washington University. Max Cowan, the former chair, had built a strong department based on new neuroanatomical tracing techniques. Modern aspects of cellular and molecular neurobiology did not advance at the same pace. With strong encouragement from Herman Eisen, who had spent 18 years at the university, and from members of the university faculty, including Cuy Hunt, Phil Needleman, and David Kipnis, we decided to uproot our family and move to the Midwest. Elissa was off to college. Peter, Mark, and Neal were ready for something new.

Many factors went into the decision. Mainly, I was attracted by the distinguished academic history of the university and by the excellence of the current faculty. In addition, we were impressed with the calming beauty of suburban St. Louis. I frequently rode my bike from our home in Clayton across Forest Park, past the Museum of Fine Arts, to the Medical Center. A significant rebirthing of downtown St. Louis was under way, spreading out from the inspiring Arch along the Mississippi River. The symphony conducted by Leonard Slatkin was excellent, and it was accessible. The St. Louis Cardinals were thrilling. Hot humid summers were “tolerated” from our home in Woods Hole.

Dean Kenton King and Vice Chancellor Sam Guze led the Medical Center. King was a quiet leader who demonstrated over and over again how the faculty could achieve great things by working closely with rather than at the expense of others. Guze was chair of psychiatry with a strong sense of the medical school’s academic mission. William Danforth, president of the university, was formerly vice chancellor for medical affairs, and he remained deeply interested in medical science. His love of the university and St. Louis had a great influence on me. I had not experienced the same degree of cooperation before coming to Washington University, and I have not enjoyed it as consistently ever since. This community made my move into more administrative duties easy and rewarding. I did not negotiate a start-up package as I was convinced that the school’s leadership would do everything possible to help me succeed. And they did.

The preclinical and clinical department chairs met each month in a forum called the Executive Faculty to debate issues of importance to all. They were meaningful and candid debates that taught me a great deal about American medicine and about constructive interactions with partner hospitals.

Ruth and I took part in university intellectual life beyond Medical Center. We attended regular soirees at the home of Eli and Lee Robbins along with members of the English, philosophy, and history departments. Our neighbors in Clayton, Att and Bob McDowell, who was formerly chair of mathematics, brought us even closer to the Arts and Sciences on the main campus. Extensive conversations with Viktor Hamburger in my office and at his home in University City gave me his personal view of neuroembryology, beginning with the embryonic organizer experiments of Hans Speemann and Hilde Mangold, his own early experiments on programmed cell death in the nervous system, and his early collaboration with Rita Levi-Montalcini.

Among those I recruited to the Washington University faculty were Larry Salkoff, Paul Taghert, Jeanne Nerbonne, Andres Burkhalter, Karen O’Malley, and Glen and Jane Phillips Conroy. Glen and Jane are physical anthropologists who carried on the tradition of comparative anatomy in medical school teaching established by the original department chair, Robert Terry, and Mildred Trotter. They became perennial Teachers of the Year. Josh Sanes and Jeff Lichtman joined the department after Cuy Hunt stepped down. And I helped recruit Joe Henry Steinbach and Chris Lingle, bot superb biophysicists, to the Department of Anesthesiology. Dale Purves, a talented neuroscientist and author, left to chair the Department of Neurobiology at Duke.

I became the founding director of the McDonald Center for Cellular and Molecular Neurobiology and, with time, I also directed the McDonald Center for Higher Brain Function. These centers played important roles in bringing faculty together across disciplines and across the basic and clinical departments, a theme that I promoted later at Harvard and Columbia.

Further Studies of Muscle and Neuronal AChRs

As noted earlier, several studies of AChR accumulation in ARIA- and NRG-treated myotubes were performed during this time at Washington University. At the same time, experiments on muscle AChR clusters induced by ciliary ganglion neurons were initiated by Lorna Role. AChRs accumulate at about 80 percent of the growth cones during the first 24 hours after muscle cultures are seeded with this relatively pure source of cholinergic neurons. Double labeling techniques showed that 80 percent of these receptors were “new”—that is, they were not in the surface membrane before innervation during the first 48 hours of co-culture. Kathy Engisch found a sevenfold increase in nicotinic α7 AChRs in chick ciliary ganglion neurons between embryonic days 6 to 18. The increase occurred despite ablation of the ganglions’ target (eye) or inputs (accessory optic nucleus).

Regulation of Glutamate and GABA Receptors

In parallel with our studies of muscle and neuronal nicotinic AChRs, we studied effects of innervation on neuronal glutamate receptors. Motor neurons grown together with interneurons were six times more sensitive to glutamate than were motor neurons grown alone. Interneurons also altered the distribution of glutamate receptors. Sharp peaks of sensitivity were found along motor neuron dendrites when they were grown together with interneurons. The parallel with regulation of muscle AChRs by synaptic inputs is striking. To my knowledge, no effort has yet been made to isolate potential inducing factors.

Another interesting parallel with neuron muscle interaction is the observation that more than 25 percent of the motor neurons were dye coupled to nearby interneurons during early stages of synapse formation. Direct coupling was not detected after the first week in vitro.

Richard O’Brien led the spinal cord studies. I met O’Brien at Harvard where he was a medical student. He completed his thesis research in St. Louis before returning to Harvard and the Massachusetts General Hospital. In addition to his own work, Rich improved the work of other students in my lab, students in other labs, and many of the faculty. He is a gifted, inspiring physician and scientist.

During this time at Washington University, Larry Trussell conducted a remarkable series of experiments on rapid desensitization of glutamate receptors. He found that desensitization was fast enough to terminate synaptic currents. Thus receptor desensitization must be considered along with diffusion and reuptake to be a mechanism for terminating glutamate action. He also found that steady-state desensitization occurred at concentrations far below those needed for receptor activation, implying that spontaneous release of glutamate at or near synapses may regulate the efficacy of glutamatergic synaptic transmission.

Harvard Redux (1990–1998)

In 1990, important projects in my lab were in transition, and our youngest children went off to college. Therefore, when an extraordinary offer came from Harvard, we considered it carefully and, once again stepped into the unknown. Ruth was sad to leave Boston in 1981, but she was even sadder to leave St. Louis. She had thrived in the Department of Psychiatry completing her PhD thesis (from Boston University) and a master’s degree in psychiatric epidemiology, initiating important projects in medical sociology and neuroethics, and taking on important teaching roles.

As noted earlier, the Harvard Department of Neurobiology was known for its cloistered environment. No joint appointments were made, and they brought only one scientist forward for promotion to tenure in the previous 26 years. In the next nine years, we recruited nine investigators to the Quadrangle Department. Eight were promoted to tenure (Wade Regher, Linda Buck, Rod MacKinnon, Chuck Weitz, Clay Reid, Gary Yellen, John Assad, and Rick Born). Two, Linda Buck and Rod MacKinnon, went on to win Nobel Prizes. Elio Raviola and David Paul were invited to join the Neurobiology Department when the Anatomy Department was transformed into a Cell Biology Department under the leadership of Marc Kirschner. In addition, we offered appointments to scholars in hospital-based departments, including Mike Greenberg, David Clapham, Clifford Woolf, Richard Masland, David Corey, and Steve Hyman. The sense of community was further enhanced when we abolished the Neurobiology Graduate Program and took a leadership role in the school-wide Neuroscience Program.

My labs at the Quadrangle were not ready in 1990 so my first scientific home on returning to Boston was located in Charlestown in the MGH research building. I was asked to chair the MGH Executive Committee on Research so I got a broad overview of this remarkable institution, including its affiliate MacLean Hospital. The plain fact is that the hospital’s neuroscience community was more diverse than Harvard’s Neurobiology Department. But my love for the Quadrangle community was strong and that just added to my motivation.

I want to single out two recruits. Linda Buck wanted to exploit her remarkable discoveries made with Richard Axel regarding the mega-family of olfactory receptors. It was a difficult time for her with a small lab, but she advanced stride for stride with the larger, talented, well-funded Axel group. And she succeeded brilliantly. She received as much financial and emotional support as I could provide. Chuck Weitz, rather than pursue his successful postdoctoral work with Jeremy Nathans on photopigments, switched fields to study the molecular workings of circadian clocks. He wrote excellent grants, but none were funded despite excellent reviews. He followed his interests and did not give up and now is a leader in this rapidly evolving field. Our ability to support him through such difficult times might not be possible to duplicate in the current funding environment.

These were wonderful years at Harvard. We worked together, argued together, and laughed together. Jon Cohen and Bruce Bean stand out in my mind. Both focused on ion channels, Bean via electrophysiology; Cohen via biochemistry and molecular pharmacology. Both are role models of what an academic scientist should aspire to. Cohen has a high quotient of common sense that I found invaluable in my attempts to manage science in the department and in my own lab. Scores of neuroscience graduate students owe him a great debt of gratitude.

A rather unique effort during these years was the establishment of the Mind, Brain and Behavior (MBB) Initiative. Neil Rudenstein, the president of the university, called for proposals that would bring together scholars from departments throughout the university. Steve Hyman was involved from the start. MBB began as a discussion forum involving members of various departments, including psychology, biology, and English, as well as members of the business school and medical school. Our hope was that it eventually would include interdisciplinary research, but financial pressures stalled that effort. Within one year, MBB became the second largest concentration for Harvard undergraduates. The name and the interdisciplinary philosophy of the Harvard MBB Initiative were adopted some years later by Columbia University for their ambitious neuroscience project in Manhattanville.

Further Studies of NRG/ARIA at the nmj and in the CNS

Several experiments conducted at this time provide additional evidence for roles for NRG/ARIA at the nmj and in the CNS. We found that NRG immunoreactivity and mRNA are present in embryonic motor neurons and the protein is concentrated at nmjs soon after the arrival of motor axons. Jeff Loeb found that NRG accumulated along motor axons and in the synaptic cleft in association with heparan sulfate proteoglycans. NRG epitopes, identified by immuno-gold EM are associated with the presynaptic side of the cleft basal lamina as expected of a factor released from the nerve terminal. In collaboration with Cohen, we showed that the NRG receptors erB2 and erB4 were located in the depths of the secondary postsynaptic folds at the adult rat nmj. Gabriel Corfas found that NRG increased the number of voltage-gated Na channels in myotubes adding to our notion that this trophic factor increased the safety factor for neuromuscular synaptic transmission.

Al Sandrock led a group in my lab that prepared and studied NRG heterozygous mice and showed that the NRG-deficient mice were myasthenic. This was brought out during repetitive stimulation in the presence of low doses of curare. The AChR density at motor endplates, as judged by mepp amplitude and BTX binding, was reduced in the heterozygotes.

Despite this evidence for the importance of NRG, it seemed likely in 1993 and even more so in 2016, that NRG was probably not the sole factor influencing the accumulation of AChRs at developing nmjs. As expected of complex biologic phenomena, other inducing substances may serve the same or supplementary functions. AGRIN, identified by Jack McMahan in the early 1980s based on its ability to promote aggregation of muscle AChRs, was a likely candidate. Steve Burden has provided strong evidence that AGRIN, acting through its recently discovered receptor Lrp4 and the muscle specific kinase (MuSK) are important regulators of AChR accumulation at developing nmjs.

NRG is expressed in cholinergic neurons throughout the rat brain, including cranial motor nuclei and the nucleus basalis. It is not restricted to cholinergic neurons. Nerve terminals on spinal motor neurons are intensely labeled. NRG is expressed throughout DRG, but the α1NRG isoform is present only in the smallest neurons and only in the most superficial lamina in the spinal cord. Perhaps this molecule is involved in the regulation of pain at the spinal cord level. NRG is abundant in the molecular layer of the cerebellum. Bomie Han found that NRG is processed and released from subcellular fractions containing synaptosomes.

NRG also may be involved early in neuronal development. Cells in the germinal (subventricular) zones of the embryonic and early postnatal cerebellum and telencephalon were heavily labeled, suggesting roles for NRG in the proliferation or migration of neuronal and glial precursors. Interest in central actions of NRG has grown over the years. Members of the NRG and erbB families have been implicated as risk genes in autism, schizophrenia, and other neuropsychiatric disorders.

Tim Vartanian, a neurologist interested in multiple sclerosis, joined my lab at this time. We found that NRG promoted the proliferation of oligodendrocyte/astrocyte precursors (O2A cells) via actions on erB2 and erB4 receptors. NRG also promoted the proliferation of Schwann cells, but in this case, the effect was mediated via action on erB2 and erB3 receptors. This work added to the growing interest in neuron–/glia trophic interactions and demyelinating disorders.

The Salk Institute

I was invited to become a nonresident fellow of the Salk Institute in the late 1980s, and I remained in that role for more than 12 years. My first contacts with the Salk Institute began in the early 1970s when I became aware of the work of Steve Heinemann, Jim Patrick, Dave Shubert, Joe Henry Steinbach, and their colleagues on transformed muscle and neuronal cell lines. Subsequently, I followed Heinemann’s work in the molecular coning and characterization of nicotinic AChR receptor and glutamate receptor subunits. Like the MBL, the Salk Institute became a major influence on my development as a scientist and as a citizen of the larger community of life scientists.

Nonresident fellows attend faculty meetings and research retreats. They are encouraged to spend significant periods of time on campus at any time of the year. They contribute to the evaluation of candidates for promotion to tenure, they mentor junior faculty, and their comments are sought on major new research programs at the Salk Institute. In other words, it is a serious commitment. But it was always a rewarding experience as well, and over the years, a remarkable group of Young Turks on the faculty evolved into an even more remarkable set of Middle-Age Turks who assumed a great deal of responsibility in building and governing the Salk Institute. Inder Verma, Ron Evans, Wylie Vale, Terry Sejnowski, Joanne Chory, Chuck Stevens, Tom Albright, Rusty Gage, and Heinemann, among others, became world leaders in their fields. The next generation of Salk neuroscientists, too numerous to list here, is extremely strong.

Many Salk scientists lived on the edge without the advantage of a large Salk endowment. They received many attractive offers to move, but few left. I can think of three reasons for this seemingly irrational behavior. First is the physical beauty of the Louis Kahn–designed campus. The main patio grooved along its entire length by a flowing canal that seems to cascade off the edge of the earth into the Pacific Ocean and beyond suggests the limitless possibilities of fundamental science. Second is the strong sense of community. The layout of the labs contributes to this coming together, but mutual respect and years of collaboration and friendship is unmatched in my experience. Third is the growth of the surrounding biomedical community led by the closer ties to the neighboring University of California–San Diego (UCSD). New MRI technologies and stem cell research facilities, developed in collaboration with UCSD, are important added resources for Salk scientists.

NIH Redux (1998–2001)

When Harold Varmus, then director of the NIH, offered me the position of director of the NINDS, it made me rethink my priorities once again. Since my first experience at the NIH in 1966, I have had a high regard for the institution. Our universities are the envy of biomedical scientists the world over largely because of NIH-funded research. In 1953, when Ovita Culp Hobby dedicated the Clinical Center at the NIH, the NIH budget was $12 million. As of 2016, it is more than $30 billion. The impact of an active NIH director in influencing the course of science is difficult to overestimate.

I had addressed national and international audiences before, but the bully pulpit of an NIH director backed by a $1 billion plus budget is on another level. I traveled widely in this country, Europe, England, China, and Japan. Everyone I met wanted to emulate the NIH policy of funding science based on peer review rather than local politics.

Ruth was attracted to the NIH as well. Always the idealist, she saw the need to consider ethical issues on a national scale. Also, happy memories of our first tour at the NIH and our lifelong friends in Bethesda were important considerations.

Colleagues in Boston questioned my judgment in leaving the extraordinary faculty and students at Harvard to work with civil servants, demanding patient advocates, and self-centered members of Congress. But I found dedicated, talented scientists among the NINDS. The passion, knowledge, and firsthand experiences of advocacy groups were inspirational. Varmus had assembled a strong team of NIH directors and spirits were high as the NIH was in the middle of a five-year doubling of its budget.

Within NINDS, I worked with extraordinary people. The talented chief operating officer, Kevin Kirby, coordinated the efforts of Story Landis, director of intramural research; Connie Atwell, director of extramural research; and Mary Meirs, director of science policy and analysis; and he helped guide our large science staff. He also helped junior and senior officers achieve their full potential. We abolished long-standing fiefdoms within the NINDS and delegated more authority to junior staff members. Spirits soared and so did productivity.

Parkinson’s disease was a major focus. At the request of Congress, I led several other Institutes in composing a blue sky Parkinson’s disease plan that called for a $1 billion budget. L-DOPA, introduced in 1957, is a “miracle” drug that can reverse or reduce the three cardinal symptoms of Parkinson’s disease, but the beneficial effects wear off in time, and debilitating side effects, including dyskinesias, come to the fore.

Deep brain stimulation (DBS) of neurons within the basal ganglia had been successful in selected cases, and the first results called for more intensive efforts. Mahlon DeLong, who became involved in NINDS programs during my tenure as director, shared the 2014 Lasker Award for his brilliant and brave work with nonhuman primates on the physiology of the basal ganglia and their roles in movement disorders. He identified the subthalamic nucleus as a key point of intervention. DeLong shared the Lasker Award with Amin Benabid who refined surgical and stimulation protocols so that they now benefit hundreds of thousands of patients.

In my first encounter with the Senate Appropriations Committee, I was put on the spot by the chair Arlen Spector when he asked when I thought we would cure Parkinson’s disease. I hesitated citing recent advances but also explained that future advances were difficult to predict. He did not relent in his demands to know if it would take 5 or 10 years. I said, “within 10 years—I hope.” I have not yet lived that down and can still hear the gasps of my fellow NIH directors. My reasoning depends on the word “cure.” DBS is not a cure in that the degenerating dopaminergic neurons are not restored or replaced, but it is a cure in that normal function can be restored and maintained, in some cases, for more than 15 years. Not bad for a neurodegenerative disorder.

Working together with extramuaral and intramural scientists and with strong advocacy groups, the staff organized a series of workshops that changed the course of research in several areas. One effort that stands out in my mind was a White House–supported conference on “Curing Epilepsy: Focus on the Future.” The emphasis of this meeting, which took place in 2000, was on mechanisms of epileptogenesis and their reversal rather than on symptomatic treatments. Benchmarks were established that have been reviewed periodically over the past 15 years. Cures have not yet been achieved, but a feeling of optimism persists.

Other major efforts during my stay at NINDS included the following: revision and expansion of our clinical trials program; a new effort in highthroughput screening for therapeutics to treat rare “orphan” diseases; a renewed emphasis on multiple sclerosis; supporting emergency room stroke centers to facilitate rapid diagnosis and treatment; an expanded program to improve treatment of spinal cord and brain injury; numerous presentations before Congress; and improved communication about neurological disorders, working with Marion Emr to create a revitalized go-to website.

We encouraged collaborations via Program Project Grants (R01) and U54 contracts. But the emphasis remained on individual investigator R01 grants. About 80 percent of our grants each cycle were awarded based strictly on review panel recommendations. That left 20 percent to be selected by the staff, sometimes out of order, based on the originality and promise of the work and the needs of the field. This is a responsibility we all accepted.

Perhaps my most enduring legacy at the NIH is the role I played in creation of the John Porter Neuroscience Center. I understand the special interests that convinced Congress to create separate Institutes, but a case can be made that the science underlying psychiatric and neurological disorders, substance abuse, communicative disorders, aging, and vision is coming closer together. Scientists funded by the separate Institutes have a lot to learn from each other. It made sense to set an example for the nation by bringing labs in different Institutes together in one building. This dream was initiated with Steve Hyman and Bob Desimone from NIMH and Story Landis in NINDS. The magnificent 600,000-square-foot building is now a reality on the NIH campus. It is a fitting tribute to John Porter, congressman from Illinois, who helped shape the NIH budget during the doubling years.

Continued Laboratory Research

Experiments on neuronal nicotinic AChRs continued at the NIH with Y. Liu and Q. Chang. Chronic application of NRG increased the number of α7-nAChRs in hippocampal pyramidal neurons and on GABAergic interneurons. In addition to this effect on neuronal receptors, we found that NRG increased the proliferation of neuronal precursors isolated from E11 mouse telencephalon. Mary Anne Mann, who moved with me from Harvard, managed the lab and continued our experiments on nerve-muscle synapses. I enjoyed walking from my office in Building 31 up the hill to my lab in Building 36 where I worked so many years ago.

Dark Clouds Form

In 2001, after a period of five years in which the NIH budget was doubled, dark clouds gathered on the horizon that are still very much with us. Budgets were flat or cut, and the purchasing power in the research market plummeted. Earmarks from Congress kept coming, but with no added money. Such requests are important in that they serve to focus attention, but without added funds, other disorders and basic research are further squeezed. I also worry about the length of time it takes a young scientist to achieve independence. On average, the first independent NIH grant is received at age 42. I was a tenured professor at that age and the father of four children.

My departure from the NIH was unexpected but it was inevitable. When Harold Varmus announced his retirement, Donna Shalala, secretary of U.S. Department of Health, Education, and Welfare, nominated me to replace him as the NIH director. Shalala was informed about the NIH and was sensitive to the political climate in Washington. She was also bold. Realizing that any nomination was at risk in the final months of the Clinton administration, she decided it was worth the effort. After weeks of positive interviews on the Hill, and meetings with FBI investigators, the relevant senate committee was reluctant to confirm my nomination.

My advocacy for human embryonic stem cell research may have been an unstated factor. The Dickey/Wicker amendment to the U.S. Department of Health and Human Services (HHS) appropriations bill, adopted in 1996, prohibited the creation of stem cell lines from human embryos using NIH funds. My strong statements in favor of human stem cell research would have been appreciated during my first tour at the NIH in 1970, but we were in a different era in 2001, and I was at risk. When it became clear that politics might prevail, the secretary, reluctantly, decided that the best path forward for the administration (and for me) was to withdraw the nomination. Lawyers inside and outside of HHS advised me to consider leaving government service.

Columbia University (2001–2006)

My decision was made easier when Columbia offered an interesting alternative. George Rupp, then president of Columbia University and Jonathan Cole, provost, recruited me as executive vice president (EVP) for Health Sciences and dean of the Medical School. This is a big job at Columbia, as the deans of four schools (Dental, Medicine, Public Health, and Nursing) and the College of Physicians and Surgeons (P&S) report to the EVP. Despite this, I asked that my title be expanded to EVP for Health and Biomedical Sciences. Significant challenges included a large structural deficit and a severely balkanized medical center with 384 independent business units. This Tower of Babel needed a coherent sense of community beyond their own microenvironments. Rupp and Cole were enormously helpful as I was forced to learn on the fly.

Once again, Ruth gave up a rewarding position to begin anew in a different context. She helped in many ways over the next five years especially as a strong partner in many fundraising ventures. She also established a university-wide Center for Bioethics, contributed to training programs, and established new courses for medical and graduate students. Her Ethics for Lunch program organized with Ken Prager and supported by the Arnold P. Gold Foundation remains an important forum for discussion of difficult ethical issues that arise during the course of hospital practice.

Our move to Manhattan completed an odyssey from New York City to Seattle to Bethesda, to Boston, to St. Louis, back to Boston, back to Bethesda, and, finally back to New York City. I assembled a strong administrative staff that included Kevin Kirby (COO), who joined me from the NIH; Michael O’Conner (CFO); Harvey Colten (academic affairs); Joe Tennenbaum and Eric Rose (clinical affairs); Marian Carlson (research affairs); Marian Jakubiak (executive assistant); and Marion Greenup (operations officer).

We embarked on a planning process that addressed research, education, and patient care in each of the four schools. In collaboration with the New York–Presbyterian Hospital, we also conceived a long-range space plan for growth of the Medical Center. More than 200 faculty, students, and administrators were involved. When we began, spirits were low as the NIH budget continued to fall, and the horror of the September 11 terrorist attacks that occurred in plain view from Washington Heights became a chronic worry.

Perhaps our most significant accomplishment was a change in spirit throughout the Medical Center. The atmosphere was more open, hopes were raised, and enthusiasm was high. I believe that the Medical Center was on a better tack when I stepped down in 2006. Some specific accomplishments follow.

The Herbert Irving Cancer Center was completed and a new director, Ricardo Della Favera, was appointed. The Human Genome Center was revitalized with the recruitment of James Rothman, a future Nobel Laureate, as director. A new Center for Computational Biology was created under the leadership of Andreas Califano and Barry Honig. The sophisticated mathematics and statistics promoted by this center hold the keys to a better understanding of the human genome and the future of therapeutics. A new Motor Neuron Research Center was established, and the renowned Center for Neurobiology and Behavior was transformed into a Department of Neuroscience to give the program a “place at the table” of medical center affairs. A new dean for Dental Medicine was appointed, and, at the medical school, new chairs were recruited in genetics, physiology, psychiatry, ob/gyn, medicine, and anesthesiology. Interim chairs were appointed in biochemistry, microbiology, radiation, oncology, and pediatrics.

Nearly all of the endowed chairs at Columbia Medical Center had been donated by grateful patients and resided in clinical departments. Over the course of five years we established many chairs in preclinical departments. P&S alumni are among the most generous in the university. A Health Science Council was established to raise awareness and help raise additional funds. Roy Vagelos, a P&S alumnus, was the first director of the council. Our goal was raise $1 billion, and we came close by the time I stepped down.

At the request of the New York Police Department, Fred Kass, now vice chair of psychiatry, and Dr. Ellen Stevenson organized a remarkable effort to treat thousands of New York City policemen and firemen who suffered from post-traumatic stress disorder following September 11. Confidentiality was essential to maintain job security and avoid stigma. This remarkable, still underappreciated, effort is a wonderful example of how talented university faculty can help their community.

The faculty practice plan is a $500 million-plus per year business, but many physicians were dissatisfied over issues ranging from electronic medical records, billing procedures, physical resources, compensation, and governance. This income adds significantly to the borrowing capacity of the university so the trustees were rightly concerned. We radically changed the plan, now called Columbia Doctors, granting greater autonomy to the physicians. This overhaul took two years to accomplish as visits were made to medical centers across the country and an executive director of the plan was recruited. Physicians tell me that this transformation will be my greatest legacy at Columbia.

A significant effort was devoted to revamping the medical school curriculum with an emphasis on tools for self-learning. The Glenda Garvey Teaching Academy was established to enhance the teaching mission throughout the health sciences, with divisions in each of the four schools at the medical campus.

Renovation of the library was begun. Discussion of a new student education center was given impetus by a pledge from Roy and Diana Vagelos. We did not accomplish all of our goals. A center for outpatient medicine and a hotel for families to be constructed on the 165th Street parking lot remained a dream. A new neuroscience research building at the Medical Center was put aside as plans for the university-wide MBB Initiative evolved.

With the merger of the New York Hospital and Presbyterian Hospital, the name Columbia Presbyterian Medical Center no longer existed. Something had to change. After a great deal of consultation, we decided on a new name, the Columbia University Medical Center. Objections were raised. Many distinguished faculty bore the Columbia Presbyterian Medical Center name proudly. The schools of nursing and public health felt that their unique missions were not sufficiently recognized. Despite the challenges and distractions, the new brand gradually took hold. Marilyn Laurie, a trustee with expertise in rebranding efforts, was particularly helpful.

The New York–Presbyterian Hospital presented many benefits and many challenges. Our interests were aligned, but they were not always identical. When one hospital is dealing with two academic centers, there are bound to be tensions and disagreements. We reached agreement on appointment of clinical department chairs and many other matters, including insurance claims and academic programs of mutual interest. We struggled to maintain hospital affiliations that were steeped in history and social awareness, including Harlem Hospital, Mary Imogene Bassett, and St. Lukes–Roosevelt. Business decisions often carried the day.

The university also had interests that were aligned with the Medical Center but were not always identical. When money is in short supply, tensions emerge. When I arrived, Rupp and the trustees were considering a major expansion of the campus. Two options were discussed: a large area between 125th and 133rd Street, Broadway, and the Hudson River versus a comparable area downtown, farther away from the Medical Center. In my role as EVP for Biomedical as well as Health Sciences, I had spent significant time trying to integrate neurosciences, psychology, molecular biology, and electrical engineering across the campuses at Morningside Heights and Washington Heights, so I advocated strongly for the former. Manhattanville, as the 125th Street option came to be called, is a grand vision now being realized by President Lee Bollinger and his team. The lead project in Manhattanville is a new building to house the MBB Initiative headed by Tom Jessell.

There are only 24 members of the Columbia University Board of Trustees, most of whom focus on the Morningside Heights campus. The small Health Sciences Trustee Sub-Committee knew little about the inner workings of the medical campus in Washington Heights, but they were eager to learn. We initiated regular meetings uptown, including tours of the physical plant, and I offered a series of Medical School 101 tutorials. They were shocked to realize how little the university contributed to salaries or research funding for even the most distinguished medical scientists. This, of course, is not unique to Columbia. As the trustees learned more, their enthusiasm grew.

When I accepted the EVP position, I believed that this individual, like a lab chief, or a department chair, or even a NIH director, could be a role model for faculty and students of every stripe. I now understand Samuel Johnson’s sentiments expressed in the preface to the first edition of his Dictionary of the English Language (1979).

It is the fate of those who toil at the lower employments of life—to be exposed to sensure [sic], without hope of praise; where success would have been without applause and diligence without reward. — Among these unhappy mortals is the writer of dictionaries [EVP for Health Sciences] —. Every other author may aspire to praise; the lexicographer [EVP] can only hope to escape reproach —.

The dictionary worked out well for Johnson, and the Columbia EVP job worked out well for me. I am proud of our accomplishments during a difficult time in academic medicine.

My lab remained active throughout this hectic period, but with much less input from me. Marian Mann, a former student at Harvard, who moved with me to the NIH, and then to Columbia, carried the ball as Senior Research Assistant. We collaborated with Bob Darnell at Rockefeller University who found that AGRIN was regulated by the transcription factors NOVA1 and NOVA2. We found that when AGRIN was restored in NOVA1, 2 knockouts, synaptic AChR clusters reappear, but the mice remain paralyzed. A proximal deficit, perhaps on motor neuron excitability, may be at work. This apparently simple system holds many lessons for more complicated multifactorial brain disorders. We also continued work during these busy years on effects of NRG on CNS neurons.

Simons Foundation (2006–present)

Jim and Marilyn Simons established the Simons Foundation in 1993 with the goal of supporting research in basic science and mathematics. With time, they became interested in research on autism and began by awarding a small number of grants. They picked excellent investigators, but as they began to explore the complexity of autism science, they sought advice. Several informal conversations and an important roundtable meeting devoted to autism research followed.

Soon after I stepped down as dean and began a sabbatical year, Jim Simons and I shared pastrami sandwiches at Arties’ delicatessen on Broadway. He planned to ask me to help search for a director of the expanding Simons Foundation autism research program. Instead, he offered me the job. I accepted immediately. This impulse has led to one of the most challenging experiences of my career in science and to an enduring friendship.

My interest in autism and other developmental disorders had been awakened at the NIH. It was a frustrating time there because, despite the efforts by informed advocacy groups such as Cure Autism Now and the National Alliance for Autism Research, little progress had been made. Two things were clear at the start. First, autism is primarily a genetic disorder so a search for genetic variants that enhance the risk of autism offered the best route to a deeper understanding of autism traits. Second, the field needed an influx of excellent scientists to explore molecular, cellular, and systems mechanisms suggested by genetic discoveries.

Michael Wigler, a long-standing colleague of Jim’s, had already decided to study autism. His insight, perhaps influenced by his studies of cancer genetics, led to a search for de novo genetic variants in autistic individuals. Such variants, which arise in the germ line of a parent, are highly penetrant. Each one is extremely rare (less than 1 percent of cases), but together they may contribute to a large fraction of individuals on the autism spectrum. Therefore, a large sample of “simplex” families was needed. This is easier said than done. We established the Simons Foundation Autism Research Initiative (SFARI) to coordinate the efforts of 12 university autism clinics across the United States and Canada to recruit nearly 3,000 simplex families that include one and only one individual on the autism spectrum.

Led by Cathy Lord, clinicians in the clinics and staff at the foundation standardized clinical evaluations, collected blood samples, and shared data. The result is a cohort that set new standards for the field of neuropsychiatric disorders and that will be used in autism research for years to come. We showed that complex behavioral assessments could be quantitated and reproduced from site to site.

At the time of writing, more than 70 de novo genetic risk factors have been identified with high confidence. Current estimates are that more than 300 genes contribute to the risk of autism. This is a big number, but we must remember that we are dealing with human social cognition, communication, and persistent behaviors. Efforts to identify more de novo variants and to extend the genetic landscape beyond de novo mutations are under way.

Gene discovery will provide important clues, but the human brain lies between genes and behavior. We must move beyond current oversimplifications, such as autism is a “synaptic disorder” or an “excitation/inhibition imbalance” or a “disconnection syndrome,” and confront the complexity of coding and dynamics in neuronal populations involved in social cognition.

Perhaps our greatest accomplishment in the first years was the recruitment and shaping of an interactive community of superb scientists from diverse fields to focus on autism. Our meetings at the foundation are exciting, informative, and tinged with a sense of urgency. Many participants feel that the Simons Foundation has revolutionized the study of autism. What did it take? Money helps, but I believe the community would not have coalesced if scientific opportunities were not evident. Powerful cell and molecular and imaging tools offer new approaches to pressing questions. Vision and leadership are also essential, and they can be practiced at the foundation with few constraints. I cannot overemphasize the impact of Jim and Marilyn Simons. They “show up” and participate on a meaningful level at staff meetings, seminars, journal clubs, and major lectures. Their curiosity, generosity, values, and passion inspire internal staff and external supported scientists. In many ways, I am reliving my role as director of the NINDS during the era when Congress recognized the importance of science and provided adequate funds.

The notion of a “social brain” has emerged as a useful concept in autism studies. The definition has become more specific in recent years. This is a functional rather than an anatomical designation. My bet is that neural correlates of autism will be found in these interconnected regions. I also believe that we must look for key changes in brain function at or before birth. Even though the seeds of autism are sown early, studies of mice bearing mutated human genes have shown that abnormal behaviors can be reversed in adult life. It is never too late, and we must never lose hope for improvements in the quality of life for those on the autism spectrum.

The Simons Foundation has grown from fewer than 10 employees when I began in 2006 to more than 120 just 10 years later. We moved from adequate space (about 12,000 square feet) to magnificent quarters (about 75,000 square feet) a few blocks away in Chelsea. The scope of the foundation has expanded to include many new topics in life sciences, mathematics, and physics. I stepped down as director of SFARI in 2013, to assume the role of chief scientist. I have remained involved in SFARI, but my charge in this new role is to foment, advise, and help decide on new projects.

Several large collaborations named “Big Ideas” projects have emerged in recent years. Each one addresses an important topic and each one must promise to revolutionize thinking in their field; they must have enlisted excellent scientists; they must define landmarks and demonstrate progress over the course of the grant; and they must demonstrate a need for funding as well as a plan for continued funding after 5–10 years. Such collaborations emerge from extensive internal discussions as well as discussions with candidates and with outside experts. The Simons Collaboration on Data Analysis, headed by Leslie Greengard, is the first in-house Big Idea project.

It has been exciting to work with the Simons Senior Science Staff: Marian Carlson in life sciences, Yuri Tschinkel and Andy Millis in mathematics and physics, and Leslie in planning and evaluating new proposals. A sample of collaborations now under way includes microwave evidence for the Big Bang, algebraic geometry, the many electron problem, ocean microbiota, the origin of life, and the global brain. In addition, the foundation has provided support for the New York Genome Center and for Cryo-Electron Microscopy at the New York Structural Biology Center. It often appears to me that Jim Simon uses the foundation as his laboratory to learn more about the world we live in and beyond. I often think of the Simons Foundation as a young Howard Hughes Medical Institute, but with a broader mandate. It is a joy to help shape the journey.

At the moment, I am most involved with the Simons Collaboration on the Global Brain (SCGB), an effort to identify principles of coding and dynamics in populations of neurons that are active in the formation and recall of memories, motor planning, spatial navigation, other decisions, and other internal mental states interposed between sensation and motor output. Experimental approaches require electrical or optical recordings at single-cell resolution in real time. Novel statistical approaches are needed to detect neural signatures that may not be evident in the original recordings.

This ambitious, transformative plan first suggested by Bill Newsome and now directed by David Tank is advised by a steering committee that includes Tony Movshon, Larry Abbott, Adrienne Fairhall, Dora Angelaki, Newsome, and me. We have awarded 41 grants—each one involving collaboration between experimentalists and mathematicians. The challenge now is to promote meaningful interactions among the various groups in the SCGB. Curiosity drives most investigators in the SCGB. Quite simply, they seek a better understanding of mental life. I share that respect for curiosity-driven research, but I do hope that such approaches will lead to useful biomarkers for neuropsychiatric disorders.

In Sum

In my career, I have worked my way up from the nmj to the spinal cord to the midbrain, to the basal ganglia to the archicortex, to the neocortex, and now to the social brain, cognition, and consciousness. In retrospect, this was my dream from the start as I entered medical school in 1960. Each step along the way demanded intense study of the relevant literature and experimental approaches. Each step has had its unique rewards. As the director of technology transfer at MIT told me years ago, “Gerry, at your age it is a privilege to have a steep learning curve.”

Throughout my career, I have tried to pick important questions, find important collaborators, persevere, and have fun. The profound questions have not changed significantly over the decades, but new techniques have revolutionized our approaches to these persistent questions.

Beyond my own laboratory, I believe that I have influenced the productivity and, ultimately, the careers of many scientists, young and old.

What is next? I look forward to less social and academic noise. I would like more time to write to clarify my thoughts about the past and about future directions. As I think back over my time in research, I am satisfied but not completely fulfilled. I accept the fact that I am no longer a postdoctoral fellow at the NIH, but thoughts about unfinished experiments recur and exciting new ideas emerge. As time slips away, Ruth and I want to spend more time with our wonderful children, grandchildren, extended family, and close friends.

Selected Bibliograpy

Berg, D.K., and G.D. Fischbach. 1978. Enrichment of spinal cord cell cultures with motoneurons. J Cell Biol. 77:83–98.

Buc-Caron, M.H., P. Nystrom, and G.D. Fischbach. 1983. Induction of acetylcholine receptor synthesis and aggregation: partial purification of low-molecular-weight activity. Dev Biol. 95:378–386.

Buonanno, A., and G.D. Fischbach. 2001. Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol. 11:287–296.

Bursztajn, S., and G.D. Fischbach. 1984. Evidence that coated vesicles transport acetylcholine receptors to the surface membrane of chick myotubes. J Cell Biol. 98:498–506.

Carr, C., G.D. Fischbach, and J.B. Cohen. 1989. A novel 87,000-Mr protein associated with acetylcholine receptors in Torpedo electric organ and vertebrate skeletal muscle. J Cell Biol. 109:1753–1764.

Chalazonitis, A., and G.D. Fischbach. 1980. Elevated potassium induces morphological differentiation of dorsal root ganglionic neurons in dissociated cell culture. Dev Biol. 78:173–183.

Chang, Q., and G.D. Fischbach. 2006. An acute effect of neuregulin 1 beta to suppress alpha7-containing nicotinic acetylcholine receptors in hippocampal interneurons. J Neurosci. 26:11295–11303.

Choi, D.W., D.H. Farb, and G.D. Fischbach. 1977. Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature. 269:342–344.

Choi, D.W., D.H. Farb, and G.D. Fischbach. 1981a. Chlordiazepoxide selectively potentiates GABA conductance of spinal cord and sensory neurons in cell culture. J Neurophysiol. 45:621–631.

Choi, D.W., D.H. Farb, and G.D. Fischbach. 1981b. GABA-mediated synaptic potentials in chick spinal cord and sensory neurons. J Neurophysiol. 45:632–643.

Choi, D.W., and G.D. Fischbach. 1981. GABA conductance of chick spinal cord and dorsal root ganglion neurons in cell culture. J Neurophysiol. 45:605–620.

Cohen, S.A., and G.D. Fischbach. 1973. Regulation of muscle acetylcholine sensitivity by muscle activity in cell culture. Science. 181:76–78.

Cohen, S.A., and G.D. Fischbach. 1977. Clusters of acetylcholine receptors located at identified nerve-muscle synapses in vitro. Dev Biol. 59:24–38.

Connolly, J.A., P.A. St John, and G.D. Fischbach. 1982. Extracts of electric lobe and electric organ from Torpedo californica increase the total number as well as the number of aggregates of chick myotube acetylcholine receptors. J Neurosci. 2:1207–1213.

Corfas, G., D.L. Falls, and G.D. Fischbach. 1993. ARIA, a protein that stimulates acetylcholine receptor synthesis, also induces tyrosine phosphorylation of a 185-kDa muscle transmembrane protein. Proc Natl Acad Sci U S A. 90:1624–1628.

Corfas, G., and G.D. Fischbach. 1993. The number of Na+ channels in cultured chick muscle is increased by ARIA, an acetylcholine receptor-inducing activity. J Neurosci. 13:2118–2125.

Corfas, G., K.M. Rosen, H. Aratake, R. Krauss, and G.D. Fischbach. 1995. Differential expression of ARIA isoforms in the rat brain. Neuron. 14:103–115.

Dichter, M.A., and G.D. Fischbach. 1977. The action potential of chick dorsal root ganglion neurones maintained in cell culture. J Physiol. 267:281–298.

Dubinsky, J.M., and G.D. Fischbach. 1990. A role for cAMP in the development of functional neuromuscular transmission. J Neurobiol. 21:414–426.

Dubinsky, J.M., D.J. Loftus, G.D. Fischbach, and E.L. Elson. 1989. Formation of acetylcholine receptor clusters in chick myotubes: migration or new insertion? J Cell Biol. 109:1733–1743.

Dubinsky, J.M., M. Morgan, and G.D. Fischbach. 1988. Variation among acetylcholine receptor clusters induced by ciliary ganglion neurons in vitro. Dev Biol. 130:209–219.

Dunlap, K., and G.D. Fischbach. 1978. Neurotransmitters decrease the calcium component of sensory neurone action potentials. Nature. 276:837–839.

Dunlap, K., and G.D. Fischbach. 1981. Neurotransmitters decrease the calcium conductance activated by depolarization of embryonic chick sensory neurones. J Physiol. 317:519–535.

Engisch, K.L., and G.D. Fischbach. 1990. The development of ACH- and GABA-activated currents in normal and target-deprived embryonic chick ciliary ganglia. Dev Biol. 139:417–426.

Engisch, K.L., and G.D. Fischbach. 1992. The development of Ach- and GABA-activated currents in embryonic chick ciliary ganglion neurons in the absence of innervation in vivo. J Neurosci. 12:1115–1125.

Falls, D.L., D.A. Harris, F.A. Johnson, M.M. Morgan, G. Corfas, and G.D. Fischbach. 1990. Mr 42,000 ARIA: a protein that may regulate the accumulation of acetylcholine receptors at developing chick neuromuscular junctions. Cold Spring Harb Symp Quant Biol. 55:397–406.

Falls, D.L., K.M. Rosen, G. Corfas, W.S. Lane, and G.D. Fischbach. 1993. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 72:801–815.

Farb, D.H., D.K. Berg, and G.D. Fischbach. 1979. Uptake and release of [3H]gammaaminobutyric acid by embryonic spinal cord neurons in dissociated cell culture. J Cell Biol. 80:651–661.

Fenelon, K., J. Mukai, B. Xu, P.K. Hsu, L.J. Drew, M. Karayiorgou, G.D. Fischbach, A.B. MacDermott, and J.A. Gogos. 2011. Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc Natl Acad Sci U S A. 108:4447–4452.

Fenelon, K., B. Xu, C.S. Lai, J. Mukai, S. Markx, K.L. Stark, P.K. Hsu, W.B. Gan, G.D. Fischbach, A.B. MacDermott, M. Karayiorgou, and J.A. Gogos. 2013. The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion. J Neurosci. 33:14825–14839.

Fischbach, G.D. 1970a. The different effect of neuromuscular inactivity and muscle atrophy on speed of contraction. Exp Neurol. 28:189–190.

Fischbach, G.D. 1970b. Synaptic potentials recorded in cell cultures of nerve and muscle. Science. 169:1331–1333.

Fischbach, G.D. 1972. Synapse formation between dissociated nerve and muscle cells in low density cell cultures. Dev Biol. 28:407–429.

Fischbach, G.D. 1987. An introduction to molecular approaches in studies of neuronal development and synapse formation. Res Publ Assoc Res Nerv Ment Dis. 65:143–153.

Fischbach, G.D. 1992. Mind and brain. Sci Am. 267:48–57.

Fischbach, G.D. 2006. Schizophrenia: signals from the other side. Nat Med. 12:734–735.

Fischbach, G.D. 2007. NRG1 and synaptic function in the CNS. Neuron. 54:495–497.

Fischbach, G.D., H. Aratake, G. Corfas, D.L. Falls, A. Goodearl, and K.M. Rosen. 1994. Trophic interactions at developing synapses. Prog Clin Biol Res. 390:173–190.

Fischbach, G.D., D.K. Berg, S.A. Cohen, and E. Frank. 1976. Enrichment of nervemuscle synapses in spinal cord–muscle cultures and identification of relative peaks of ACh sensitivity at sites of transmitter release. Cold Spring Harb Symp Quant Biol. 40:347–357.

Fischbach, G.D., and S.A. Cohen. 1973. The distribution of acetylcholine sensitivity over uninnervated and innervated muscle fibers grown in cell culture. Dev Biol. 31:147–162.

Fischbach, G.D., S.A. Cohen, and M.P. Henkart. 1974. Trophic functions of the neuron. I. Development of neural connections. Some observations of trophic interaction between neurons and muscle fibers in cell culture. Ann N Y Acad Sci. 228:35–46.

Fischbach, G.D., and M.A. Dichter. 1974. Electrophysiologic and morphologic properties of neurons in dissociated chick spinal cord cell cultures. Dev Biol. 37:100–116.

Fischbach, G.D., K. Dunlap, A. Mudge, and S. Leeman. 1981. Peptide and amine transmitter effect on embryonic chick sensory neurons in vitro. Adv Biochem Psychopharmacol. 28:175–188.

Fischbach, G.D., D. Fambrough, and P.G. Nelson. 1973. A discussion of neuron and muscle cell cultures. Fed Proc. 32:1636–1642.

Fischbach, G.D., and R.L. Fischbach. 2004. Stem cells: science, policy, and ethics. J Clin Invest. 114:1364–1370.

Fischbach, G.D., E. Frank, T.M. Jessell, L.L. Rubin, and S.M. Schuetze. 1978. Accumulation of acetylcholine receptors and acetylcholinesterase at newly formed nerve-muscle synapses. Pharmacol Rev. 30:411–428.

Fischbach, G.D., and Y. Lass. 1978a. Acetylcholine noise in cultured chick myoballs: a voltage clamp analysis. J Physiol. 280:515–526.

Fischbach, G.D., and Y. Lass. 1978b. A transition temperature for acetylcholine channel conductance in chick myoballs. J Physiol. 280:527–536.

Fischbach, G.D., and C. Lord. 2010. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 68:192–195.

Fischbach, G.D., and G.M. McKhann. 2001. Cell therapy for Parkinson’s disease. N Engl J Med. 344:763–765.

Fischbach, G.D., M. Nameroff, and P.G. Nelson. 1971. Electrical properties of chick skeletal muscle fibers developing in cell culture. J Cell Physiol. 78:289–299.

Fischbach, G.D., and N. Robbins. 1969. Changes in contractile properties of disused soleus muscles. J Physiol. 201:305–320.

Fischbach, G.D., and N. Robbins. 1971. Effect of chronic disuse of rat soleus neuromuscular junctions on postsynaptic membrane. J Neurophysiol. 34:562–569.

Fischbach, G.D., and K.M. Rosen. 1997. ARIA: a neuromuscular junction neuregulin. Annu Rev Neurosci. 20:429–458.

Fischbach, G.D., and S.M. Schuetze. 1980. A post-natal decrease in acetylcholine channel open time at rat end-plates. J Physiol. 303:125–137.

Fischbach, R.L., and G.D. Fischbach. 2005. The brain doesn’t lie. Am J Bioeth. 5:54– 55; discussion W55.

Fischbach, R.L., and G.D. Fischbach. 2008. Neuroethicists needed now more than ever. Am J Bioeth. 8:47–48.

Fischbach, R.L., M.J. Harris, M.S. Ballan, G.D. Fischbach, and B.G. Link. 2015. Is there concordance in attitudes and beliefs between parents and scientists about autism spectrum disorder? Autism. doi: 10.1177/1362361315585310.

Ford, B.D., B. Han, and G.D. Fischbach. 2003a. Differentiation-dependent regulation of skeletal myogenesis by neuregulin-1. Biochem Biophys Res Commun. 306:276–281.

Ford, B.D., Y. Liu, M.A. Mann, R. Krauss, K. Phillips, L. Gan, and G.D. Fischbach. 2003b. Neuregulin-1 suppresses muscarinic receptor expression and acetylcholine-activated muscarinic K+ channels in cardiac myocytes. Biochem Biophys Res Commun. 308:23–28.

Ford, B.D., J.A. Loeb, and G.D. Fischbach. 1999. Neuregulin stimulates DNA synthesis in embryonic chick heart cells. Dev Biol. 214:139–150.

Frank, E., and G.D. Fischbach. 1977. ACh receptors accumulate at newly formed nerve-muscle synapses in vitro. Soc Gen Physiol Ser. 32:285–291.

Frank, E., and G.D. Fischbach. 1979. Early events in neuromuscular junction formation in vitro: induction of acetylcholine receptor clusters in the postsynaptic membrane and morphology of newly formed synapses. J Cell Biol. 83:143–158.

Fukuda, J., G.D. Fischbach, and T.G. Smith, Jr. 1976a. A voltage clamp study of the sodium, calcium and chloride spikes of chick skeletal muscle cells grown in tissue culture. Dev Biol. 49:412–424.

Fukuda, J., M.P. Henkart, G.D. Fischbach, and T.G. Smith, Jr. 1976b. Physiological and structural properties of colchicine-treated chick skeletal muscle cells grown in tissue culture. Dev Biol. 49:395–411.

Goodearl, A.D., A.G. Yee, A.W. Sandrock, Jr., G. Corfas, and G.D. Fischbach. 1995. ARIA is concentrated in the synaptic basal lamina of the developing chick neuromuscular junction. J Cell Biol. 130:1423–1434.

Han, B., and G.D. Fischbach. 1999a. Processing of ARIA and release from isolated nerve terminals. Philos Trans R Soc Lond B Biol Sci. 354:411–416.

Han, B., and G.D. Fischbach. 1999b. The release of acetylcholine receptor inducing activity (ARIA) from its transmembrane precursor in transfected fibroblasts. J Biol Chem. 274:26407–26415.

Harris, D.A., D.L. Falls, R.M. Dill-Devor, and G.D. Fischbach. 1988. Acetylcholine receptor-inducing factor from chicken brain increases the level of mRNA encoding the receptor alpha subunit. Proc Natl Acad Sci U S A. 85:1983–1987.

Harris, D.A., D.L. Falls, and G.D. Fischbach. 1989. Differential activation of myotube nuclei following exposure to an acetylcholine receptor-inducing factor. Nature. 337:173–176.

Harris, D.A., D.L. Falls, F.A. Johnson, and G.D. Fischbach. 1991. A prion-like protein from chicken brain copurifies with an acetylcholine receptor-inducing activity. Proc Natl Acad Sci U S A. 88:7664–7668.

Hourani, B.T., B.F. Torain, M.P. Henkart, R.L. Carter, V.T. Marchesi, and G.D. Fischbach. 1974. Acetylcholine receptors of cultured muscle cells demonstrated with ferritin-alpha-bungarotoxin conjugates. J Cell Sci. 16:473–479.

Hume, R.I., L.W. Role, and G.D. Fischbach. 1983. Acetylcholine release from growth cones detected with patches of acetylcholine receptor-rich membranes. Nature. 305:632–634.

Jacobs, M.P., G.D. Fischbach, M.R. Davis, M.A. Dichter, R. Dingledine, D.H. Lowenstein, M.J. Morrell, J.L. Noebels, M.A. Rogawski, S.S. Spencer, and W.H. Theodore. 2001. Future directions for epilepsy research. Neurology. 57:1536–1542.

Jessell, T.M., R.E. Siegel, and G.D. Fischbach. 1979. Induction of acetylcholine receptors on cultured skeletal muscle by a factor extracted from brain and spinal cord. Proc Natl Acad Sci U S A. 76:5397–5401.

Lass, Y., and G.D. Fischbach. 1976. A discontinuous relationship between the acetylcholine-activated channel conductance and temperature. Nature. 263: 150–151.

Liu, Y., B. Ford, M.A. Mann, and G.D. Fischbach. 2001. Neuregulins increase alpha7 nicotinic acetylcholine receptors and enhance excitatory synaptic transmission in GABAergic interneurons of the hippocampus. J Neurosci. 21:5660–5669.

Liu, Y., B.D. Ford, M.A. Mann, and G.D. Fischbach. 2005. Neuregulin-1 increases the proliferation of neuronal progenitors from embryonic neural stem cells. Dev Biol. 283:437–445.

Loeb, J.A., and G.D. Fischbach. 1995. ARIA can be released from extracellular matrix through cleavage of a heparin-binding domain. J Cell Biol. 130:127–135.

Loeb, J.A., and G.D. Fischbach. 1997. Neurotrophic factors increase neuregulin expression in embryonic ventral spinal cord neurons. J Neurosci. 17:1416–1424.

Loeb, J.A., A. Hmadcha, G.D. Fischbach, S.J. Land, and V.L. Zakarian. 2002. Neuregulin expression at neuromuscular synapses is modulated by synaptic activity and neurotrophic factors. J Neurosci. 22:2206–2214.

Loeb, J.A., T.S. Khurana, J.T. Robbins, A.G. Yee, and G.D. Fischbach. 1999. Expression patterns of transmembrane and released forms of neuregulin during spinal cord and neuromuscular synapse development. Development. 126:781–791.

Loeb, J.A., E.T. Susanto, and G.D. Fischbach. 1998. The neuregulin precursor proARIA is processed to ARIA after expression on the cell surface by a protein kinase C-enhanced mechanism. Mol Cell Neurosci. 11:77–91.

Mann, M.A., S. Das, J. Zhang, M. Wagner, and G.D. Fischbach. 2006. Neuregulin effect on quantal content dissociated from effect on miniature endplate potential amplitude. J Neurophysiol. 96:671–676.

Mann, M.A., D.M. Knipe, G.D. Fischbach, and B.N. Fields. 2002. Type 3 reovirus neuroinvasion after intramuscular inoculation: direct invasion of nerve terminals and age-dependent pathogenesis. Virology. 303:222–231.

Martinou, J.C., D.L. Falls, G.D. Fischbach, and J.P. Merlie. 1991. Acetylcholine receptor-inducing activity stimulates expression of the epsilon-subunit gene of the muscle acetylcholine receptor. Proc Natl Acad Sci USA. 88:7669–7673.

Mudge, A.W., S.E. Leeman, and G.D. Fischbach. 1979. Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration. Proc Natl Acad Sci U S A. 76:526–530.

O’Brien, R.J., and G.D. Fischbach. 1986a. Characterization of excitatory amino acid receptors expressed by embryonic chick motoneurons in vitro. J Neurosci. 6:3275–3283.

O’Brien, R.J., and G.D. Fischbach. 1986b. Excitatory synaptic transmission between interneurons and motoneurons in chick spinal cord cell cultures. J Neurosci. 6:3284–3289.

O’Brien, R.J., and G.D. Fischbach. 1986c. Isolation of embryonic chick motoneurons and their survival in vitro. J Neurosci. 6:3265–3274.

O’Brien, R.J., and G.D. Fischbach. 1986d. Modulation of embryonic chick motoneuron glutamate sensitivity by interneurons and agonists. J Neurosci. 6:3290–3296.

O’Brien, R.J., S. Kamboj, M.D. Ehlers, K.R. Rosen, G.D. Fischbach, and R.L. Huganir. 1998. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron. 21:1067–1078.

Robbins, N., and G.D. Fischbach. 1971. Effect of chronic disuse of rat soleus neuromuscular junctions on presynaptic function. J Neurophysiol. 34:570–578.

Role, L.W., and G.D. Fischbach. 1987. Changes in the number of chick ciliary ganglion neuron processes with time in cell culture. J Cell Biol. 104:363–370.

Role, L.W., V.R. Matossian, R.J. O’Brien, and G.D. Fischbach. 1985. On the mechanism of acetylcholine receptor accumulation at newly formed synapses on chick myotubes. J Neurosci. 5:2197–2204.

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Sten Grillner

BORN:

Stockholm, Sweden

June 14, 1941

EDUCATION:

University of Göteborg, Sweden, Med. Candidate (1962)

University of Göteborg, Sweden, Dr. of Medicine, PhD (1969)

Academy of Science, Moscow, Visiting Scientist (1971)

APPOINTMENTS:

Docent in Physiology, Medical Faculty, University of Göteborg (1969–1975)

Professor, Department of Physiology III, Karolinska Institute (1975–1986)

Director, Nobel Institute for Neurophysiology, Karolinska Institute, Professor (1987)

Nobel Committee for Physiology or Medicine, Chair, 1995–1997 (1987–1998)

Nobel Assembly at the Karolinska Institutet, Member Chair, 2005 (1988–2008)

Chairman Department of Neuroscience, Karolinska Institutet (1993–2000)

Distinguished Professor, Karolinska Institutet (2010)

HONORS AND AWARDS:

Member of Academiae Europaea 1990–

Member of Royal Swedish Academy of Science 1993–

Chairman Section for Biology and Member of Academy Board, 2004–2010

Member of Norwegian Academy of Science and Letters, 1997–

Member American Academy of Arts and Sciences, 2004–

Honorary Member of the Spanish Medical Academy, 2006–

Foreign Associate of Institute of Medicine of the National Academy, United States, 2006–

Foreign Associate of the National Academy, United States, 2010–

Associate of the Neuroscience Institute, La Jolla, 1989–

Member EMBO, 2014–

Florman Award, Royal Swedish Academy of Science, 1977

Grass Lecturer to the Society of Neuroscience, Boston, 1983

Greater Nordic Prize of Eric Fernstrom, Lund, Sweden, 1990

Bristol-Myers Squibb Award for Distinguished Achievements in Neuroscience, 1993

Reeve/Irvine Research Medal, New York, 2002

Neuronal Plasticity Prize, Fondation Ipsen, Paris, 2003

Ralph Gerard Prize, Society for Neuroscience, Washington, DC, 2005

Ragnar Granit Prize, Finland, 2006

Linnéan Zoology Award, Lund, Sweden, 2007

The Kavli Prize in Neuroscience, United States/Norway, 2008

The King’s Medal–Band of the Serafimer Order, Sweden, 2012

Sten Grillner is a neurophysiologist with a focus on the cellular bases of motor behavior, initially in mammals, but later utilizing a lower vertebrate model, the lamprey. This has enabled him to unravel intrinsic functions of microcircuits generating locomotor movements at the brainstem–spinal cord level, the midbrain control mechanisms for steering, and the forebrain mechanisms underlying selection of behavior. His research extends from ion channels and synapses to network mechanisms utilizing a multitude of techniques. On the basis of detailed experimentation, he has successfully modeled the networks underlying locomotion including steering and posture. The lamprey central nervous system is evolutionary conserved and serves as a blueprint of the mammalian motor system.

Sten Grillner

My first memories are from Filipstad, a small picturesque town in western Sweden with a long tradition of mining, where my father was physician and responsible for the health care. We later moved to Norrköping, a midsize city, south of Stockholm, where I went to school to finish in 1960. I have fond memories from this time and had rather broad interests, perhaps more toward literature than science. My parents were always supportive, and they let me follow my own inclination. My exposure to research was limited, although I had an uncle geologist, who explained his different projects with great enthusiasm, which I found interesting.

I was uncertain of what I liked to study but finally decided on the Medical Faculty in Göteborg (Gothenburg), and was moderately engaged in the curriculum, until the course in physiology, which I found quite interesting, in particular, neurophysiology. After the course, I was allowed to join Anders Lundberg’s laboratory as an unpaid amanuensis, in parallel with the continued studies. This was a stimulating environment with visiting scientists from all parts of the world. During the first summer, I was allowed to explore a project I had come up with myself. Do the cells of the adrenal medulla (of neural origin) display action potentials when activated? I failed—although I could occasionally impale these cells, I was not able to hold them because of arterial pulsations. Later it was shown that they indeed could generate action potentials.

The First Steps toward Becoming a Neurophysiologist

I subsequently learned neurophysiological techniques together with Staffan Lund, an older graduate student, and Toshinori Hongo, a postdoc from the University of Tokyo who later became head of the Brain Research Institute at this university. I very much enjoyed working with both of these colleagues, and together we carried out a series of studies on the fast conducting vestibuloand reticulospinal pathways, which we found to have direct monosynaptic connections to extensor and flexor motoneurons, respectively. These studies, still cited, were cutting edge at the time. One day, a fellow student asked me, what is their role in the behaving animal: I then realized that we simply did not know, we could just infer their role. This made me understand the need to relate the cellular findings to behavior, if they were to provide insight related to brain function.

My thesis dealt with the supraspinal and segmental control of gammamotoneurons that control the sensitivity of muscle spindles. It also addressed how these neurons became activated during the late reflex discharges induced after injecting the noradrenergic precursor dihydroxyphenylalanine (DOPA) in the spinal animal. Lundberg and colleagues had proposed that these discharges result from an activation of part of the locomotor network. I could show that, indeed, the gamma-motoneurons become activated in parallel with the alpha-motoneurons.

In Lundberg’s laboratory, the PhD students were rather independent and left to their own initiatives, but in a stimulating environment. He was involved mainly in reviewing the manuscripts—but he did not co-author them unless he had been running the experiments himself—a practice that is quite different today but common at the time. This fostered independence but could be difficult for some students.

This gave me freedom to explore alternative routes, and I found that DOPA also induced tonic stretch reflexes, a finding that many colleagues found interesting, including Ragnar Granit, the Nobel laureate of 1967, who was encouraging and supporting. This finding was closer to behavior, and therefore I found it particularly interesting. After completing my PhD, I further analyzed the recruitment pattern of motor units, and the role of muscle properties for load compensation during standing and locomotion. These studies led me to emphasize the importance of muscle properties (length–tension curves), and I found myself opposing Peter Matthews, the spindle authority at the time, in his argument for a sensory contribution of the group II spindle afferents. This led to a public and rather intense discussion.

Another result that I found interesting during my thesis work was that after administration of DOPA, several bouts of alternating flexor and extensor activity could be elicited in the spinal animal. In addition, and as important, I could induce alternating limb movements resembling locomotion in a spinal animal with no further operation. This experiment, which was reported on in only a few lines in my thesis, had a major impact on my future research. I found these results satisfactory, and from then on, I was hooked on motor control and the neural bases of locomotion. In May 1969, I defended my PhD thesis within the Medical Faculty.

Postdoc in Moscow in the Middle of the Cold War

Instead of going to Harvard for a postdoc in the Physiology Department to study the properties of stretch reflexes, as originally planned, I decided to spend 5 months at the Academy of Science in Moscow, in the middle of the Cold War. The reason was that Grigori Orlovsky and Mark Shik had developed a reduced preparation (without forebrain) that allowed detailed studies of the neural control of locomotion and posture. They had shown that stimulation of a circumscribed area in the midbrain (the mesencephalic locomotor region, MLR) could elicit well-coordinated locomotor movements on the treadmill. This opened up the possibility to study the neural bases of motor behavior, without the ethical constraints that limits experiments on intact animals or the need to use animals under anesthesia.

We then could show that subthreshold activation of MLR indeed released reflex discharges similar to that of DOPA and a suppression of other shortlatency responses. We then suggested that the MLR indeed caused locomotion by releasing the spinal network activated by DOPA. This is still a valid conclusion, but now not only the noradrenergic but also the glutamate and 5-hydroxytryptamine (5-HT) systems are known to contribute. In the Moscow Laboratory, the research groups tended to have interesting questions, but at the same time outdated equipment. I was even recording rapid events with a mirror galvanometer—a piece of equipment used before oscilloscopes emerged—but it was to the point for our questions.

I interacted closely with Orlovsky, who performed elegant and technically demanding experiments on the fast-descending tracts modulated by cerebellum during each step cycle, and the pathways to cerebellum that conveyed information on the ongoing movements, as well as efference copy information about the spinal commands. Novel findings. Typically, Orlovsky was running the actual experiments with his special skills, but around him stood several colleagues, often smoking, with different expertise (physics, mathematics, biology) discussing the possible significance of the findings. He thus had a group with different background training but with a focus on understanding the same mechanisms—an excellent strategy for success in science.

The laboratory at the Academy in Moscow was high profile, led by Israel M. Gelfand, a renowned mathematician who later received the Kyoto Prize. For example, in the evaluation of different reports in seminars or workshops, the focus was explicitly on whether or not new fundamental insights had been gained. If an elegant study made with the most refined novel techniques reported just a new fact, without at the same time leading to new understanding, Gelfand and colleagues were not impressed. This was an important take-home message. Still today, the area of neuroscience is characterized by an accumulation of facts and much less of synthesis.

The Social Life as a Postdoc at the Academy

To Moscow, I came alone traveling in midwinter through Finland, Leningrad, and Novgorod in a big Volga I had bought in Sweden—an adventure in itself. As I arrived in Moscow, I was installed in the Hotel of the Academy of Science together with scientists from all around the Soviet Union, in itself an interesting experience. For breakfast I usually had tea and bread, while my senior Russian colleagues in the cafeteria, often with a sign of political distinction, not rarely would have a full drinking glass of Russian cognac.

The time in Moscow in the middle of the Cold War was a great experience personally as well as scientifically. During the first few weeks, my many colleagues seemed friendly but somewhat reserved, but once they accepted me as a reliable human being (particularly important in a society in which informers could be expected at any instant), the conditions changed. The laboratory was composed of a nice set of colleagues, many of Jewish origin that took extremely good care of us all at a personal level. My wife Lena (a medical doctor) joined me after some weeks (with a separate grant in parasitology), together with our two daughters, ages one and three, and a very nice au pair, Lena Larsson, from Göteborg.

We had a lovely time not only for science but also for interactions with my colleagues, in particular Orlovsky and his family in addition to Mark Shik, Olga Fucson, Sergeij Kashin, and Yuri Arschavsky. They made us understand the many interesting aspects of Russian culture, older and contemporary art (the latter shown unofficially), literature, history, and so forth. At the same time, they made us realize how difficult it was to live in a society where everybody assumed that the telephones were bugged (including in our flat), where one does not quite know who could be informers to the KGB (the main security agency) or the local scientific Soviet. This was a scary society in which to live. The children of dissidents had difficulties gaining admission to universities, not to speak of the difficulties encountered by the dissidents themselves. And yet the situation had improved markedly from the times of Stalin, when one could be sentenced for even speaking to a foreigner.

Back in Göteborg—Spinal Organization of Locomotion in Mammals

When I returned home to Göteborg, as a young PI (principal investigator), I had the fortune of getting competent postdocs and visiting scientists like Serge Rossignol, Reggie Edgerton, Claude Perret, and Sergei Kashin, as well as graduate students like Peter Zangger, Hans Forssberg, and Peter Wallén. We had a productive period establishing that the spinal cord networks in cats could generate the detailed motor pattern underlying locomotion, but that these networks indeed were assisted by a number of well-designed sensory reflexes that adapt the motor pattern to outside events.

Spinal Animals Can Generate Locomotor Movements

One important finding was that animals (cats) that had received a transection of the spinal cord (thoracic level) in the first few weeks after birth could generate well-coordinated locomotor movements, as would adult animals, when the spinal cord was activated by DOPA or noradrenergic agonists. When the hind limbs of the spinal animals were put on a moving treadmill belt, with the belt speed set on low, the two limbs generated alternating locomotor movements. But when the speed was increased, the coordination of the limbs changed to in phase locomotor movements like in a gallop. This thus demonstrated that the two basic modes of coordination could be generated by the spinal cord devoid of any influences from the brain. When the detailed motor pattern was recorded, in terms of electromyography (EMG) of the different limb muscles, the pattern was virtually identical to that of the intact animal. We thus concluded that the spinal cord networks with sensory input indeed could generate the detailed locomotor programs, rather than just simple alternating movements. Although reports from Charles Sherrington and others had indicated that alternating muscle activity could be produced in spinal animals, it was a different thing to show that the actual movements and EMG pattern could be generated in a spinal animal.

Rossignol in Montreal has over the years continued this line of research in an elegant way, showing that these conclusions also apply to mouse and rat—for a long time claimed by some not to follow this scheme. This has been a problem in many reports of spinal cord injury research, claiming functional regeneration over the lesion, when in reality the spinal central pattern generator networks (CPGs) have been recruited into action. Edgerton, who spent some time in the laboratory in 1975, also has worked along these lines over many years. Inspired by our old spinal cat experiments, and his own, he initiated a training programs for patients with spinal cord injury similar to that used to train the spinal cats. This human work is forcefully continued by Susan Harkema, Edgerton’s previous collaborator, and has been successful for patients with partial spinal cord injury.

Central Pattern Generator Networks Provide Detailed Timing

The next-level question was to ask how much of this control depends on networks within the spinal cord, and how much is dependent on sensory input from the moving limb. We could show that the intricate motor pattern with timing of the different muscles in the step cycle could be retained after all afferents to the limb had been transected by cutting the dorsal roots and thereby abolishing the sensory input from the moving limb. This clearly established that the networks in the spinal cord itself could coordinate the timing of the different muscles active in the step cycle.

These findings also showed that the favored hypothesis at the time was incorrect. It assumed that the spinal central networks would generate a simple flexion extension pattern (as Graham Brown indicated), on which afferents were to sculpt the final pattern and produce the characteristic complex motor pattern observed during locomotion (with the reflexes identified by among others Lundberg). We showed, in contrast, that the spinal cord networks themselves could generate the timing. For many years, the proponents of the original hypothesis had difficulties accepting that it was simply incorrect. This led to undue tension with my former supervisor Lundberg and unfortunate animosity lasting throughout his life, which has been perhaps the most depressing experience of my scientific life. Something that I had not imagined would ever happen, when I set out to do these experiments. I believe, as a researcher, one should strive to explain the existing findings in the most rational way—nothing is wrong with an incorrect hypothesis, as long as the experimental findings are correct. We thus demonstrated that a characteristic of the locomotor system was the presence of networks (CPGs) within the spinal cord that contained the necessary information to generate the coordinated activation of the different muscle groups.

Sensory Input Interacts with the CPG

The presence of CPGs in the spinal cord does not mean that sensory information arising during the movement is not of major importance. The ability of the sensory input from the moving limb to adapt the movements to the actual mechanical events is critical. Rossignol and I defined one main factor adapting the step cycle in relation to the position of the hip in each step. We could show that, when the limb had reached a posterior position, the sensory input from the hip helped trigger the transition to flexion—a critical mechanism in the control of locomotion. In parallel, Keir Pearson and colleagues showed that receptors signaling the load on the limb also were providing important feedback.

Throughout most of the 20th century, it appeared to be a sometimesbitter rivalry between two camps: those that argued for a dominance of central networks such as Brown and Erich von Holst and those that were focused on the sensory contribution like Sherrington, James Gray, and H.W. Lissmann. In 1985, in an article I published in Science, I emphasized the need to consider both aspects to have a successful locomotor control, and I thought I had put this rivalry to rest, but some years later one-sided arguments for one side or the other still popped up and continue to do so. Despite a clear demonstration that both aspects are critical, this type of difference persists to some degree—most researchers tend to overemphasize the importance of what they currently are doing. The tendency to do so has increased with the unfortunate emphasis in later years on impact factors in scientific publishing.

Phase-Dependent Reflex Reversals and Placing Reactions

Another unexpected mechanism was our demonstration of a phase-dependent reflex reversal. A sensory stimulus to the dorsum of the paw would generate an enhanced flexion, if it occurred during the swing phase of the step, but the identical sensory stimulus instead would lead to an enhanced extension, if it occurred during the support phase. This central gating of the reflex response is behaviorally meaningful in that a limb touching something during the swing phase should try to instantaneously overcome the obstacle by an enhanced flexion. Conversely, if the same stimulus occurred during the support phase, it could be disastrous, if it led to a flexion that would make the limb collapse; therefore, it is functional to instead have an enhanced extensor activity. This provides an example of a clever design that the spinal cord has developed during evolution.

In Search of an Experimentally Amenable Model to Study the Intrinsic Function of the Locomotor Networks: First Dogfish and Then Lamprey

My central interest at the time was to understand not only that spinal networks were coordinating locomotion but also their intrinsic mode of operation. We started to explore the neuronal activity that took place when the mammalian network was active, but we soon realized that recordings of interneuronal spike activity did not provide sufficiently rigorous information to understand how a network operates. Much more precise information was needed, and I started to search for a simpler experimental model that still needed to be a vertebrate, if the knowledge obtained ultimately would be regarded as a model system for mammals.

The first candidate was the dogfish (a small shark). It had a special methodological attraction in that the spinal cord continued to generate swimming movements even after a transection of the spinal cord, as demonstrated by A. Bethe and I. Steiner at the end of the 19th century. Pharmacological or electrical activation thus was not needed. In August 1972, I set up a laboratory at the Marine Biology Laboratory of the Academy of Science, at Kristineberg, a scenic site on the Swedish west coast for a few months. This was a lovely environment, and it was excellent that they required no fees and collected the dogfish without any costs for me (quite different nowadays). For me, it was also a new and an interesting environment—a mix of a variety of researchers from ecology to biophysics with interesting goals in mind. For a decade, Wallén and I had a lab for a few months each year at Kristineberg.

At the time, it was thought that the locomotor movements in the dogfish resulted from a chain reflex, as argued by Gray and Lissmann in Cambridge, England. Zangger and I could show, on the contrary, that after inactivation of the sensory input, the spinal cord could generate rhythmic activity recorded in the ventral roots. Moreover, the phase-lag between rostral and more caudal segments that generate the propulsion during swimming remained after deafferentation. Thus, as in mammals, the shark spinal cord contains a CPG network that generates the basic locomotor coordination.

What about the sensory contribution? Wallén as a young PhD student could show that the sensory input that occurs during the locomotor movements can entrain the CPG network at frequencies above or below the basic frequency of the CPG network at rest. Thus, the sensory input could drive the spinal CPGs, a finding that we later could show applied also to both mammals and lamprey. In other words, a central spinal generation of locomotion was combined with a sensory modulation of the movements.

It turned out, however, that the dogfish spinal cord was technically less favorable when it came to intracellular recordings from several neurons at the same time. On the one hand, for the first time, we had demonstrated that in fish (as in cats) an organization with a CPG was assisted by sensory input from the moving body. On the other hand, we could not pursue our ambition to get at the intrinsic mechanisms of how the spinal network operates.

After experimenting with the dogfish for a few years, we instead zoomed in on the lamprey, which represents the first group of vertebrates to evolve, but with all parts of the vertebrate nervous system already present. Because of its strategic position in vertebrate evolution, a reasonable amount of neuroanatomy was available, starting with two papers of the young Sigmund Freud, then still a neurologist, and many others to follow in the early middle part of the 20th century. Another important factor was that some basic cellular neurophysiology was available from Carl Rovainen’s studies starting in 1967.

Moving to Stockholm

In 1975, the Swedish Government appointed me to a professor position, at the Department of Physiology III of the Karolinska Institute. In January 1976, I moved my laboratory to Stockholm. Two of my graduate students Forssberg and Wallén joined me, and together the three of us rapidly managed to build up the new laboratory. Forssberg continued the experiments on the phasedependent reflex reversal in cat, while Wallén was engaged in developing the lamprey spinal cord as a viable preparation, together with Avis Cohen, who joined as a postdoc. We presented our first lamprey report in Paris at the International Union of Physiological Sciences meeting in 1977.

At the time, I also had received funding for setting up a computer-based movement laboratory for recording EMG, forces, and movement together. At this time, this was a demanding task, as the computers were far from what they are today. Another student with a physics background from the Netherlands, Junt Halbertsma, helped develop the laboratory, which was to become, for some time, one of the best equipped movement laboratories anywhere. Forssberg and Halbertsma did nice studies on the cat, correlating movement and behavior. Forssberg further initiated studies on the development of walking in children from the early stages and onwards, which he continued in the pediatrics department. He later became professor at Karolinska’s children’s hospital and provost of the Karolinska Institute.

I also initiated an independent group led by Alf Thorstensson (PhD) that used our new movement, force, EMG recording system to study human locomotion and equilibrium control with a focus on the trunk and adaptations to speed and load. This provided a series of important studies on basic aspects of human locomotion that required the new digital technology developed to measure motion through multiple light-emitting diodes (referred to as the Selspot system) just being available at the time, and the adaptations of the motor pattern that occur as the speed increases and if a load is carried. These data have served as controls for considering clinical movement deficits. Thorstensson continued the development of this laboratory and later became professor in biomechanics.

The Lamprey Model—The Intrinsic Function of the Spinal CPG

The development of the lamprey as a model system for understanding the intrinsic function of the CPG was without question the main aim of my research at this time. We had to investigate this in systematic fashion step by step, showing first that the isolated spinal cord could generate coordinated locomotor activity when excited by stimulation of the spinal cord, or better, by bath-applying glutamate or its agonists. Glycinergic crossed inhibition was found to generate the alternation between the left and right side. On the other hand, we could show that the hemicord (separated along the midline) could generate rhythmic burst activity without glycinergic inhibition, which was an important piece of the jigsaw puzzle provided by Lorenzo Cangiano. Wallén and later Lennart Brodin used pharmacology to analyze the network and demonstrated the role of glycinergic transmission as well as glutamatergic transmission, and also revealed how NMDA and AMPA receptors contribute in separate ways to the network operation. The oscillatory properties induced by NMDA were another important feature that we explored (with Karen Sigvardt and Wallén). The identification of cellular properties, subtypes of ion channels, and the identification of calciumdependent potassium channels were important steps toward understanding network operation.

After these baseline studies, we had ideal conditions to start to probe for interneurons with paired recordings between pre- and postsynaptic neurons. Wallén and I detailed the motoneurons together with Jack Feldman, on sabbatical from Northwestern, and showed that they received periods of excitation alternating with inhibition and had an intricate morphology—the latter being a critical piece of information. On the ipsilateral side, excitatory premotor interneurons were identified, initially through stimulation of single axons by Nick Dale. The final important demonstration of glutamatergic premotor interneurons of the network and their connectivity was achieved through paired recordings between the presynaptic interneurons and the postsynaptic neurons. Jim Buchanan and I published these findings in Science in 1987. These data were critical for understanding the network design and provided the bases for the initial network simulations.

Some years later, Simon Alford and Abdel El Manira joined the laboratory, and we then uncovered a phasic presynaptic modulation that occurs in each swim cycle. It occurs not only in sensory afferents, but also in both inhibitory and excitatory premotor interneurons. This means that the synaptic efficacy will vary throughout the swim cycle, which was an important finding. As yet, the presynaptic modulation of premotor interneurons has been demonstrated only in lamprey, but the difficulty of these experiments is so great that no serious attempt, that I am aware of, has been made in other species. Most likely it also occurs in mammals. Alford has continued elegant studies on synaptic transmission in his own laboratory in Chicago. El Manira, now for many years professor at the Karolinska Institute, has uncovered many intriguing aspects of metabotropic control at the synaptic, cellular, and network level in lamprey, in recent years working mostly in zebrafish.

The metabotropic modulation of neuronal properties (ion channel subtypes) on the presynaptic and cellular level represents a central control of network function exerted via aminergic, peptidergic, and metabotropic GABA and glutamate receptors (mGluRs). These different modulator systems are of critical importance for the fine-tuning of the network operation and has been the focus in a long series of studies, including not only by El Manira but also by Wallén, Russell Hill, Martin Wikström, Toshiya Matsushima, Fulvia Bongianni, Weiqi Zhang, Judith Schotland, and Di Wang.

Modeling—An Indispensable Tool for Network Analyses

After several years, in 1987, the main players in the network had been identified. We could characterize the network underlying locomotion and the connectivity of both excitatory and inhibitory neurons, their transmitters, and their membrane properties. We then had sufficient information to test whether the detailed knowledge we had acquired could account for the behavior—and the only way to achieve this was to use modeling in which the model neurons “expressed” the same type of ion channels as did their biological counterparts, that is, each model neuron was a close replica of its biological cousin. The model neurons (network interneuron subtypes) interacted synaptically, as found experimentally through subtypes of glutamate (NMDA and AMPA) and glycine receptors. We then were able to show with Anders Lansner at the Royal Institute of Technology (KTH) in Stockholm that the components we had identified, indeed, could account for the locomotor behavior. The model network, constrained by detailed experimental data, could reproduce all aspects of its biological counterparts with regard to network performance. This meant that the experimental evidence obtained could account for the behavior.

Jeanette Hellgren, then a graduate student, extended these simulations from the single segment level to intersegmental coordination, incorporating phase coupling to produce the undulatory wave that moves the lamprey forward. This advance was based on a series of physiological experiments that involved Matsushima. This collaboration still continues, and it has been immensely useful to make in silico experiments and interact both ways between biology and simulation—to study, for example, the contributions of different subtypes of ion channels to network function.

Recently, with Hellgren and Alexander Kozlov, we simulated the entire brainstem–spinal cord network that generates the locomotor activity. The appropriate number of neurons was simulated with great precision using a Blue Gene supercomputer. This simulation includes network locomotor activity, steering, and initiation of locomotor activity from the basal ganglia (see the following). Moreover, we also have included neuromuscular simulations, in which the network controls a model lamprey swimming through simulated water.

One interesting finding that came out of these large simulations was that the variability of cellular properties that had been observed experimentally was actually important. If all neurons of a given class were given the same properties (e.g., average of input resistance, ion channel composition), the network was less stable and operated only in a limited range. If, however, the observed variability was introduced, the network performed much better because the model neurons were recruited in a gradual fashion. Essentially, we could conclude that the variability observed experimentally was an evolutionary design feature and not a mistake by nature.

Our knowledge of this network is now so detailed that we can predict what effect a modification of a gene-product like an ion channel in a given type of neuron will have on the activity of these neurons, and how it will affect the network and ultimately the locomotor behavior. We thus can go from a modification of a gene product (e.g., ion channel availability) over cell, synapse, and network to behavior. Many of the modulator systems that we have characterized (e.g., GABA-B, mGluRs, 5-HT, dopamine, peptides) act on different ion channels. Simulating the action of different modulators on the single cell level in the model network has often explained the overall network effects observed experimentally. In this system, we can bridge from gene to behavior, which is a rare occasion in other systems.

How the Simulation Team Evolved

When we started the simulations in 1987, Wallén, Brodin, and I provided the biological basis for the project, while Lansner, Örjan Ekeberg, and Hans Tråvén were the computer scientists, interested in simulating the nervous system. It was important to align our competences, so we spent a lot of time in the beginning getting through the biophysics of the nervous system, like the Hodgkin–Huxley equations, and the systems biology, while we also went over the different ways of making efficient and fast simulations. This was an important process in that we then acquired a common language to interact in a creative and productive way. We were able to bridge the gap between biology and physics–computer science to a large degree. We obtained a common grant for simulation from the Science Research Council in 1987, which still funds this collaborative research program. Through this collaboration, we have produced a long series of studies, which have been critical for the understanding of the microcircuits and networks of the lamprey. A series of PhD students, with a combined background in neuroscience and modeling, graduated. Lansner had completed his PhD before we started this collaboration, but Ekeberg, Tråvén, Tom Wadden, Jesper Tegnér, and Hellgren participated as PhD students and postdocs partially financed through this grant. Some decades later, they are professors at the Karolinska Institute (Tegnér) and at the KTH in Stockholm (Hellgren and Ekeberg); Tråvén took a position in industry and Wadden returned to Canada.

Immunohistochemistry—Interaction with Tomas Hökfelt

Although my laboratory has been oriented primarily toward neurophysiology, it became apparent that structure was an important aspect to understand function. The first step was the utilization of intracellular dyes, like Lucifer yellow or horseradish peroxidase, to elucidate the dendritic morphology of motoneurons and interneurons in the spinal cord and to determine their detailed morphology (important for the simulations) and axonal projections, and possible synaptic contacts.

In the 1980s, we started to use immunohistochemistry to identify putative transmitters and peptides in the different cell types in the brainstem and spinal cord. We completed an extensive mapping of the brainstem–spinal cord mostly in collaboration with Tomas Hökfelt, who provided outstanding expertise. We collaborated over many years in an enjoyable and positive atmosphere while describing the morphology of the lamprey central nervous system utilizing optimal methods. Through Hökfelt, we had the expertise required not to make mistakes. A series of collaborators were engaged like Paul van Dongen and Brodin, with whom we described the 5-HT, dopamine, and a number of peptidergic systems, often in combination with retrograde transport of different markers to identify the axonal projections to different areas. Oleg Shupliakov extended our repertoire to electronmicroscopy (EM)—and in particular immunoEM—to be able to identify glutamatergic, glycinergic, and GABAergic transmitter vesicles. This was important for identifying transmitters at the synaptic vesicle level and other different aspects. Brodin and Shupliakov are now, and have long since been, professors in the Department of Neuroscience at the Karolinska Institute.

In the past decade, Brita Robertson, an outstanding and likeable colleague, joined the laboratory, and we used the same methods to explore the intrinsic circuitry of the forebrain with the basal ganglia, habenulae, dopamine system, and cortex (pallium) with astounding results. Robertson continues to supervise several excellent postdocs or students using these techniques, including Marcus Stephenson-Jones, Elham Jalalvand, Kazuya Saitoh, Juan Perez-Fernandez, and Lorenza Capantini.

Development of 3D Confocal Microscopy—Interaction with Nils Åslund

In the early 1980s, we started to interact with Nils Åslund and his team in the physics department of KTH. They had started to develop three-dimensional (3D) confocal analyses—but only two dimensional was becoming available at the time. We realized the great advantage of having accurate reconstruction without the laborious procedure of redrawing the shape. Their 3D confocal microscope was first tested on our Lucifer yellow–stained cells from the lamprey. In particular Wallén from our side was deeply involved over many years. After some time, they developed a microscope called Sarastro, after a figure in Mozart’s opera The Magic Flute, and started a small company to sell what was, at the time, the only confocal microscope to accurately create 3D images with good control of the z-axis. The first microscope was placed in our laboratory with the promise to provide demonstrations when needed. For a period, the Sarastro confocal microscope was the best on the market. After some time, the big players in terms of economy took over the market like BioRad, Zeiss, Leica, and Nikon and Åslund’s company was bought up. With better economic backing for Åslund’s group, the situation could have been quite different.

Moving up to the Brainstem and Forebrain Level

Brainstem Control—Locomotion, Body Orientation, and Posture

We showed very early, with Andrew McClellan, that lamprey locomotor activity could be initiated from the brainstem level corresponding to the MLR and an activation of reticulospinal cells. Rejean Dubuc has studied MLR in much greater detail, later in his own laboratory in Montreal. The ascending control from the spinal cord to the brainstem level was the focus of studies carried out by Dubuc and Laurent Vinay, which led to the demonstration that that the spinal CPGs forwarded information to the brainstem level to elicit a phasic modulation of cells in the different reticulospinal nuclei. The functional significance of this modulation was elaborated in a recent modeling study with Kozlov and Hellgren.

Another critical aspect in the control of motion is the ability of most animals to stabilize their body orientation during locomotion, whether flying, walking, or swimming. In 1989, when Russia opened up, during Glasnost, it was possible for my colleagues Orlovsky and his wife and colleague Tatiana Deliagina to come to Stockholm as visiting scientists. Rather than returning, they have remained in Sweden and are now Swedish citizens. They have become an essential part of our common laboratory and have contributed importantly to the lamprey work but also have continued their independent work on mammals.

Orlovsky and Deliagina have focused on the control system stabilizing body orientation, through elegant experiments in which the vestibular control of the brainstem circuits has been analyzed in the isolated brainstem with the vestibular apparatus being intact. This work has allowed for an identification of the circuitry and connectivity in this control system and for the demonstration of separate inputs from the vestibular apparatus to different classes of reticulospinal neurons, each responding maximally at a different body orientation. The total impact of the impressive work conducted by Orlovsky and Deliagina, sometimes working collaboratively with me, has led to an understanding of this complex control system. The lamprey, as an aquatic creature, relies primarily on the vestibular apparatus for this control. There is also an interaction with visual input, but the vestibular signals dominate. In terrestrial animals, there is an additional input from the limbs, which Orlovsky and Deliagina have detailed in a series of studies on mammals. These lamprey experiments are technically demanding, and they have been possible only through the outstanding experimental skills of Orlovsky. This represents a critical part of the control system for motion: without the control of body orientation, no meaningful control of behavior would occur.

Optic Tectum Eye—Orienting and Evading

To understand the control of motion, particularly in relation to steering, we explored the lamprey optic tectum, which corresponds to the superior colliculus of mammals. Kazuya Saitoh and I therefore started to investigate the effect of stimulating different parts of the optic tectum and found that we could elicit eye movements in different directions in a site-specific way. We also could elicit orienting movements of the head and trunk and evasive movements that would be used to avoid an obstacle. Thus, there was a motor map in the optic tectum, as in other vertebrates. We subsequently investigated the input from retina and showed that there is indeed a retinotopic projection pattern, and a sensory map matching the motor map. The microstructure of the optic tectum is similar to that of other vertebrates, and the output neurons are of two types: those that project to the ipsilateral reticulospinal neurons, and a smaller subpopulation that have crossed axons and activate contralateral reticulospinal neurons. This is the neural substrate for either eliciting orienting movements toward an object (contralateral axons) or evasive movements to avoid an obstacle or predator (ipsilateral axons). Along with Andreas Kardamakis, we then explored the control of the output neurons from the eye and established an intricate organization in which an input from retina would activate a selected group of tectal output neurons, whereas all other parts of retina would provide a prominent inhibition. This was also the substrate for considering the possibility of a selection between two different visual objects, which would compete for attention. The most prominent would win—a winner-take-all arrangement.

We took up this area of research because we needed to explore steering in the context of locomotion. We also needed to consider selection of behavior not only in terms of locomotion but also in terms of steering the movements toward left or right and up or down. In this process, one needs to have input to the locomotor centers as well as to the tectal motor map for steering movements. In this context, the basal ganglia play a major role, as does the region of pallium/cortex that has motor projections to tectum.

Selection of Behavior—The Lamprey Blueprint of the Mammalian Forebrain

Having elucidated the basic organization underlying locomotion, control of body orientation, and steering, the next step was to understand the mechanisms that determine when a given motor program should be called into action. This required an understanding of the forebrain structures. In mammals, these different capacities can be generated in an automatic fashion in decerebrate animals (those lacking forebrain). The goal-directed aspect of behavior, however, requires that the forebrain remains intact to reach defined goals. In particular, the basal ganglia appears critical for this goal-directed aspect as well as the dopamine reward system, the habenulae, and the frontal lobe.

My expectation was that we would find a simplified organization for the control of the limited behavioral repertoire of the lamprey. I had begun work on this topic with Manuel Pombal and El Manira in the late 1990s. A major effort, however, started later with Stephenson-Jones, Robertson, and Jesper Ericsson. We set out to explore the organization of the basal ganglia and related structures. To our surprise, we found that the detailed organization of the basal ganglia in mammals was also present in the lamprey. This finding applied to the detailed organization of striatum, with the two types of projection neurons corresponding to the so-called direct and indirect pathways. The input from pallium/cortex, with two types of projections, also was present as well as a prominent thalamic input. Additionally, the ion channel expression was similar, and also the transmitters and peptides of the projection neurons and of the interneurons. Moreover, the two output nuclei (globus pallidus interna and substantia nigra reticulata) and the subthalamic nucleus also were found to have similar characteristics to those of the rodent basal ganglia.

The detailed similarities we established meant that the structures must have been present at the point in vertebrate evolution, when the line leading up to the lamprey separated from that to mammals. This happened around 560 million years ago. It follows that the basic organization of the basal ganglia and related structures was present early in vertebrate evolution and has remained virtually unchanged. We have inferred that the basal ganglia are subdivided into modules that can release a given motor program. These modules contain the circuits to initiate a motor program and also to suppress competing motor activities. The lamprey would have rather few modules corresponding to its restricted behavioral repertoire. During evolution, a progressively increasing number of modules have been added, corresponding to an increasingly sophisticated behavioral repertoire from lamprey to primates. In evolutionary terms, this process is called exaptation. An analogy is the progressive increase in the number of cortical columns from mice to men.

The Motor Projections from Pallium/Cortex Are Evolutionary Conserved

Recently, we also set out to investigate whether pallium (cortex in mammals) could have a motor function, and if so, in what respect. We could show, contrary to expectations, that stimulation over a restricted area of pallium could elicit eye and orienting movements as well as oral movements and locomotion. Thus, there seems to be a type of motor cortex. We then could show that from this area, there were separate projections to the optic tectum (superior colliculus), reticulospinal neurons, and the spinal cord, as well as other target areas corresponding to the mammalian projection pattern. Essentially, we had established that the identical pattern was present in lamprey, as previously found in mammals. The lamprey system is thus a sort of blueprint of the mammalian system also with regard to pallium/cortex. At the same time, one must realize that, for instance, the projections to the spinal cord in lamprey can serve only to generate movements of the head and trunk, because limbs are yet to evolve.

Karolinska Institute and Neuroscience

I initially was working in Physiology Department III and was recruited to the Nobel Institute for Neurophysiology in 1986. This was an ideal time with comparatively good resources with staff and infrastructure from the university. I had over the years the good fortune of having a stimulating environment with several groups with converging interests. In my own group, I was fortunate that Wallén decided to remain as senior lecturer in my laboratory; Hill (docent) was responsible for the technical development over many years; and, in 2005, Robertson joined, providing other expertise. In the early 1990s, the Orlovsky–Deliagina group would get positions initially through the research council; El Manira moved up the ranks to full professor and formed his own laboratory focusing on zebrafish; Ole Kiehn came from Copenhagen in the beginning of 2002 with his focus on the locomotor CPG in mouse, combining genetics with neurophysiology; and Gilad Silberberg, initially a postdoc in our group, is now an associate professor working on the rodent basal ganglia. Finally, Hellgren, while professor in neuroinformatics at KTH, has supervised PhD students and occupies an office in our department, bringing her modeling expertise to bear on these research problems. This has become a positive and interactive environment with common seminars and social interaction between PhD students, postdocs, and the many colleagues. Over the years, I have had more than 50 postdocs, many from North America, and some 16 PhD students.

In the late 1980s and early 1990s, I was quite active in the faculty board and engaged in restructuring the faculty from having some 140 mostly small departments to around 25 large departments in 1993. In this process, we created a neuroscience department from several smaller departments, including my own. The staff of the new department included from the beginning several distinguished neuroscientists like Hökfelt, Kjell Fuxe, Lars Olson, Gunnar Grant, Lars Gösta Elfvin, Staffan Cullheim, Krister Kristensson, Per Roland, and myself. As the founding chair of the department, it was a stimulating but not always an easy task to make the scientific cultures of these different areas interact. This coincided with a period of diminishing funding of research in Sweden, which meant that all departments received less funding. The Karolinska Institute nevertheless was favored, in that it received no less than around 40% of the total external national funding in life science and medicine, with the rest being shared among the universities in Uppsala, Lund, Göteborg, Umeå, and Linköping. Over the past 20 years, individual researchers now depend primarily on external funding—a situation quite different from earlier times, and this, it seems, has had a negative effect on the impact of Swedish science.

Selecting Nobel Laureates

I took part in the process of selecting Nobel laureates in Physiology or Medicine from 1986 to 2008 and chaired the Nobel committee for two years. This was a stimulating endeavor and allowed me to scrutinize a number of interesting studies in many different areas. The task was to identify important discoveries and determine who were the key individuals responsible (not more than three). The process was developed in 1901 (the first award), and has been important in maintaining a secure routine. For all nominations being submitted (around 200 to 300 each year), a written preliminary report is provided, and for those that seem of particular interest, reports by different specialists are commissioned. Over several years, different reports are obtained that usually clarify the importance of a given discovery and that specify who are the main individuals responsible. The next question was to compare different prize constellations and which would be the most prize worthy in a given year. When comparing widely different areas, there can be no absolute justice, but the area chosen needs to represent a breakthrough. What has been critical to ascertain is that the laureates chosen for a given area are those who were instrumental in making the discovery. The Nobel Prizes awarded for the most part have been well received, and the 1901 strategy with written reports most certainly has been important in this context because it allows for going back to reports written years earlier. In contrast, most international prizes rely mostly on deliberations during committee meetings. The Nobel reports remain in secrecy for 50 years and then can be released, for example, to historians of science.

International Engagement

Since early on, I have had the privilege of interacting with colleagues in different parts of the world. An important early step was when I along with Paul Stein, Douglas Stuart, and Richard Herman co-organized a meeting of the neural control of locomotion in 1975 near Philadelphia. In this meeting, we, for maybe the first time, compared locomotion in vertebrates with that of invertebrates to look for common principles. This was at an early stage, but a creative interaction took place with the invertebrate model systems, like Crustaceans, Tritonia, locust, and cockroach, and on the vertebrate side, the experiments on humans and cats dominated but also a little bit of fish. Not surprisingly, we found that CPGs tended to be present in practically all model systems explored and similarly, in most cases, a sensory contribution was present helping to adapt the movements to the surrounding world. We continued to have a meeting every 10th year, in Stockholm in 1985, then Tuscon in 1995, and in Stockholm again in 2005. These meetings were stimulating, and useful for the field, and Rossignol, Forssberg, Wallén, El Manira, and Kiehn joined the organizing committee in different phases and combinations.

I always have had good interactions with different groups in North America over many years, and I was honored when SfN invited me to give the Grass Lecture in 1983, in which I talked about our studies on spinal organization of locomotion in the cat and also about our new findings in the lamprey. At that time, there were only two or three plenary lectures at SfN, and I was terrified to meet an audience 10 or 20 times bigger than I previously had experienced. The lecture was summarized in an article in Science in 1985. Afterward, I had the fortune to be asked to participate in many challenging events of this type.

I have had the pleasure of interacting with many different groups early in my career, including those with Stein in Saint Louis, Rossignol and Dubuc at the University of Montreal, Stuart in Tucson, Edgerton at UCLA, and Feldman working on the respiratory system at UCLA and invertebrate groups like those of Al Selverston (UCSD) and Eve Marder (Brandeis). I also was influenced and impressed by Eric Kandel’s (Columbia) work on learning in Aplysia and of his ability to synthesize and integrate knowledge of the brain, an ability that he shares with Jean-Pierre Changeaux at Collège de France in Paris. Whereas Kandel received the Nobel Prize many years later (2000), this prize as yet has not been awarded to Changeaux. During later years, I have very much appreciated the interaction with Torsten Wiesel and his clear judgment in science and organization of research in a local and global perspective.

Over the years, in addition to collaborating with previous postdocs, I have interacted with many different groups like that of Francois Clarac in Marseille. We had a common EU grant and three of his PhD students (Jean-Yves Barthe, El Manira, and Vinay) joined my laboratory as postdocs. Vinay later made a stellar career in Marseille, working on mouse spinal cord, but sadly died unexpectedly at age 50 from an acute heart condition. Around 2000, I coordinated another EU grant on microcircuits (spinal cord, hippocampus, neocortex, and cerebellum) with Eric De Schutter, Jörn Hounsgaard, Eberhard Buhl, Lansner, and a young Henry Markram. In another important EU Select-and-Act Grant on the basal ganglia, we had a rewarding interaction with Paul Bolam, Hagai Bergman, and Ann Graybiel, and in yet another more robot-oriented grant, Lampetra, we worked with Paolo Dario in Pisa and with Auke Ijsbeert, Ekeberg, and Jean-Marie Cabelguen. Without a formal grant, there has been a close interaction with many, including Ansgar Buschges, who spent a year in our laboratory just before he was appointed as chair in Cologne.

FENS and IBRO

In 1990, I had taken on the task of organizing the European Neuroscience Association (ENA) annual meeting in Stockholm, with Per Andersen, then president of the society. This was demanding with limited and uncertain funding, but it worked. John Eccles and Ragnar Granit represented the Nobel laureates who provided a perspective on neuroscience, and Bert Sakmann, the year before he was awarded. Later, ENA was replaced by the Federation of European Neuroscience Societies (FENS), which organizes a pan-European meeting every second year, alternating with the meetings of the many national societies. I served FENS from 2010 to 2012 as president and promoted the establishment of a permanent FENS office in Brussels with an executive director and staff to work in the interest of the neuroscience community on many different levels. At the time, we also initiated a plan to develop one or two permanent training sites in Europe (like Cold Spring Harbor), which was realized together with the International Brain Research Organization (IBRO) in Champalimaud (Lisbon) and Bordeaux in 2015. The interaction with Fotini Stylianopoulou as secretary general and Domnique Poulain as executive director during these two FENS years was joyful and productive.

I was subsequently elected as secretary general of IBRO from 2013 to 2015. The profile of IBRO is different from FENS; it has regional committees largely one for each continent and has an intention to promote neuroscience in middle- and low-income countries. One important aspect of this work is to promote training by PhD/postdoc courses in the different regions and another is to give short- and long-term travel grants and postdoc stipends. IBRO has an efficient secretariat led by Stephanie de la Rochefoucauld, which handles thousands of grant applications and interacts with all parts of the world. It has been interesting and rewarding to experience that many of these actions make a real difference and to try to further develop these activities.

The Need for Neuroinformatics—INCF and the Human Brain Projects

As I realized the importance of simulations in my interaction with Lansner and Hellgren, it also meant that I became engaged in trying to promote computational neuroscience and neuroinformatics. In the late 1990s, I became the Swedish representative to a group organized by the Organisation of Economic Co-operation and Development (OECD) in Paris and its Megascience Forum, which was tasked with exploring the possibilities of developing neuroinformatics on a global scale. At the NIH, it had been realized that databases should be important for neuroscience to facilitate retrieval of findings from different organizational levels, ranging from structural biology to microcircuits, systems, and behavior. Similarly, the importance of being able to develop detailed simulations was in focus. Rather than each country developing its own databases and infrastructure, the intention was that this should be a collaborative effort on a global scale. This OECD exploration resulted in a 2005 report calling for the formation of an International Neuroinformatics Coordinating Facility (INCF), which was endorsed by all ministers of research within OECD.

The next step was to actually form INCF, which happened in a telephone conference in August 2005 with seven member countries participating, and with me as the interim chair. The next question was where the secretariat should be located. The Swedish government at the time was interested in making a bid for a location in Stockholm. After a tight competition, an international high-level committee decided to locate the secretariat in Stockholm, at the Karolinska Institute, but with the KTH as a co-host of the secretariat. The Karolinska Institute offered space for the secretariat, and KTH offered a professorship in neuroinformatics and also provided support from the KTH computer center. To build up the secretariat from scratch was a demanding task, with a staff of 12 people, mostly PhDs, who would mostly be program officers for the different projects. Jan Bjaalie was the first executive director, and did a good job in building up INCF, while I served as the founding chair of the board for the first seven years. INCF now has 18 member states that provide project funding; in addition, INCF receives funding as part of different international projects.

These activities also led to my involvement in the large EU flagship, the Human Brain Project (HBP), which started in 2013 and aims to develop new and more advanced software to allow detailed simulations extending from the subcellular level to synapses, neurons, microcircuits, and systems, and, ultimately, to behavior and cognition. This is a formidable ambition that will not be realized quickly. Nevertheless, I think it is critical to build up these important tools, because I am convinced that without detailed simulations, there will be no possibility to understand any complex process in the brain in terms of cells, synapses, and microcircuits. Unfortunately, this project has been plagued with a number of shortcomings and conflicts partially because of unrealistic expectations.

Last but Most Important: My Family

I met my wife Lena when we were both medical students in Göteborg. She specialized initially in infectious diseases, but then took up clinical virology and received her PhD in 1975, just before we moved to Stockholm. She changed over to the clinical virology department at the Karolinska hospital and after some years became its head. Subsequently, after fusion of some microbiology laboratories in the Stockholm area, she became the head of Clinical Microbiology in Stockholm, with millions of tests for bacteria and viruses each year.

We have two daughters: Pernilla, who is now a pediatrician and neurooncologist, and Katja, who is an architect and professor at the KTH. When they were in school, we had a nice companionship in that one of the daughters and I were responsible every second week for preparing the dinner, buying the food, and setting the menu of the week, and my wife with the other daughter were responsible in the alternating weeks. It was fun to plan together and take responsibility, and I think this was a nice thing to do and the children at the same time gained useful experience. It also meant that every second week, I was free in relation to conduct experiments and so forth. This was also a good way for my wife and I to split responsibilities, with both of us having a lot of demands on our time. For the children, it may have been more demanding to be with me, as I had rather often other things coming up. The children spent time in the lab or at the Marine Biology Station, where they sometimes helped. Since Pernilla was born, we have had a summerhouse, an old harbor pilot’s house, on an island outside Göteborg, which is scenic and provides a relaxing environment, allowing time for some sailing and snorkeling. It also has been good for writing and planning our next steps to take in science. We could not wish to have had a more enjoyable time with our children, and they are now the parents of a set of wonderful grandchildren. Although we both have had demanding careers, I owe very much to Lena for always being there to make things happen in a nice way and for keeping track of me, when I was overcommitted or just had made some of my many mistakes.

Conclusion

If we are to understand the operation of the brain in terms of cells, synapses, microcircuits, and beyond, we need to work with different approaches and select appropriate model systems. My ambition in this demanding endeavor has been to understand the detailed operation of the networks underlying the control of motion from the basic microcircuits in the spinal cord to the forebrain mechanisms underlying selection of motor programs. By using the lamprey as a model system, we have achieved this goal in many aspects. I believe we now have an integrated understanding of not only the neural bases of the locomotor networks but also the control of body orientation, tectal control, and forebrain mechanisms underlying selection of behavior, which taken together provides a more complete knowledge than in other vertebrate species. Moreover, we have shown that these circuits, including those in the forebrain, are conserved in evolutionary terms, which means that the basic design of these aspects of the motor system was conceived early in vertebrate development, some 560 million years ago.

Selected Bibliography

Work on Mammalian Motor System

Forssberg, H., and S. Grillner (1973). The locomotion of the acute spinal cat injected with Clonidine i.v. Brain Res. 50, 184–186.

Forssberg, H., S. Grillner, and J. Halbertsma (1980). The locomotion of the low spinal cat. I. Coordination within a hindlimb. Acta Physiol Scand. 108, 269–281.

Forssberg, H., S. Grillner, and S. Rossignol (1975). Phase dependent reflex during walking in chronic spinal cats. Brain Res. 85, 103–107.

Forssberg, H., S. Grillner, J. Halbertsma, and S. Rossignol (1980). The locomotion of the low spinal cat. II. Interlimb coordination. Acta Physiol Scand. 108, 283–295.

Georgopoulos, A.P., and S. Grillner (1989). Visumotor coordination in reaching and locomotion. Science 245, 1209–1210.

Grillner, S. (1972). The role of muscle stiffness in meeting the changing postural and locomotor requirements for force development by the ankle extensors. Acta Physiol Scand. 86, 92–108.

Grillner, S. (1973). Locomotion in the spinal cat. In Control of Posture and Locomotion, Stein R.B., Pearson K.G., Smith R.S., and Redford J.B., Eds., 515–535. New York: Plenum Press.

Grillner, S. (1975). Locomotion in vertebrates—Central mechanisms and reflex interaction. Physiol Rev. 55, 247–304.

Grillner, S. (2011). Human locomotor circuits conform. Science 334, 912–913.

Grillner, S., and T. Hongo (1972). Vestibulospinal effects on motoneurones and interneurones in the lumbosacral cord. In Basic Aspects of Central Vestibular Mechanisms. Progress in Brain Research, Vol. 37, A. Brodal and O. Pompeiano, Eds., 243–262.

Grillner, S., T. Hongo, and S. Lund (1971). Convergent effects on alpha motoneurones from the vestibulospinal tract and a pathway descending in the medial longitudinal fascicle. Exp Brain Res. 12, 457–479.

Grillner, S., J. Nilsson, and A. Thorstensson (1978). Intra-abdominal pressure changes during natural movements in man. Acta Physiol Scand. 103, 275–283.

Grillner, S., and S. Rossignol (1978). On the initiation of the swing phase of locomotion in chronic spinal cats. Brain Res. 146, 269–277.

Grillner, S., and M.L. Shik (1973). On the descending control of the lumbosacral spinal cord from the “mesencephalic locomotor region.” Acta Physiol Scand. 87, 320–333.

Grillner S., and P. Zangger (1975). How detailed is the central pattern generation for locomotion? Brain Res. 88(2), 367–371.

Experiments on Spinal Locomotor Mechanisms in Dogfish

Grillner S. (1974). On the generation of locomotion in the spinal dogfish. Exp Brain Res. 20(5), 459–470.

Grillner, S., C. Perret, and P. Zangger (1976). Central generation of locomotion in the spinal dogfish. Brain Res. 109, 255–269.

Grillner, S., and P. Wallén (1982). On peripheral control mechanisms acting on the central pattern generators for swimming in the dogfish. J Exp Biol. 98, 1–22.

Experiments on Locomotor Networks in the Lamprey Spinal Cord

Alford, S., and S. Grillner (1991). The involvement of GABAB receptors and coupled G-proteins in spinal GABAergic presynaptic inhibition. J Neurosci. 11(12), 3718–3726.

Buchanan, J.T., and S. Grillner (1987). Newly identified ‘glutamate interneurons’ and their role in locomotion in the lamprey spinal cord. Science 236, 312–314.

Cangiano, L., and S. Grillner (2005). Mechanisms of rhythm generation in a spinal locomotor network deprived of crossed connections: The lamprey hemicord. J Neurosci. 25, 923–935.

Dale, N., and S. Grillner (1986). Dual-component synaptic potentials in the lamprey mediated by excitatory amino acid receptors. J Neurosci. 6(9), 2653–2661.

El Manira, A., J. Tegnér, and S. Grillner (1994). Calcium-dependent potassium channels play a critical role for burst termination in the locomotor network in lamprey. J Neurophysiol. 72(4), 1852–1861.

El Manira, A., J. Tegnér, and S. Grillner (1997). Locomotor-related presynaptic modulation of primary afferents in the lamprey. Eur. J Neurosci. 9, 696–705.

Grillner, S. (1985). Neurobiological bases of rhythmic motor acts in vertebrates. Science 228, 143–149.

Grillner, S. (1991). Recombination of motor pattern generators. Simple neuronal networks combine to produce complex versatile motor patterns. Curr Biol. 1(4), 231–233.

Grillner, S. (1996). Neural networks for vertebrate locomotion. Scientific American. January, 64–69.

Grillner, S., H. Markram, E. De Schutter, G. Silberberg, and F.E.N. LeBeau (2005). Microcircuits in action—from CPGs to neocortex. TINS 28(10), 525–533.

Grillner, S., and T. Matsushima (1991). The neural network underlying locomotion in lamprey-synaptic and cellular mechanisms. Neuron. 7, 1–15.

Grillner, S., and P. Wallén (1980). Does the central pattern generation for locomotion in the lamprey depend on glycine inhibition? Acta Physiol Scand. 110, 103–105.

Grillner, S., and P. Wallén (1985). Central pattern generators for locomotion with special reference to vertebrates. Ann Rev Neurosci. 8, 233–261.

Grillner, S., T. Williams, and P-C Lagerbäck (1984). The edgecell, a possible intraspinal mechanoreceptor. Science 223, 500–503.

Matsushima, T., and S. Grillner (1992). Neural mechanisms of intersegmental coordination in lamprey—Local excitability changes modify the phase coupling along the spinal cord. J Neurophysiol. 67, 373–388.

Schotland, J., O. Shupliakov, M. Wikström, L. Brodin, M. Srinivasan, Z. You, M. Herrera-Marschitz, W. Zhang, T. Hökfelt, and S. Grillner (1995). Control of lamprey locomotor neurons by colocalized monoamine transmitters. Nature. 374, 266–268.

Wallén, P., K. Carlsson, A. Liljeborg, and S. Grillner (1988). Three-dimensional reconstruction of neurons in the lamprey spinal cord in whole-mount, using a confocal laser scanning microscope. J Neurosc Meth. 24, 91–100.

Central Canal Cells and the pH Control of Motor Activity

Jalalvand, E., B. Robertson, P. Wallén, and S. Grillner (2016). Ciliated neurons lining the central canal sense both fluid movements and pH through ASIC3. Nature Com. 7, 10002.

Jalalvand, E., B. Robertson, P. Wallén, R.H. Hill, and S. Grillner (2014). Laterally projecting cerebrospinal fluid-contacting cells in the lamprey spinal cord are of two distinct types. J Comp Neurol. 522(8), 1753–1768.

Jalalvand, E., B. Robertson, H. Tostivint, P., and S. Grillner (2016). The spinal cord has an intrinsic system for the control of pH. Curr Biol. doi:10.1016/j.cub.2016.03.048.

Simulation of Locomotor Activity in Lamprey

Ekeberg, Ö., P. Wallén, A. Lansner, H. Tråvén, L. Brodin, and S. Grillner (1991). A computer based model for realistic simulations of neural networks. I. The single neuron and synaptic interaction. Biol Cybern. 65, 81–90.

Hellgren Kotaleski, J., A. Lansner, and S. Grillner (1999). Neural mechanisms potentially contributing to the intersegmental phase lag in lamprey. II Hemisegmental oscillations produced by mutually coupled excitatory neurons. Biol Cybern. 81, 299–315.

Kozlov, A., M. Huss, A. Lansner, J. Hellgren Kotaleski, and S. Grillner (2009). Simple cellular and network control principles govern complex patterns of motor behavior. Proc Natl Acad Sci USA. 106, 20027–20032.

Kozlov, A.K., A.A. Kardamakis, J. Hellgren Kotaleski, and S. Grillner (2014). Gating of steering signals through phasic modulation of reticulospinal neurons during locomotion. Proc Natl Acad Sci USA. 111, 3591–3596.

Tråvén, H.G.C., L. Brodin, A. Lansner, Ö. Ekeberg, P. Wallén, and S. Grillner (1993). Computer simulations of NMDA and non-NMDA mediated synaptic drive—sensory and supraspinal modulation of neurons and small networks. J Neurophysiol. 70(2), 695–709.

The Lamprey Brainstem and Midbrain Control of Body Orientation and Steering

Asteriti, S., S. Grillner, and L. Cangiano. A Cambrian origin for vertebrate rods. Elife. 4,. e07166. doi: 10.7554/eLife.07166

Deliagina, T.G., G.N. Orlovsky, S. Grillner, and P. Wallén (1992). Vestibular control of swimming in lamprey. II. Characteristics of spatial sensitivity of reticulospinal neurons. Exp. Brain Res. 90, 489–498.

Grillner, S., and R. Dubuc (1988). Control of locomotion in vertebrates: Spinal and supraspinal mechanisms. In Advances in Neurology, Vol. 47, Functional Recovery in Neurological Disease, Waxman, S.G., Ed., 425–453. New York: Raven Press.

Kardamakis, A.A., K. Saitoh, and S. Grillner (2015). Tectal microcircuit generating visual selection commands on gaze-controlling neurons. Proc Natl Acad Sci USA. 112(15), E1956–E1965.

Lamprey Basal Ganglia and Habenulae

El Manira, A., M.A. Pombal, and S. Grillner (1997). Diencephalic projection to reticulospinal neurons involved in the initiation of locomotion in adult lampreys Lampetra fluviatilis. J Comp Neurol. 389, 603–616.

Pombal, M.A., A. El Manira, and S. Grillner (1997). Afferents of the lamprey striatum with special reference to the dopaminergic system: A combined tracing and immunohistochemical study. J Comp Neurol. 386, 71–91.

Stephenson-Jones, M., J. Ericsson, B. Robertson, and S. Grillner (2012). Evolution of the basal ganglia; dual-output pathways conserved throughout vertebrate phylogeny. J Comp Neurol. 520, 2957–2973.

Stephenson-Jones, M., O. Floros, B. Robertson, and S. Grillner (2012). Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems. Proc Natl Acad Sci USA. 109, 164–173.

Stephenson-Jones, M., A.A. Kardamakis, B. Robertson, and S. Grillner (2013). Independent circuits in the basal ganglia for the evaluation and selection of actions. Proc Natl Acad Sci USA. 110(38), E3670–E3679.

Stephenson-Jones, M., E. Samuelsson, J. Ericsson, B. Robertson, and S. Grillner (2011). Evolutionary conservation of the basal ganglia as a common vertebrate mechanism for action selection. Curr Biol. 21, 1081–1091.

Pallial/Cortical Control of Movements in Lamprey—Projection Patterns Conserved

Ocaña, F.M., S. M. Suryanarayana, K. Saitoh, A.A. Kardamakis, L. Capantini, B. Robertson, and S. Grillner (2015). The lamprey pallium provides a blueprint of the mammalian motor projections from cortex. Curr Biol. 25(4), 413–423.

The Respiratory Network in Lamprey

Cinelli, E., B. Robertson, D. Mutolo, S. Grillner, T. Pantaleo, and F. Bongianni (2013). Neuronal mechanisms of respiratory pattern generation are evolutionary conserved. J Neurosci. 33, 9104–9012.

Cinelli, E., D. Mutolo, B. Robertson, M. Contini, T. Pantaleo, and F. Bongianni (2014). GABAergic and glycinergic inputs modulate rythmogenic mechanisms in the lamprey respiratory network. J Physiol. 592, 1823–1838.

Other Works Mentioned in the Text

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Howard Kaas

BORN:

Fargo, North Dakota

September 13, 1937

EDUCATION:

Northland College, Ashland, WI, BA (1959)

Duke University, Durham, NC, PhD (1965)

APPOINTMENTS:

Postdoctoral Fellow, University of Wisconsin, Laboratory of Neurophysiology (1965–1968)

Assistant Professor, University of Wisconsin (1968–1972)

Associate Professor of Psychology, Vanderbilt University (1972–1978)

Visiting Scientist, University of California at San Francisco (1975 Summer)

Professor, Vanderbilt University (1978–2001)

Visiting Scientist, The Neurosciences Institute, New York (1982 Summer)

Visiting Scientist, Department of Physiology and Pharmacology, University of Queensland, Australia (1984 Summer)

Kennedy Center, Senior Fellow and Investigator, Vanderbilt University (1987–present)

Centennial Professor of Psychology, Vanderbilt University (1987–2011)

Distinguished Professor of Psychology, Vanderbilt University (2001–present)

Distinguished Visiting Professor, International Institute of Neuroscience, Natal, Brazil (2011)

Gertrude Conaway Professor, Vanderbilt University (2011–present)

HONORS AND AWARDS (SELECTED):

Krieg Cortical Discoverer Award, Cajal Club, 1980

The Earl Sutherland Prize for Achievement in Research, awarded by Vanderbilt University, 1985

Javits Neuroscience Investigator Award, 1987

Elected Fellow, American Association for the Advancement of Science, 1991

American Psychological Association Distinguished Scientific Contribution Award, 1994

Elected Member, International Neuropsychology Symposium, 1994

Elected Member, La Jolla Group for Explaining the Origin of Humans, 1998

Fellowship, Center for Advanced Study in the Behavioral Sciences, Stanford University, 1999–2000

Elected Member, National Academy of Sciences, 2000

Elected Fellow, American Academy of Arts and Sciences, 2001

Elected Member, Society of Experimental Psychologists, 2001

Karl Spencer Lashley Award, American Philosophical Society, 2006

Elected Associate, Neurosciences Research Program, The Neurosciences Institute, San Diego, 2009

Excellence in Graduate Mentoring Award, Vanderbilt University, 2009

Distinguished Visiting Professor, International Institute of Neuroscience, Natal, Brazil, 2011

George A. Miller Prize in Cognitive Neuroscience, Cognitive Neuroscience Society, 2014

Palay Award, Journal of Comparative Neurology, award by Wiley Publishing, 2014

Honorary Life Member, J. B. Johnson Club for Evolutionary Neuroscience, 2014

Jon Kaas is known for his comparative studies of the organizations of sensory and motor systems, especially in primates. A major interest has been in deducing the likely organization of the forebrain in early mammals, and how this organization has been altered in many ways in extant mammals. Other research efforts have been on how sensory and motor systems respond to injury and sensory loss. Contrary to early views, this research has demonstrated the remarkable plasticity of mature nervous systems.

Jon Howard Kaas

Introduction

Looking back on my career, I feel that my path was very unlikely and that I was extremely lucky. Quite simply, my background does not suggest an academic career. My parents came from large families that had limited means. My mother was from North Dakota and my father from northern Wisconsin. After he finished high school, my father received training and became a store manager, so we were somewhat better off, and this made a difference. I was born in Fargo, North Dakota, and after moving around a bit, we settled in a small town in northern Wisconsin (Spooner) but soon moved seven miles out of town, on the beautiful Namekagon River (now a National Wild River). This resulted in my grade school education being in a two-room school with no running water, and the same teacher for four years. Class sizes ranged from two to seven. At age 13, I was bused back to Spooner for high school, where I found support from a wonderful chemistry teacher, and enjoyed history class, which was well taught and interesting. But at home I was isolated, and read a lot in a somewhat random and unsupervised manner that somehow included Darwin, Poe, and Freud. To my surprise, Darwin’s Origin of the Species had never been checked out from the school library, and was certainly unavailable elsewhere. No one I knew ever talked about any of these three. For religious reasons, my father clearly disapproved when he saw me reading Darwin, but he did nothing to stop me.

After graduation from high school, I briefly held a job on local road construction, and then at the local creamery, first cleaning pipes, and then, because of my high school chemistry, testing milk. Soon thereafter, while enjoying myself in a local tavern, although still only 17, I met a student from the nearest college, Northland College, some 80 miles north on Lake Superior. He suggested that I should attend Northland and that it wasn’t too late to apply and be admitted for the fall semester. He thought, with my high school record, I would likely get a scholarship to cover most of the expenses. This proved to be true, and at the end of summer, I found myself at Northland, at the time a college of only 250 students, in a small dorm room with two other new students who soon became my close friends. While I continued to work some weekends and then in the summer, my parents were able to help me with fifty dollars per month and sometimes the use of a car. At Northland, teaching, as in high school, was uneven, but I had good-to-very-good classes in chemistry, physics, and math. I was most impressed with a new professor from New York, who took special interest in his students. He invited us to his home to discuss readings and took some of us on field trips, including to the annual meeting for Midwest Sociological Society. For one of his classes, we were expected to do original research and this requirement made an impression on me. In my final semester, the rather young president of this small college offered a class in abnormal psychology. For a class paper, I combined two of my high school interests and tried to interpret the symbolic meanings of poems and stories of Edgar Alan Poe. With more experience, I would have thought it foolish and presumptuous to attempt such an effort, but the school president was impressed, and suggested that I should go to graduate school. He offered to help me and provided a strong letter of recommendation. This was way past the assumed deadline for graduate school applications, but he said not to worry, and soon I had offers in psychology from roughly six to seven universities. I wanted to work with Harry Harlow at the University of Wisconsin, and at first that seemed possible, but he was on leave, and he didn’t take any students. I was told this by the acting director of graduate admissions at Wisconsin, who was a visiting professor from Duke. I answered that I would take my second choice of graduate school, and go to Duke. He said, “I’ll see you there.”

The Duke offer was impressive in that it was in a new interdisciplinary program funded by NSF in the Anatomical and Physiological Bases of Behavior. This program seemed so different from my background and interests in social psychology that it strongly appealed to me. On arriving at Duke on a very hot August day, I soon found that I was in way over my head. The new program meant that I and the other three students in the program would take basically all of the courses of first-year medical school, and, for me at least, most of the classes for first-year psychology students. When the lab instructor for gross anatomy found out how little I knew, compared to the well-prepared medical students, he quietly told me “you’re never going to make it.” But I did, and that year of medical school classes was very good for me and sometimes fun.

The most important thing that happened to me in graduate school was taking a first-year class with Irving Diamond. The class consisted of a series of assigned readings that the other students in the NSF program and I would discuss with Diamond in his office. This fit well with my habit of reading more about each topic from related papers, and Diamond was impressed enough to ask me to join his lab. I was too shy at that stage to have asked him myself (see autobiography, Diamond 1996). Diamond was a new faculty member just arrived from the University of Chicago, where he was known for his ablation-behavior studies of auditory cortex with Dewey Neff. I greatly appreciated my opportunity to work with Diamond, as he stressed understanding over rote learning and he asked questions like “why do you think the authors of a paper wrote the Introduction as they did?” He taught us to focus on the major contributions of published papers (why was this paper important) rather than weakness. He encouraged me to make up for my weak background in biology by taking graduate classes in genetics and comparative physiology. As a result, I was lucky to have taken a class with a fantastic comparative physiologist, Knut Schmidt-Nielson (see Schmidt-Nielsen 1984), an experience that influenced my subsequent research greatly. Importantly, Diamond treated those of us in the laboratory as members of a family. I always knew I had his support. When I joined his laboratory, he told me that my thesis would be published in the Journal of Neurophysiology, and I would go on to the best of laboratories for my postdoc and training. Both predictions came to be true. While I was a graduate student with Diamond, I first worked on studies of the somatosensory system without much progress, and then I turned to do a thesis on the role of the corpus callosum in auditory behavior for my PhD (Kaas et al. 1967). This would not be considered adequate progress today.

During this time, I was very impressed with Bruce Masterton, who had joined the lab as an older student who left his position in mathematics to become a graduate student in psychology. Bruce completed his PhD with a series of brilliant studies on the roles of parts of the auditory system in sound localization and other behavior, and left for a faculty position at Vanderbilt, my present university. I also became close friends with two other graduate student members of the laboratory, Bill Hall and Herb Killackey, who later became collaborators. The focus of the Diamond laboratory had changed while I was a student from studies on the auditory system of cats to comparative studies of brain organization. This new direction greatly influenced my goals for the future.

My Years at the University of Wisconsin

After finishing my PhD, Diamond’s strong recommendation got me accepted as a postdoctoral fellow in the Laboratory of Neurophysiology at the University of Wisconsin, headed by Clinton Woolsey. Woolsey was internationally known for his comparative studies of cortical and thalamic organization. He had moved from the Johns Hopkins University School of Medicine to forge his own laboratory, independent from any department, at the University of Wisconsin. He attracted an outstanding cast of faculty, some promoted after training in the laboratory (Robert Benjamin, Joseph Hind, Wally Welker, and John Brugge), and Jerzy Rose recruited from Johns Hopkins. Under the leadership of Jerzy Rose, the Wisconsin auditory facility and group was widely recognized as the best for studying the neurophysiology of the auditory system. I had planned to continue working on the auditory system, with a comparative approach across species. However, on my arrival Woolsey told me that the laboratory had enough fellows working on the auditory system and that I should work on the visual system; more specifically on the organization of visual cortex in cats. Since no one else in the laboratory was working on the visual system, and Woolsey had published a paper on visual areas I and II in rabbits, he would help me. (At this time and for sometime afterward, Roman numerals were used to denote early visual, somatosensory, and auditory areas.)

This change of direction led to years of work on trying to map visual cortex in cats. Immediately, it became apparent that the earlier method used by Woolsey, that of flashing light from a row of bulbs into the visual field while recording evoked potentials from the surface of the brain, did not provide a uniform stimulus. With the help of trainees in neurosurgery during their research rotation, we outfitted a standard visual field evaluation device from the ophthalmology clinic with a strobe light so that we could flash a small one-degree spot of light anywhere in the visual field of the experimental animal. We continued the tradition in the Woolsey lab of recording from electrodes placed on the surface of the brain, but now we could also average evoked responses to reduce noise with the help of a new innovation, a large but computationally limited LINK computer—a firstgeneration computer for use in the biological sciences. We collected a lot of data on the retinotopic organization of visual cortex in cats, and later in a prosimian primate (slow loris), but the methods provided only a gross view of visual cortex organization. Our only published paper, a summer project for a medical student, was on the retinotopic organization of the very large superior colliculus of ground squirrels. Subsequently, Woolsey presented our maps of visual cortex in cats in a review (Woolsey 1971), but I foolishly declined his offer to be coauthor as I felt that our resolution of the retinotopy of extrastriate cortex was not good enough to distinguish VII and VIII, although a good map of VI was obtained. A breakthrough in procedures occurred when my friend from graduate school days at Duke, Bill Hall, came to work with me for a month on visual cortex of a small mammal, the hedgehog. We soon realized that brain surface recordings provided results that were too crude to reveal retinotopy in the small hedgehog brain, and so we switched to microelectrodes, something that Wally Welker (see Welker autobiography, 2001) was using as he mapped somatosensory cortex in his laboratory across the hall. In addition, Vincente Montero, a member of the Woolsey neurophysiology lab with experience mapping visual cortex in rats, advised us on anesthetics and the use of a translucent plastic hemisphere to present stimuli in the visual field. The altered methods worked, and we obtained evidence of the existence of visual areas I and II in hedgehogs (Kaas et al. 1970). By this time, despite my poor publication record, I was promoted to assistant professor in the Woolsey laboratory at Wisconsin. This meant that I had my own small lab, in part of a room, where I could set up to map visual cortex. Now I could go on to map visual cortex in other mammals.

To start, I took a leave for one summer and returned to the Diamond lab at Duke, where I was able to map visual cortex in grey squirrels (Hall et al. 1971) and tree shrews (Kaas et al. 1972a) with microelectrodes and a plastic hemisphere with my close friends, Bill Hall and Herb Killackey. At the same time, my wife, Judith, returned to Duke with me to finish her PhD thesis. While I was at Duke, John Allman had come to Wisconsin from the University of Chicago to work with Woolsey on a PhD project on the pulvinar. This relationship did not seem to be working, and on my return, Woolsey suggested that John and I work together. This was extremely fortunate for me, as I had, as of yet, no one else to work with, and John turned out to be an exceptionally talented researcher. We started with the visual cortex, since it was more accessible than the pulvinar, and used owl monkeys, as Woolsey had obtained a number of them from another laboratory. Soon we were joined by graduate student Ron Lane and by Fran Miezin who had a master’s degree in engineering. Both were great additions, but at first John and I worked alone and at a pace that would be hard to ever do again. We produced a series of papers on visual cortex of owl monkeys, providing the first complete retinotopic maps in any primate of V1 (Allman and Kaas 1971a) and V2 (Allman and Kaas 1974a). Perhaps our most important discovery was that of a systematic, retinotopic representation of the contralateral visual field in cortex, displaced from V1 in the caudal part of the middle temporal gyrus of owl monkeys, an area we termed the middle temporal visual area, MT. We demonstrated that MT was histologically distinct due to its dense myelination and that its neurons responded well to moving visual stimuli (Allman and Kaas 1971b). The homologous area in the cortex of the superior temporal sulcus of macaque monkeys, known to get direct inputs from V1 (Kuypers et al. 1965), was subsequently called V5 by Semir Zeki (Zeki 1983). Zeki had spent a few months at Wisconsin with Ray Guillery during this time, where I got to know him. John and I mapped a number of other visual areas, including the dorsolateral area (DL; Allman and Kaas 1974b) that largely overlapped the macaque area Zeki called V4, the dorsomedial area (DM; Allman and Kaas 1975), and the medial area (M; Allman and Kaas 1976). We also mapped the retinotopic organization of the superior colliculus in squirrels and tree shrews (Lane et al. 1971), owl monkeys, galagos (Lane et al. 1973), and cats (Lane et al. 1974), providing clear evidence that the representations in primates were of the contralateral hemifield only, while other mammals had a complete representation of the contralateral eye. Following John’s original interest, we mapped a lateral nucleus in the inferior pulvinar of owl monkeys (Allman et al. 1972). We also started recording from the optic tectum of seagulls with a graduate student from biology, but the graduate student soon left and we dropped, what could have been, a very interesting project.

While working with John on these various studies, I also started to collaborate with Ray Guillery, a professor in the Anatomy Department who was in an adjacent part of the building (see autobiography, Guillery 1998). Guillery was working on the effects of producing an imbalance in binocular competition in the developing visual system by rearing cats with reduced vision in one eye. This led to us extending this model to the well-developed visual system of squirrels producing results very much like that reported for cat visual cortex. In addition, Guillery was using the newly emerging Nauta methods of revealing brain connections, and discovered that the projections of the retina to the lateral geniculate nucleus of Siamese cats were abnormal. Soon we were using anatomical and physiological methods to study abnormalities in the Siamese cat visual system that resulted from their misdirected retinal projections (e.g., Kaas and Guillery 1973), and extended these studies to include a white tiger (Guillery and Kaas 1973), and ultimately in an albino monkey (Guillery et al. 1984). As our results on Siamese cats differed somewhat from those of Hubel and Wiesel (1971) in Boston, Guillery proposed that we assume that two patterns of cortical organization exist, one for Midwestern Siamese cats, and one for Boston Siamese cats. This seemed to be a practical way of resolving the differences. Through Guillery, I got to work with two of his postdocs, John Harting from the Diamond lab at Duke, and Ken Sanderson from P.O. Bishop’s lab in Australia. John remained at Wisconsin, and later became chair of the Anatomy Department. As for teaching at Wisconsin, I was only required to offer a seminar. I scheduled it for 10–12 Saturday morning to discourage attendance. When only one student showed up, Denis Steindler, I suggested playing basketball 10–12, followed by an hour of discussion in the Badger Tavern. He agreed, and it didn’t hurt him too much, as he went on to a successful career in neuroscience. Later I had the opportunity to collaborate with him when he was a faculty member at the University of Tennessee Medical School in Memphis, Tennessee.

My situation at Wisconsin had been perfect for me as I was well funded through Woolsey’s center grant and surrounded by great investigators. Woolsey’s efforts had provided outstanding histological services, a shop person within the laboratory, equipment repair and service, a trained assistant for animal surgery, and fantastic illustration and photographic services. My now-comfortable environment at Wisconsin soon radically changed as a result of being invited to interview by the Department of Psychology at Vanderbilt University in Nashville, Tennessee.

Starting at Vanderbilt

Sometime after my former classmate Bruce Masterton left Vanderbilt for Florida State, and his replacement did not get tenure, Diamond suggested me for the vacant position at Vanderbilt and encouraged me to at least interview there. The interview was in May while the snow was piled high in Wisconsin, and it was spring in Nashville. An outdoor party with the faculty reminded me of how long the winter was in Wisconsin. After some negotiating, I received an offer that was raised to that of associate professor, but the real inducement was an offer of a research position for my wife at the Vanderbilt University Kennedy Center. I didn’t want to leave Wisconsin, but this was a great opportunity for positions for both my wife and me, and so we moved. I started my position in 1973. I had the remarkably low startup funds of $15,000, and a few rooms abandoned by the departed investigator who didn’t get tenure. As a parting gift, this investigator had the rooms painted purple. I quickly realized I wasn’t in Kansas (Wisconsin) anymore and scrounged what I could in equipment. I spent half of the $15,000 on a microscope, and soon spent the rest to support a graduate student, Rick Lin, who came from the Diamond lab, and most important, he knew how to do histology. Jennette Norden, a graduate student at Vanderbilt, joined me for her PhD research. She later received many awards for her outstanding teaching of neuroanatomy at Vanderbilt Medical School. My attempts to get a vision grant from NIH failed, to my surprise, but I was rescued by NSF and, soon thereafter, by a second NSF grant on somatosensory cortex. By 1975, I got my vision grant from the National Eye Institute (NEI), and in 1980, my National Institute of Neurological Disorders and Stroke (NINDS) grant on the somatosensory system. I have retained both of these NIH grants to this day. Having this consistent funding has been very important in my being able to maintain a functional laboratory. Unfortunately, funding for neuroscience has become much less dependable.

Teaching at Vanderbilt

As research dominated my time while I was in the medical school at Wisconsin, my teaching role in psychology at Vanderbilt was quite an adjustment. I was assigned two courses per semester, which meant six hours in class per week, and this continued until I was well past the level of full professor. I taught Physiological Psychology, which I renamed Introduction to the Neurosciences, when students asked, “Where is the psychology?” I started to teach animal behavior, with no relevant background, and it became my most fun class. I was asked to coteach human sexuality with Leslie Smith, but soon found this was too difficult for me, while Leslie continues this popular course on her own.

The teaching did me a lot of good, as I was always stressed when giving public talks, and my nervous system adjusted as it couldn’t be stressed that many times a week. Teaching also taught me to keep things simple and to not put too much in a lecture. However, I have not been completely successful. Recently, my daughter, Lisa, sent me a book Don’t Be Such a Scientist (2009) by Randy Olson, which listed all the mistakes scientists commonly make when giving talks. I recognized that I made, or make, most of them.

Early Research at Vanderbilt

At first, Rick Lin and I focused on anatomical studies of the connections of the visual system on monkeys, using the Nauta methods I learned from Guillery. Then we added autoradiographic methods with the help of Vivien Casagrande, who had a PhD from the Diamond lab, and did a postdoc with Guillery at Wisconsin. I helped recruit Vivien for the Anatomy Department at Vanderbilt, and Vivien and I continue to collaborate on studies of the visual system. I also spent two summers at the University of California, San Francisco, studying auditory cortex with Mike Merzenich, as we had became close friends while both of us were postdocs in the Woolsey laboratory. This allowed me to learn about mapping auditory cortex, which paid off later, but also, and most importantly, to get Mike to come to Vanderbilt for a very productive year of collaborative research on the somatosensory system. As I had switched from auditory to visual system research in Woolsey’s Laboratory, Mike had switched from his somatosensory background during his PhD with Vernon Mountcastle to auditory research at Wisconsin (see autobiography, Merzenich 2012). Thus, Mike was the leading collaborator for a series of studies on the organization of the somatosensory system in monkeys and then on the functional recovery of this system after sensory loss in mature monkeys.

I had wanted to expand my research program to include the somatosensory system, but needed to create a larger group of investigators. This started with the arrival of Rick Lin from Duke, and then Randy Nelson, a new graduate student with experience in the Diamond laboratory at Duke as an undergraduate. I was also very fortunate to be able to attract Dan Felleman to join the lab as a graduate student, as he had considerable experience as an undergraduate investigating the response properties of single neurons in the visual cortex of cats with Bob Emerson at the University of Rochester. In addition, I became the PhD thesis supervisor of Mriganka Sur, a gradate student in the Department of Electrical Engineering at Vanderbilt, through the help of a psychology professor, Bob Fox. Bob was very active in recruiting me to Vanderbilt and was a dependable supporter. Because I didn’t have the funds, Bob supported Mriganka for me for a year. All these PhD students went on to complete postdocs in other laboratories and have productive research careers at major universities.

With graduate students like these, and Mike Merzenich joining us, how could we not become successful? We soon established that the traditional “S1” representation in primates consists of four complete representations of the contralateral body, one for each of the four classical architectonic areas of Brodmann: areas 3b, 3a, 1, and 2 (Merzenich et al. 1978; Kaas et al. 1979). On the basis of neuron response properties, and thalamic connections (e.g., Lin et al. 1979), we regarded area 3b as the primary tactile area, with areas 1 and 2 as higher levels of processing, and area 3a as the primary proprioceptive area. We were able to distinguish modular segregations of neurons responding to rapidly or slowly adapting cutaneous receptors in area 3b (Sur et al. 1981), determine quantitative features of the somatotopic representations in areas 3b and 1 (Sur et al. 1980), and described the somatotopic organization of the ventroposterior nucleus in detail (Kaas et al. 1984). We also defined ventroposterior superior nucleus that relays proprioceptive information to areas 3a and 2, often by branches of the same neurons (Cusick et al. 1985). We mapped the somatotopy of area 3b or “S1 proper” in macaques, owl monkeys, squirrel monkeys, cebus monkeys, galagos, cats, grey squirrels, and tree shrews. We also mapped the somatotopy of area 2 in macaque monkeys and determined its connections (e.g., Pons and Kaas 1986). Much of this early research was made possible by the addition of Tim Pons as a graduate student, Preston Garraghty as a visiting graduate student, and Cassie Cusick as a postdoc from Ray Lund’s lab.

In parallel with the above studies, we started a series of investigations of the responses of mature somatosensory system to sensory loss. We started by cutting the cutaneous median nerve to the thumb side of the glabrous skin of the hand, and tying the proximal end to prevent regeneration. This experiment was meant to be a control for studies on the regeneration of sensory nerves (cut nerves regenerate with errors, while a crushed nerve regenerates perfectly, as demonstrated with a postdoc, John Wall (Wall et al. 1983). However, when regeneration was prevented, our experiments revealed that the deprived cortical territories of the median nerve in areas 3b and 1 were reactivated by inputs from other parts of the hand over a period of weeks (Merzenich et al. 1983a, 1983b). This was at a time when it was widely believed that the organizations of sensory systems were mutable only during a narrow sensitive period of development. Our early experiments started us on a series of plasticity studies of the somatosensory system of adult primates that continue to this day. Also during this time period, additional experiments on the somatosensory system and studies of motor cortex were due to the arrival of Harry Gould after his PhD with Ford Ebner, and the help of Herb Killackey as visiting faculty. Sherre Florence joined us as a postdoc from Vivien Casagrande’s lab. Sherre was instrumental in continuing the somatosensory plasticity studies, along with Preston Garraghty when he returned to my lab after postdoctoral research with Mriganka Sur at Yale and MIT. Mike Sesma came over from the Casagrande lab for a short period and produced a remarkable paper on area 17 projections in tree shrews (Sesma et al. 1984). Mike is now chief of the postdoctoral training branch at NIH.

Branching Out with a Second Wave of Co-investigators

I got to work with another group of investigators when Mike Huerta from the John Harting lab and graduate students Lynn Leuthke and Leah Krubitzer from Vanderbilt Speech and Hearing joined my lab. Rosalyn Weller was a new graduate student, and Iwona Stepniewska, an expert on motor cortex, came as a postdoc from the Nencki Institute in Poland (Iwona has now been with me for 25 years). Todd Preuss came as a postdoc with an interest in brain evolution and frontal cortex from the Pat Goldman-Rakic lab at Yale, and Neeraj Jain, with a background in molecular biology, joined us from India. Patricia Gaspar came on leave for a short time from her research position in Paris, where she studied neural development. Additionally, Ken Catania, while working on his PhD with Glen Northcutt, came to investigate the somatosensory system of star-nosed moles, and he stayed on as a postdoc. Later additions were graduate students Carolyn Wu, Pamela Beck, Troy Hackett, Pei-Chun Fang, and David Lyon. Marcie Pospichal, a postdoc from another lab at Vanderbilt, headed experiments on visual cortex in cats.

From the many important contributions of this group, I will mention only a few. Harry Gould led our first efforts to use stimulating microelectrodes to map motor and premotor cortex in monkeys, and we were the first to conclude that the organization of the primary area, M1, has an overall crude somatotopy, but with regionally formed mosaics where adjoining sites evoke different, but related, movements (Gould et al. 1986; see Kaas 2012, on the possible significance of the “fractured” somatotopy). This was followed by a number of studies on the organization and connections of motor and premotor cortex in various primates and other mammals. Mike Heurta produced one of the best comparative studies of the connections of the frontal eye field across New and Old World monkeys (Heurta et al. 1987). In a series of comparative and developmental studies, Rosalyn Weller showed that 80 percent of the retinal ganglion cells that project to the parvocellular geniculate layer in primates selectively degenerate after lesions of primary visual cortex (e.g., Weller and Kaas 1989). This suggests that those ganglion cells have no axon terminals in other targets to sustain them, and, of course, they can play no role in the “blindsight” reported in humans with V1 lesions. With our studies of the connections of visual and somatosensory system, and the plasticity of the somatosensory system after injury continuing, we branched out to study the reactivations of visual cortex after lesions of the retina (Kaas et al. 1990) with the collaboration of Yuzo Chino, and auditory cortex after a hearing loss in adult monkeys (Schwaber et al. 1993). Thus, the organizations and functions of somatosensory, visual, and auditory systems are not fixed during development, but are capable of structural and functional modifications that may compensate, in part, for sensory loss. One reviewer of our paper on visual cortex reactivation argued that our results could not be correct, as the lack of plasticity of the mature visual system of mammals was well established. The paper was published anyway.

As a member of the laboratory, Ken Catania continued to describe the strange somatosensory system of the star-nosed mole (Catania et al. 1993; Catania and Kaas 1997), while moving on to study cortical organization in shrews, opossums, and hedgehogs (e.g., Catania et al. 1999). Ken has many other unique accomplishments, and he is now a chaired professor in the Biology Department at Vanderbilt. Leah Krubitzer discovered that the region of somatosensory cortex known classically as SII contains two somatotopic representations, which we named S2 and PV (for parietal ventral), first in squirrels (Krubitzer et al. 1986) and then in other mammals, including monkeys (Krubitzer and Kaas 1990). In related experiments, Cassie Cusick discovered a new “ventral” somatosensory area (VS) in monkeys (Cusick et al. 1989). These newly discovered areas have now been described for humans.

Our Studies of the Auditory System

I always felt that there was much we could learn by studying the auditory system in parallel with our studies of the visual and somatosensory systems. I had started working on auditory cortex with my PhD thesis, continued with a study with Ralph Beital, completed while I was at Wisconsin, but only published 20 years later when Ralph came back to neuroscience (Beital and Kaas 1993). Additionally, I had helped map auditory cortex in squirrels and tree shrews with Mike Merzenich in San Francisco. The opportunity to do more finally came when Lynn Leuthke (Huerta) from the Speech and Hearing Department at Vanderbilt wanted to do her PhD thesis with me on auditory cortex. This got us started on studies of auditory cortex organization and connections in squirrels (Leuthke et al. 1988) and marmosets (Leuthke et al. 1989). Lynn married Mike Huerta, and both ended up in administrative positions at NIH. The studies continued with the arrival of Anne Morel, after a PhD in auditory physiology in Switzerland and a postdoc on the organization and connection of the auditory thalamus in cats with Tom Imig in Kansas. We were able to use microelectrode mapping methods to define subdivisions of auditory cortex and then determine their connections in owl monkeys (Morel and Kaas 1992) and then, with the help of Preston Garraghty, in macaque monkeys (Morel et al. 1993). Anne and I applied for an NIH grant to continue these studies, and it was awarded. But before it could start, Anne received an offer of a research position in Switzerland that was too good to turn down, and our joint research plans and the grant funding were abandoned. Fortunately, Troy Hackett, another graduate student from the Speech and Hearing Department, wanted to do his PhD with me, and we subsequently picked up where Morel and I had left off. We studied the connections of the third level of auditory cortex in macaques, the region we defined as the parabelt, with the belt and core areas (Hackett et al. 1998). Troy continued with related anatomical studies, including comparative studies of auditory core areas in macaque monkeys, chimpanzees, and humans (Hackett et al. 2001). We proposed a general model for auditory cortex organization and connections in primates (Kaas and Hackett 2000) that became widely accepted. Troy has stayed at Vanderbilt, becoming a professor in the Speech and Hearing Department, and has become the foremost authority on the anatomical organization of the auditory system in primates. I continue to value his advice and experience, as Troy continues his research at Vanderbilt. Corrie Camalier, a recent graduate student who helped develop single unit recording from auditory cortex in macaques with Troy, also wrote a nice review with me (Camalier and Kaas 2011). Corrie moved on to auditory research at NIH as a postdoc.

Studies of the Response Properties of Single Neurons in Somatosensory Cortex

My experience with quantitatively characterizing the properties of single neurons was initially limited to those conducted on MT and V1 of owl monkeys with Dan Felleman (Felleman and Kaas 1984). Dan truly amazed me as he constructed a motor-driven mechanical system for projecting visual stimuli on a screen, rotating the image, and moving it about, all under the control of a primitive PDP-8 computer. Later, I was encouraged to do more studies of neuron responses by Miguel Nicolelis, who convinced me of the value of using chronically embedded microelectrode arrays to study the processing of somatosensory information across cortical areas in monkeys (Nicolelis et al. 1998). Miguel has become a close friend, and he helped and advised me in many ways. With his guidance, I continued the chronic recording studies with Neeraj Jain and Hui-Xin Qi (e.g., Jain et al. 2001). Hui-Xin finished her PhD in Switzerland on motor cortex of monkeys, and came to me as a postdoc in 1996. She has stayed with me ever since, while gradually taking over our program on the organization and plasticity of the somatosensory system in primates. Hui-Xin convinced me that we should continue our single neuron recording studies by using the 100-electrode Utah array that was used for the visual cortex of cats in the nearby laboratory of A. B. Bonds. With the help of a very talented graduate student, now a postdoc, Jamie Reed, we were able to demonstrate that neurons in primary somatosensory cortex (area 3b) of monkeys integrate information from all over the hand, while having small excitatory receptive fields on only small parts of the hand (e.g., Reed et al. 2010). We also showed that this integration of information included that from stimuli on both hands (Reed et al. 2011), even though there are very few direct corpus callosal connections in the hand representation of area 3b. More recently, we have used this multielectrode approach to study the response properties of neurons in area 3b of monkeys after behavioral recovery from a sensory loss of the dorsal column branches of tactile afferents from the hand. The return of nearly normal response properties to reactivated cortical neuron representation suggests that these reactivated neurons play a critical role in the behavioral recovery of hand use (Qi et al. 2014). We are currently investigating potential anatomical sources of this reactivation with the help of Chia-Chi Liao, an outstanding postdoc from the National Taiwan University (Liao et al. 2015). The evidence suggests that the preservation of even a few of the normal connections can be very important, as they become potentiated and activate larger populations of neurons. In addition, new connections appear to play a role in the reactivation (see Kaas and Bowes 2014). As part of her PhD thesis with me, Charnese Bowes demonstrated that treatment of a brainstem nucleus with an enzyme, after a sensory loss, promoted the growth of new connections and the reactivation of somatosensory cortex (Bowes et al. 2012).

Counting Neurons and Other Cells in Brains

At a neuroscience meeting in Natal, Brazil, in 2004, and again at the Society for Neuroscience meeting in 2004, I met a most remarkable woman from Brazil at her posters. Suzana Herculano-Houzel had invented a more productive way of counting the numbers of neurons and other cells in any brain or part of brain by homogenizing the tissue and counting cell nuclei from samples (the isotropic fractionator method; Herculano-Houzel and Lent 2005). The great advantage of her new method was that accurate estimates of neuron numbers in any structure could be rapidly obtained (see Herculano-Houzel et al. 2015 for an evaluation of methods). By determining the numbers of neurons in rodent brains of different sizes, Suzana showed that neuron-packing densities were not maintained with increases in brain size, so that the larger brains of larger rodents had fewer neurons than expected from brain size. We decided to collaborate on counting from primate brains of different sizes, and found that primate brains do maintain neuron packing densities with increasing brain sizes (Herculano-Houzel et al. 2007). Thus, to the extent that neuron numbers reflect brain functions, primates have an increasing advantage over rodents (and other mammals) as brain sizes increase. Given the astonishing lack of reliable information on neuron numbers for brain structures across the many animal taxa, and the effectiveness of these new methods, there has been an explosion of efforts from several groups to obtain new data on neuron numbers in brains and brain parts. Christine Collins, who had worked with me on the visual system as a postdoc and research assistant professor for a number of years, took over this part of our program for neuron and cell counting, and developed an automated method of counting using flow cytometry (Collins et al. 2010). Nicole Young, a postdoc from Canada, joined us and was responsible for an important study showing that the motor cortex of baboons with spontaneous epilepsy had lost a large proportion of their neurons in motor cortex (Young et al. 2013). Many of our studies have depended greatly on Suzana, and we continue to work together. Her PhD student, Mariana Gabi, has recently joined my lab as this work continues with the help of graduate students Dan Miller and Emily Rockoff. Our studies indicate that neuron packing densities vary greatly across the cortical sheet in all primates, being low in some areas such as primary motor cortex, where average neuron size is high, and very high in primary visual cortex, where small layer 4 neurons dominate. In brief, neuron packing densities relate to average neuron size, and these anatomical specializations reflect the specializations of different cortical areas for different functions.

Studies of Networks for Action-Specific Behaviors in Parietal-Frontal Cortex in Primates

A number of years ago, I was treated to an amazing demonstration of brain function while I was visiting the laboratory of Mike Graziano at Princeton University. Mike had a microelectrode in motor cortex of an awake, somewhat bored macaque monkey, and every time he delivered a half second train of electrical pulses via the microelectrode to motor cortex, the monkey calmly brought its hand to its mouth. Mike discovered that motor and premotor cortex have subdivisions where action-specific, ethnologically relevant movements could be reliably evoked by electrical stimulations long enough (∼ 0.5 sec) to complete the movement (for details, see Graziano 2009). I realized that this type of stimulation could be a powerful tool, and introduced it to my lab in studies lead by Iwona Stepniewska, who had worked with me before on motor systems, visual cortex, and the pulvinar. We started our studies on galagos, a small prosimian primate, in which we were studying frontoparietal connections (Fang et al. 2005). We soon found that we could study the functionally related cortical subdivisions we called domains, in anesthetized as well as awake primates. In prosimian galagos, we discovered that as many as eight domains existed in motor cortex, again in premotor cortex, and a third time in posterior parietal cortex (Stepniewska et al. 2005). Domains included those for grasping, reaching, hand-to-mouth, head or body defense, running, face aggressive, and looking. Functionally matched domains across the three critical regions were serially interconnected, and the evoked motor behavior was dependent on the contributions of primary motor cortex. Omar Gharbawie, a postdoc from Canada, joined these efforts, and we extended our studies to New World monkeys and then macaque monkeys (for a review, see Kaas and Stepniewska 2015). Omar focused his studies on macaque monkeys and recently moved to become an assistant professor at the University of Pittsburgh.

While our studies revealed major similarities in the organization of posterior parietal cortex and frontoparietal networks across the prosimian, New World monkeys, and Old World monkey branches of primate evolution, the elaboration of posterior parietal cortex and these frontoparietal circuits was not seen in tree shrews (Remple et al. 2007), a close relative of primates. Thus, a major expansion and involvement of posterior parietal cortex in motor behavior evolved in the ancestors of early primates but not in the close relatives of primates (Kaas and Stepniewska 2015).

It may seem unusual to study neural networks that relate to specific behaviors with electrical stimulation, but this approach gives us a higher level of control over the outputs of these networks as we alter them in various ways. For example, we have determined the effects of complex patterns of movement of selectively deactivating parts of the network with muscimol (Stepniewska et al. 2014) or with cortical cooling (with Dylan Cook and Leah Krubitzer) while electrically stimulating other parts of the network. Our studies continue, and they give me the opportunity to continue to collaborate with two of my former PhD students, Leah Krubitzer and David Lyon.

Optical Imaging of Cortical Responses

I have benefited greatly through collaborations with other faculty members at Vanderbilt, including former members of my lab after they became faculty (Troy Hackett and Ken Catania), but especially Vivien Casagrande, as we have worked together on many projects, and Anna Roe, a major addition to the faculty of my department. Anna finished her PhD at MIT with one of my first PhD students, Mriganka Sur. Vivien started the optical imaging research at Vanderbilt. This method of visualizing cortical activity was well suited to studies in our usual experimental primates, galagos, owl monkeys, and squirrel monkeys, as these primates have few cortical fissures so that more cortical regions of interest are exposed for study. Thus, we were able to image functionally related activity in visual area MT (e.g., Xu et al. 2004) and other visual areas, as well as somatosensory cortex. With the arrival of Anna Roe as a new faculty member, such experiments continued in her lab, with the help of Peter Kaskan (Kaskan et al. 2009), a talented graduate student. With the help of other graduate students, Reuben Fan and Mary Baldwin, we used optical imaging to demonstrate the location and retinotopy of dorsal V3 along the rostral border of V2 in galagos (Fan et al. 2012). Other experiments involved imaging MT after lesions of visual cortex to reveal a prominent loss of visually evoked activity, ocular dominance columns in primary visual cortex, and patterns of cortical activity evoked by focal microstimulation of cortical sites.

The Organization of the Pulvinar Complex in Mammals

I have been interested in the visual pulvinar since my early mapping studies of part of the inferior pulvinar with John Allman (Allman et al. 1972). In primates, the pulvinar has been historically divided into inferior, lateral, and medial “nuclei.” A breakthrough in my understanding came early in my career at Vanderbilt when my graduate student, Rick Lin, provided clear evidence in owl monkeys that the traditional inferior pulvinar contained at least three separate nuclei, including IPp, or posterior division of the inferior pulvinar, projecting to temporal cortex; a medial division, IPm, projecting to MT; and a large central division, IPc (Lin and Kaas 1979). IPp and IPc received dense inputs from the superior colliculus. Cassie Cusick, after she left my lab for a faculty position at Tulane (e.g., Gutierrez et al. 1995), and Iwona Stepniewska (e.g., Stepniewska and Kaas 1997) further defined the subdivisions of the pulvinar complex on the basis of striking histochemical differences and patterns of cortical and subcortical connections. The results led us to subdivide the large IPc subdivision into central lateral and central medial nuclei of the inferior pulvinar, IPcl and IPcm. We have summarized our views on pulvinar organization across New and Old World monkeys and proposed that the large nucleus of the inferior pulvinar, IPcl, and large ventrolateral nucleus of the lateral pulvinar, PIvl, are connectionally related to early visual areas V1, V2, and V3, and they largely contribute to the ventral stream of cortical processing. The three remaining nuclei of the inferior pulvinar, IPp, IPm, and IPcm, all have connections with the MT complex of visual areas, which contributes to the dorsal stream of visual processing (Kaas and Lyon 2007). Most recently, graduate students Pooja Balaram and Mary Baldwin (now postdocs at Harvard and University of California, Davis) further studied pulvinar organization in prosimian galagos, and a range of nonprimate mammals, in an effort to identify homologous nuclei across mammals and suggest how the pulvinar complex in primates evolved (e.g., Baldwin et al. 2013). Relevant studies by other members of the lab that contributed to our present understanding include an early study on pulvinar connections to VI in galagos by Laura Symonds (Symonds and Kaas 1978), my early study of pulvinar connections in squirrels with Bill Hall and Irving Diamond (Kaas et al. 1972b), and David Lyon’s description of pulvinar organization in tree shrews (Lyon et al. 2003).

Studies of Cortical Chemoarchitecture

When I started in the field of neuroscience, there were only a few ways to determine how brains are functionally organized or anatomically connected. To anatomically recognize subdivisions of the cortex and thalamus, we largely depended on the traditional Nissl and myelin stains (e.g., Kaas et al. 1972b). A friend from my time at Wisconsin, Margret Wong-Riley, later introduced us to the useful cytochrome oxidase methods (Wong-Riley 1979). Now there is a vast array of powerful methods that more clearly reveal subdivisions of the brain of functional significance. Many graduate students, postdocs, and faculty collaborators helped bring these newer methods into common use in the laboratory. To mention a few, Todd Preuss (now faculty at Emory) and Iwona Stepniewska initiated our early histochemical studies, including those involving ape and human brains (Preuss et al. 1999). Fabrizio Strata, as a postdoc from Italy, described the chemoarchitecture of the somatosensory brainstem (Strata et al. 2003). Peiyan Wong, an amazingly efficient and productive graduate student from Singapore via Oxford University, really brought our studies of chemoarchitecture to a high level (e.g., Wong and Kaas 2010). Pooja Balaram, a highly productive graduate student, introduced the use of differential levels of expression of vesicular glutamate transporters to define subdivisions of the brain and suggest functions (e.g., Balaram et al. 2013). Toru Takahata, a postdoc from the Yamamori lab in Japan, introduced us to the power of using visual deprivation to alter the express of “early genes” in the visual system (e.g., Takahata et al. 2009). Currently, a project with Carl Zilles in Germany will allow us to further understand the organization in cortex of galagos by using receptorbinding procedures.

Other Important Contributors at Vanderbilt

I have been and remain fortunate to have outstanding individuals help me run the laboratory. When I arrived at Vanderbilt, a highly motivated undergraduate, Gay Spease, decided that she would manage the laboratory, organize our weekly volleyball game, and do histology. She did all this very well, but soon left for medical school, where I am sure she had great success. Other lab manager–histologists followed, but I was very lucky when Judy Ives transferred from the Medical School to become my histologist, and later hired Laura Trice to help her. Both of these wonderful and invaluable woman have been responsible for the high quality of our histology, training graduate students and postdocs in histochemistry, and making new additions to the lab feel welcome. While Judy Ives retired some years ago, Laura continues to do a great job. Many undergraduates have helped on research projects in the lab. Most have gone on to medical school, with a few to graduate school. Recently, Christina Cerkevich and Mary Baldwin finished PhDs in the lab, after starting in the lab as undergraduates. Mary is a talented illustrator and as such greatly improved our papers. In addition, as a former athlete on the Vanderbilt Track Team, she was one I could count on to share my interests in sports. Pooja Balaram, a Vanderbilt undergraduate, trained in another lab and then joined my lab for graduate school. Finally, MD/PhD student Mark Burish was such an asset to everyone, as he so willingly helped conduct their research. Mark’s father had been chair of my department, and later Vanderbilt provost, and he was both very effective and well liked. Clearly Mark reflected his father’s best traits.

International Schools and Exciting Meetings

Perhaps the most important conference for my development was the Symposium on Basic Thalamic Structure and Function in Brooklyn, New York, in 1971. A number of major investigators were invited, including my former PhD supervisor, Irving Diamond. As I was still just a postdoc in the Woolsey laboratory, I wasn’t invited at first, but Diamond insisted that I was an expert on the lateral geniculate nucleus (a major exaggeration) and eventually I was invited. The talks at the symposium were published in the new journal, Brain Behavior and Evolution, and my paper with John Allman and Ray Guillery (Kaas et al. 1972c) recently became a “Citation Classic” in that journal (Kaas 2015). My experience at the Brooklyn meeting made me more confident, and I was eager to participate in such symposia again. The next opportunity came quickly at a symposium on Developmental Aspects of Vision in 1972, where I went as a substitute for Ray Guillery, who couldn’t attend. The highlight of the meeting, for me, was a great talk by Colin Blakemore. It was easy to see, even at this early stage, that Colin would be very successful. We continued to interact over the years, and a friendship has developed. Meetings in other exciting places included an interesting conference on comparative aspects of brain organization held in Caracas, Venezuela, in 1974, which was organized in part by Sven Ebbensson, now another longtime friend. Mike Gazzaniga invited me to fantastic meetings in Barcelona and Venice. The Venice meeting featured Stephen Jay Gould taking us to the Basilica of San Marco to explain his concept of the role of repurposed structures, like the spandrels of the Basilica, in evolution (Gould and Lewontin 1979).

In 1986 I was fortunate to be invited to be a lecturer in a course on the organization and development of brains at the International Center for Theoretical Physics in Trieste, Italy, and I returned in subsequent years four times as an organizer, and I helped some of these students come to labs in the United States. The two- to four-week courses were a great success and provided interaction with advanced students from all over the world, including students from “third world countries.” I interacted with investigators from Cuba, and I then met with one of them again when I was a lecturer in a two-week IBRO workshop in Cuba in 2007. I was able to help some of the students in Trieste come to labs in the United States and one of them, Velayudhan Rema from India, came to work with Ford Ebner at Vanderbilt. Rema soon convinced me to add her boyfriend (now her husband), Neeraj Jain, to my lab as a postdoc. Both are now back in India, where Neeraj has become a productive, highly respected neuroscientist. In Trieste, an Italian PhD student, Fabrizio Strata, generously provided his car for my wife to use during our time there. It was the smallest car I have ever been in. Barbara became so used to the Italian style of driving, that she became impatient with the slow pace of Nashville drivers for months after our return. Fabrizio also introduced us to a tradition that takes place in the hills around Trieste, where in early fall the local farmers serve their new wine with local cheeses and breads in an outdoor setting in their vineyards. Later, Fabrizio came to work with me as a postdoc. A good friend, Mathew Diamond, the son of my PhD mentor, Irving Diamond, and a very successful neuroscientist in Trieste, organized subsequent sessions of the course. I have also been a lecturer, and sometimes co-organizer, of courses in Lausanne, Switzerland; the Karolinska Institute in Stockholm (thanks to G. Grant); several cities in Germany; Naples Italy, Barcelona Spain, and the Summer Institute in Cognitive Neuroscience in Santa Barbara and Lake Tahoe. All these occasions resulted in great interactions with students and other faculty, and an appreciation of other cultures.

While traveling to participate in conferences and international meetings in a number of countries, I was able to develop special ties with investigators in some of these countries early in my career. One such place was Berlin, Germany, at a Dahlem Workshop in 1977 (Kaas 1977), well before the Berlin Wall came down. A special tour was arranged to visit the great Pergamon Museum in East Berlin. This workshop was special in that we formed groups that were required to come up with a summary of agreements over a topic of concern. I was able to attend two subsequent Berlin meetings, and other meetings in Germany.

Other connections formed with investigators in Australia. It started with collaborations with Ken Sanderson while we were both at the University of Wisconsin and continued after he returned to Australia. To this day we stay in touch. My first trip to Australia was to give a talk at an international meeting in Sydney, in 1983, where I stayed in a cheap hotel to save money and discovered it was in a part of the city dominated by sailors and bars. After the meeting, I participated in a wonderful Festschrift for P.O. Bishop, where speakers were isolated on Lord Howe Island. Bishop, a leading visual neuroscientist, attracted postdocs from many countries, including Jean Bullier from France (after a PhD at Duke). There I also met Boydan Dreher, Horace Barlow, Jack Pettigrew, Jon Stone, Bob Rodieck, and Geoff Henry. I had other visits to Australia, but none better than a research stay with Jack Pettigrew to catch fruit bats, record from somatosensory cortex, see the Great Barrier Reef, and write a paper for Nature within a month (Calford et al. 1985). For the trip, I took my son, and Mike Huerta, a postdoc with me at the time, and we found it convenient to break up the long flights with a stopover in Hawaii on the way down, and in Tahiti on the way back. We were in Tahiti for Bastille Day and enjoyed a big celebration. Herb Killackey, there for other reasons, joined us.

Soon thereafter, Jean Bullier and Henry Kennedy organized a large international meeting on the visual system in Lyon, France, in 1986. It was fortunate for me that this was one of the first such meetings in France where talks could be in English. I have returned to Lyon, famous for its cuisine, many times, and remain close to Henry as a collaborator and friend. Other visits took me to Paris where my former collaborator, Patricia Gaspar, has become a leading neuroscientist. There have been many other great meetings in wonderful places that led to new relationships, such as those at the Wenner-Gren Center and the Karolinska Institute in Stockholm, the International Summer School in Amsterdam, meetings in Montreal, and the RIKEN center in Tokyo.

Two other places have special meaning for me. First, my interest in the organization of the brain in small-brained mammals led to an invitation from Roca-Miranda, known for his work on the brains of South American opossums, to visit in Rio de Janeiro, which led to an NSF U.S.–Brazil Cooperative Research Grant. This led to more visits, including those to other cities in Brazil, and to research collaborations. An early collaborator was Joao Franca, and then other Brazilians unrelated to the original funding, especially Miguel Nicolelis and Suzana Heuculano-Houzel, but also Marcello Rosa after he moved to Australia. Another place of special importance to me is Taiwan. My first graduate student recruit at Vanderbilt was Rick Lin from Taiwan, and three subsequent graduate students or postdocs have been from Taiwan: Carolyn Wu, Pei-Chun Fang, and Chia-Chi Liao, all great contributors. Wu and Fang especially collected data that led to a better understanding of cortical organization in prosimian galagos. During visits to Taiwan, I witnessed two typhoons, and with Rick Lin, visited his father’s family home (his father was a popular senator in the Taiwan government), and stayed at a beautiful lake in the mountains.

A Special Event

In 2000, I was elected to the National Academy of Sciences. This would be special for anyone, but for me it was the honor of having Mort Mishkin call and inform me of the award. Mishkin is a special hero of mine as he always interacted with me in a positive manner, and his laboratory at NIH produced so much of the research that interested me. Following this event, I received congratulations from two unexpected sources, my high school chemistry teacher, who actually remembered me, and my Northland College teacher in social psychology who meant so much to me.

While there have been other special events, I mention only one more here. For many years, I have had the privilege of serving on the editorial board of the Journal of Comparative Neurology, for a time as an associate editor. This has been a favorite journal of mine, where I have more published papers than anywhere else. One of the most outstanding editors of the journal was Sanford Palay. I enjoyed interacting with him, and receiving his detailed comments and corrections on my submitted papers. What an honor it was for me to have received the Sanford Palay Award from the Journal of Comparative Neurology and the Cajal Club in 2014.

What Has Been Accomplished?

With more than 50 years in research and many collaborations, what has been accomplished? I feel that our research has led to a much better understanding of the organization of sensory and motor systems in primates, especially at the cortical and thalamic levels. In addition, we have revealed much of the astonishing ability of these systems, in mature primates, to spontaneously recover from injuries and sensory loss. We are beginning to understand how these reactivations and recoveries occur through the strengthening of weak pathways and the growth of new ones. Our focus is starting to move toward discovering and testing treatments that may promote recoveries (Bowes et al. 2012). These advances were made in conjunction with studies from many other laboratories, all aimed at the same broad goals. In addition, much of our research effort has been directed toward understanding differences and similarities in brain organization in mammals less commonly studied than the usual model species. This includes our research on opossums, tenrecs, shrews, tree shrews, seals, tarsiers and galagos, and other prosimian primates. Our studies of forebrain organization in prosimian galagos and tree shrews have been especially important to me as galagos represent a major branch of primate evolution, and tree shrews are closely related to primates and thereby provide insights on the emergence of primates. While there are difficulties in studying such mammals, and often with little in the published literature to guide us, the payoff is in finding out things that are unlikely to be produced by other laboratories. Thus, we are able to see more of what is possible in the evolution of nervous systems, and infer what the brains of extinct mammals were like (Kaas and Preuss 2014).

We were able to maintain our research on galagos for so long by maintaining a breeding colony. Important, related discoveries have been made with this primate by members of the Diamond laboratory, Vivien Casagrande at Vanderbilt, and Mary Carlson during her graduate student years and while she was faculty at Washington University in St. Louis. This shared interest led to many collaborations and research so that the general organization of the forebrain of galagos is fairly well known. It now appears that galagos have roughly 40 cortical areas that are shared with New World and Old World monkeys. Studies on galagos and a few other prosimians make it possible to say, with considerable certainty, that all primates have inherited a collection of visual and other cortical areas, including visual area MT, from a common ancestor. MT does not appear to exist in any extant nonprimate, so studies of MT’s role in vision are possible in primates alone. While much can be learned from studies on brains much different than ours, comparative studies of brain organization have the potential of revealing what can and cannot be inferred about humans from studies on other species.

Epilogue

Things have worked out very well for me. My first wife, Judith, was a fellow graduate student, and she gave me two wonderful children, who decided early on not to be scientists. They provided me the continuing joy of six grandchildren. My second wife, Barbara Martin, works closely with me, and travels with me everywhere. She remains my closest friend. As I continue to train graduate students and postdocs, I wonder about their future. Most of my earliest coworkers are now well-established, productive neuroscientists, or for some, highly effective teachers and administrators. Two former graduate students and postdocs, Leah Krubitzer and Ken Catania, stand out because they received the highly prestigious MacArthur Fellowship for their highly original research, and more important to me, they remain good friends. Sadly, two others, Tim Pons and Yvonne Rothemund, have died, and this continues to disturb me as I think of them. With both, I enjoyed many conversations, always with good humor that lifted my spirits.

The years of research have taught me to not hold any beliefs too dear. As one example, I initially held (with John Allman) that a number of visual areas in primates border V2, rather than a V3. Experiments by David Lyon convinced me with compelling evidence that all primates have a V3 (e.g., Lyon and Kaas 2002), and this long-held view (e.g., Zeki 1978) is widely accepted today. Yet, it is important to recognize that not all reported observations on visual cortex organization in primates fit nicely into that framework (Kaas et al. 2015), and that ultimately some further modifications of present views may prevail. Quite often, for any area of study, all available observations do not point in the same direction. Thus, we should be ready to change our minds about even our long-held views.

The opportunities I had, and those my early students had, seem less available now. The best undergraduates in my lab, about 10 per year, go to medical school. Graduate students at Vanderbilt and elsewhere ask, “What else can I do?” Now, it seems that the field requires the most dedicated and success is very uncertain. But I still feel that it is most important to do what you most want to do. Have a profession that is not work, but the most enjoyable hobby you can imagine. I live in Nashville, a center for the music industry, and I meet people all the time who are struggling to be part of that industry. Competition is intense, and many will not make it, but many persevere because that is what they want to do. An academic career can be fantastic, as you can be your own boss and largely do what you enjoy. If that is what you want to do, more than anything else, perseverance with talent still pays off. Failure is possible, and even likely, but give it a shot. For me, I still love what I do, I’m funded and have a lab with great co-workers, and my oldest granddaughter, Lili, is an undergraduate at Vanderbilt. Life has been good.

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Eric Kandel

BORN:

Vienna, Austria

November 7, 1929

EDUCATION:

Harvard College, Cambridge, MA, BA (1952)

NYU School of Medicine, New York, NY, MD (1956)

APPOINTMENTS:

Intern, Montefiore Hospital, New York (1956–1957)

Associate in Research, Laboratory of Neurophysiology, NIMH, Bethesda (1957–1960)

Psychiatry Resident, Mass Mental Health Center, Psychiatry Instructor, Harvard Medical School (1960–1964)

Special Fellow, U.S. Public Health Service, College de France (Lab of Ladislav Tauc) (1962–1963)

Associate Professor to Professor, Depts. of Physiology and Psychiatry, NYU School of Medicine (1965–1974)

Professor, Depts. of Physiology, Biochemistry and Molecular Biophysics, Columbia U (1974–present)

Director, Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia U (1974–1983)

University Professor, Columbia U (1983–present)

Senior Investigator, Howard Hughes Medical Institute (1984–present)

Kavli Professor and Director, Kavli Institute for Brain Science Columbia U (2004–present)

Co-Director, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia U (2009–present)

HONORS AND AWARDS (SELECTED):

National Academy of Sciences, 1974

National Institute of Medicine, 1988

Corresponding Member, German Academy of Science, Leopoldina, 1989

Orden Pour le Mèrite für Wissenschaften und Künste, Member, 1997

Athenian Academy, Foreign Associate, 2001

Austrian Academy of Sciences, Foreign Member, 2002

The Royal Society of London for Improving Natural Knowledge, Foreign Member, 2013

Twenty-three honorary degrees

Honorary Citizenship of the City of Vienna, Austria, 2009

SCIENTIFIC AWARDS (SELECTED)

Karl Spencer Lashley Prize in Neurobiology (Awarded by the American Philosophical Society), 1981

The Dickson Prize in Biology and Medicine (Awarded by the University of Pittsburgh), 1982

Albert Lasker Basic Medical Research Award (Shared with Vernon B. Mountcastle), 1983

Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research (Awarded by Brandeis University), 1984

Gairdner International Award for Outstanding Achievement in Medical Science, 1987

Harvey Prize (Awarded by the Technion, Israel Institute of Technology, Haifa, Israel), 1993

Wolf Prize in Biology and Medicine, Israel, 1999

Dr. A.H. Heineken Prize for Medicine (Awarded by the Royal Netherlands Academy), 2000

Nobel Prize in Physiology or Medicine (shared with Paul Greengard and Arvid Carlsson), 2000

Austrian Medal of Honour for Science and Art, 2005

Benjamin Franklin Medal for Distinguished Achievement in the Sciences, American Philosophical Society, 2006

Most of Kandel’s work has been devoted to the cellular and molecular mechanisms of learning and memory, first in the snail Aplysia and later also in mice.

Eric Kandel

Prologue: Life in Vienna in the 1930s

There was little in my early life to indicate that biology would become the passion of my academic career. In fact, there was little to suggest that I would have an academic career at all. Rather, my early life was importantly shaped by my childhood experiences in Vienna, and I spent many later years coming to grips with the circumstances in Austria at the time of my birth.

I was born in Vienna on November 7, 1929, 11 years after the multiethnic Austro-Hungarian Empire fell apart following its defeat in World War I. Although Austria had been radically reduced in size (from 54 million inhabitants to only 7 million) and in political significance, its capital, the Vienna of my youth, was still one of the great cultural centers of the world. A city of one and a half million people, it was home to Sigmund Freud, Karl Kraus, Robert Musil, Arthur Schnitzler, and for a while, Arnold Schoenberg. The music of Gustav Mahler and of the earlier 19th-century Vienna School resonated throughout the city, as did the bold expressionist images of Gustav Klimt, Oskar Kokoschka, and Egon Schiele. Despite its cultural and intellectual vibrancy, however, Vienna in the 1930s was the capital city of an oppressive, authoritarian political system. I was too young to appreciate its cultural richness, but I sensed later, from the perspective of a more carefree adolescence in the United States, the oppressive conditions in Vienna that affected my childhood.

Even before the Anschluss, in 1938, anti-Semitism was endemic in Viennese life. Jews, who made up nearly 20 percent of the city’s population, were discriminated against in the civil service and in many aspects of social life. They were nonetheless fascinated by the city in which they had lived for over a thousand years. My parents genuinely loved Vienna, and in later years, I came to understand why the city exerted such a powerful hold on them. My parents loved the dialect of Vienna, its cultural sophistication, and its artistic values. “The greatest grim irony of all was the fierce attachment of so many Jews to a city that through the years demonstrated its deeprooted hate for them,” wrote George Berkley (1988), the American historian of Vienna and its Jews. This fierce attachment was considered by the historian Harvey Zohn to be the most tragically unrequited love in world history.

In spite of the hostile climate, Austrian Jews continued to make remarkable contributions to theater, music, literature, science, and medicine in the period between the two World Wars. The Salzburg Festival was directed by Max Reinhardt; the Vienna Opera was conducted by Bruno Walter. Stefan Zweig and Franz Werfel were two of the most popular writers in the German language, and Elias Canetti, who later won the Nobel Prize in Literature for his books describing his youth in Vienna, began writing in the 1930s. Two of the three Austrians awarded the Nobel Prize in Physiology or Medicine in the 1930s were of Jewish origin: Karl Landsteiner was honored in 1930 for his discovery of blood groups and Otto Loewi in 1936 for discovering acetylcholine, a chemical transmitter that slows the heart. Of the 52 Olympic medals earned by Austrians from the beginning of the modern Olympics to 1936, 18 were won by Jewish athletes. Fully half of the practicing physicians and medical faculty at the University of Vienna were Jewish. This was the last period during which Viennese medicine attracted students and patients from all over the world. They came to study with, or to be treated by, pioneers in diagnostics and therapeutic medicine, such as the pediatrician Béla Schick, the ear specialist Heinrich von Neumann, and the psychoanalyst Sigmund Freud. As this listing makes clear, the period of my early youth was “the final flowering of the Austrian Jewish intellectual activity.”

My parents were not born in Vienna, but they had spent much of their lives there, having each come to the city at the beginning of World War I, when they were very young. My mother, Charlotte Zimels, was born in 1897 in Kolomea, a town of about 43,000 inhabitants in Galicia, a region of the Austro-Hungarian Empire. (Kolomea is now part of the Ukraine and has been renamed Kolomyya.) Almost half the population of Kolomea was Jewish, and the Jewish community had a very active culture. My mother came from a well-educated middle-class family, and although she had spent only one year at the University of Vienna, she spoke and wrote English as well as German and Polish.

My father, Herman, was born into a poor family in 1898 in Olesko, a small town of about 3,500 people near Lvov (Lemberg), now also part of the Ukraine. He was drafted into the Austro-Hungarian Army directly from high school. After the war, he worked to support himself; he never went back to school.

My parents met in Vienna and married in 1923, shortly after my father had established himself as the owner of a small toy store. My older brother, Lewis, was born on November 14, 1924. We lived in a small apartment at Severingasse 8 in the Ninth district, a middle-class neighborhood near the medical school and not too far from Freud’s apartment, although we had no association with either. Both of my parents worked in the store, and we had a full-time housekeeper to help out at home.

I went to a school near our house. Like most elementary schools in Vienna, it was very traditional and very good, and I followed the path blazed by my exceptionally gifted brother in the same school with the very same teachers. Throughout my years in Vienna I felt that his was an intellectual virtuosity that I would never match. By the time I began reading and writing, he was already starting to master Greek and to play the piano.

My fondest early memories are of family get-togethers and vacations. On Sunday afternoons my Aunt Minna (my mother’s sister) and Uncle Srul would come for tea. This was an occasion for my father and uncle to play cards, games at which my father excelled and which brought out great animation and humor in him. We celebrated Passover in a festive way at the home of my grandparents Hersch and Dora Zimels, and we invariably went on vacation in August to Monichkirchen, a small farming village in the southeast portion of Lower Austria, not far from Vienna.

Just as we were about to depart for Monichkirchen in July 1934, the Austrian Chancellor, Engelbert Dollfuss, who had outlawed the Nazi Party, was assassinated by a band of Austrian Nazis disguised as policemen—the first storm to register on my newly developing political awareness. During the early years of Dollfuss’s successor, Kurt von Schuschnigg, the Austrian Nazi Party went further underground, but it continued to gain new adherents, especially among teachers and other civil servants. Paradoxically, the Austrian drive toward authoritarianism was abetted by Dollfuss’s political attitudes and actions. Modeling himself on Mussolini and Hitler, Dollfuss had renamed his Christian Socialist Party the Fatherland Front and took to wearing a modified swastika. To assure his control of the government, he abolished Austria’s constitution and outlawed not only the Nazi Party but all opposition parties. Thus, although Dollfuss opposed the efforts of the Austrian National Socialist movement to form a Pan-German state with Germany, his abolition of the constitution and of other political parties helped open the door for Hitler to march in.

And march in he did, as I well remember. Since his youth, Hitler had dreamed of a unified Austria and Germany. Not surprisingly, a key point in the Nazi program, from its very beginnings in the 1920s, was the merger of all German-speaking people into a Greater Germany. Hitler began to put this program into action in the fall of 1937 by increasing his rhetoric and threatening to move against Austria. Schuschnigg, eager to assert Austria’s independence, met with Hitler on February 12, 1938, in Berchtesgaden. Hitler showed up with two of his generals in tow and threatened to invade Austria unless Schuschnigg lifted the legal restrictions on the Austrian Nazi Party and appointed three Austrian Nazis to key positions in his Cabinet. Schuschnigg refused, but as Hitler continued to intimidate him, he compromised and agreed to legalizing the Nazi party and granting it two cabinet positions.

The agreement between Schuschnigg and Hitler so emboldened the Austrian Nazis that they began to challenge the Austrian government in a series of incidents that the police had difficulty controlling. Faced with Hitler’s aggression from without and the Austrian Nazi rebellion from within, Schuschnigg took the offensive on March 9 and boldly called for a plebiscite on Austria’s autonomy to be held four days later, on March 13.

This courageous move caught Hitler completely by surprise—an awkward surprise, since it seemed almost certain that the vote would favor an independent Austria. Hitler responded by mobilizing troops and threatening to invade Austria unless Schuschnigg postponed the plebiscite, resigned as chancellor, and formed a new government with an Austrian Nazi, Arthur Seyss-Inquart, as chancellor. Schuschnigg turned for help to England and Italy, two countries that had formerly supported Austrian independence. But on this occasion both countries failed to respond. Abandoned by his potential allies and concerned about needless bloodshed, Schuschnigg resigned on the evening of March 11. “Austria is yielding to force,” he announced in an emotional farewell radio address to the nation. “God protect Austria.” Even though Schuschnigg had resigned and the new President Miklos gave in to all the German conditions, Hitler nonetheless invaded Austria.

Hitler’s triumphal march into Vienna and his ecstatic reception by the Viennese public made an indelible impression on me. My brother had just finished building his first short-wave radio receiver, and on the evening of March 13, we both listened with earphones as the broadcaster described the crossing of the Austrian border by German troops on the morning of March 12. Hitler followed later that day, crossing the border first at Braunnau am Inn, his native village, and then moving into Linz, the capitol of Upper Austria, where people welcomed him in the marketplace as a native son, screaming “Heil Hitler.” Of the 120,000 people of Linz, almost 100,000 came out to greet Hitler. In the background we could hear the Horst Wessel song, a hypnotic Nazi marching song that even I found captivating. On the afternoon of March 14, Hitler’s entourage reached Vienna, where a wildly enthusiastic crowd welcomed him as the hero who had unified the Germanspeaking people.

The extraordinary reception Hitler met with in Linz and Vienna caused him to realize that Austria would not demand to be a relatively independent protectorate of Germany, as he had assumed. Instead, Austrians would readily accept—indeed, would welcome—annexation. It seemed as if everyone, from the modest shopkeepers to the most elevated members of the academic community, now embraced Hitler. In a shocking move, even Theodor Cardinal Innitzer, the influential Archbishop of Vienna, welcomed Hitler and ordered all the Catholic churches in the city to fly the Nazi flag and to ring their bells in honor of Hitler’s arrival. As the Cardinal personally greeted Hitler, he assured him of his own loyalty and that of all Austrian Catholics—which is to say, most of the population of Austria. The Cardinal promised Hitler that Austria’s Catholics would become “the truest sons of the great Reich into whose arms they had been brought back on this momentous day,” provided that the liberties of the Church were respected and its role in the education of the young guaranteed (Berkley 1988 p 323).

That night, and for days on end, all hell broke loose. Viennese mobs erupted in a nationalistic fervor, which they expressed by beating up Jews and destroying their property. Foreign commentators, long accustomed to Nazi tactics in Germany, were astonished by the wanton brutality of the Austrian Nazis; even German Nazis were amazed and emboldened by the viciousness of the attacks in Vienna. In his autobiography, the German playwright Carl Zuckmayer, who had moved to Austria in 1936 to escape Hitler, described Vienna during the days following the annexation as a city transformed “into a nightmare painting of Hieronymus Bosch.” It was as if

Hades had opened its gates and vomited forth the basest, most despicable, most horrible demons. In the course of my life I had seen something of untrammeled human insights of horror or panic. I had taken part in a dozen battles in the First World War, had experienced barrages, gassings, going over the top. I had witnessed the turmoil of the post-war era, the crushing uprisings, street battles, meeting hall brawls. I was present among the bystanders during the Hitler Putsch in 1923 in Munich. I saw the early period of Nazi rule in Berlin. But none of this was comparable to those days in Vienna. What was unleashed upon Vienna had nothing to do with [the] seizure of power in Germany…. What was unleashed upon Vienna was a torrent of envy, jealousy, bitterness, blind, malignant craving for revenge. All better instincts were silenced…only the torpid masses had been unchained…. It was the witch’s Sabbath of the mob. All that makes for human dignity was buried (Zuckmayer 1966).

Having watched the build-up of anti-Jewish laws in Germany following Hitler’s rise to power in 1933, my parents needed no convincing that the violence in Austria was not likely to fade away. We knew that we had to leave—and as soon as possible. My mother’s brother, Berman Zimels, had emigrated a decade earlier to New York and established himself as an accountant. He quickly provided us with affidavits stating that he would support us upon our arrival in the United States, but even with the affidavits, it took about a year for my parents’ Polish quota number to be called. When the number finally was called, we had to emigrate in stages because of U.S. immigration laws. My mother’s parents left first, in February 1939, my brother and I next, in April 1939, and finally my parents, in September 1939, only days before World War II broke out.

During the year that we lived under Nazi rule, we experienced directly Vienna’s humiliating form of anti-Semitism. The day after Hitler marched into Vienna, every one of my non-Jewish classmates—the entire class, with the exception of one girl—stopped talking and interacting with me. In the park where I played, I was taunted and roughed up. This viciousness toward Jews, of which my treatment was a mild example, culminated in the horrors of Kristallnacht on November 8, 1938. On the morning of November 7, 1938, a 17-year-old Jewish youth, distraught over his parents’ tragic fate at the hands of the Nazis, shot a third secretary in the German Embassy in Paris, mistaking him for the German Ambassador. In retaliation for this act, almost every synagogue in Germany and Austria was set on fire. Of all the cities under Nazi control, Vienna saw the most wanton destructiveness on Kristallnacht. Jews were taunted and brutally beaten. They were expelled from their businesses and temporarily evicted from their homes so that their neighbors could loot them. My father, together with hundreds of other Jewish men, was rounded up by the police. He was released a few days later only because he had fought in the Austro-Hungarian army as a soldier in World War I.

I remember Kristallnacht, more than 75 years later, almost as if it were yesterday. It fell two days after my ninth birthday, on which I had been showered with toys from my father’s shop. When we returned to our apartment a week or so after having been evicted, everything of value was gone, including my toys.

My last year in Vienna fostered in me a profound sense of gratitude for the life I have led in the United States. It is probably futile, even for someone trained in psychoanalytic thinking, as I am, to attempt to trace the complex interests and actions of my later life to a few selected experiences of my youth. Nevertheless, I cannot help but think that the experiences of my last year in Vienna helped to determine my later interests in mind, in how people behave, the unpredictability of motivation, and the persistence of memory. Over the years, my professional interests evolved from a youthful exploration of European intellectual history at Harvard, where I studied the motivation of German intellectuals during the Nazi era, to the allure of psychoanalysis and its more systematic approach to mental processes, and finally to my fascination with the biology of conscious and unconscious memory.

My early experiences in Vienna almost certainly contributed to my curiosity about the contradictions and complexities of human behavior. How are we to understand the sudden eruption of such great viciousness in so many people? How could a highly educated and cultured society that at one moment nourished the music of Haydn, Mozart, and Beethoven descend in the next moment into barbarism?

The answer to this question is complex, and many scholars have attempted partial answers. One conclusion, troubling to an academic like myself, is that a society’s culture is not a reliable indicator of its respect for human life. This rather simplistic conclusion raises the question: How can values within a society become so radically dissociated? As far as I can tell, the Viennese achieved it by shifting their frame of reference. By defining Jews in racial rather than religious terms, they were able to exclude Jews from the more highly evolved European Aryan race, the race they believed to be responsible for the rise of Western civilization.

My last year in Vienna was likely also an important factor in my later interest in the mechanisms of memory. I am struck, as others have been, with how deeply the traumatic events of childhood are burned into memory—and I would again emphasize that my experiences were trivial compared to those of so many who were seriously harmed or killed. For me, the frightening experiences of my last year in Vienna are certainly the most powerful of my “flashbulb memories,” the emotionally charged and vivid memories of significant events in our lives.

Resettlement in the United States

Needless to say, arriving in the United States in April of 1939 was like a breath of fresh air. I never actually said, “Free at last,” but I felt it then and have felt it ever since. We settled in Brooklyn and lived at first with my mother’s parents. My grandfather was a religious and scholarly man who was somewhat unworldly. My brother said that my grandfather was the only man he knew who could speak seven languages but could not make himself understood in any of them. My grandfather and I liked each other a great deal, and he readily convinced me that he should tutor me in Hebrew during the summer of 1939 so that I might be eligible for a scholarship at the Yeshiva of Flatbush, an excellent parochial school that offered both secular and religious studies at a very high level. Under his tutelage, I succeeded in gaining a scholarship and entered the Yeshiva in the fall of 1939. By the time I graduated, in 1944, I spoke Hebrew almost as well as English, had read through the five books of Moses, the books of Kings, the Prophets, and the Judges in Hebrew, and also learned a smattering of the Talmud.

After my parents arrived, my father worked in a toothbrush factory. Even though he was not fond of his job, he threw himself into the work with his usual energy and was soon reprimanded by the union steward for producing toothbrushes too quickly and making the other workers appear slow. My father was undeterred. He simply loved America—he often referred to it as the “golden Medina,” the golden state. Even while still in Vienna he had read avidly the novels of Karl May, an author whose books celebrated the conquest of the American West and the bravery of the American Indians.

In time, my father managed to save enough money to rent and outfit a modest clothing store at 411 Church Avenue in Brooklyn. We lived in an apartment above the store. My father and mother worked together and sold simple women’s dresses and aprons, as well as men’s shirts, ties, underwear, and pajamas. They earned enough not only to support us all, but also to send me to college and medical school. My father worked in that store until the week before he died, at age 78, in 1976. My mother sold the store soon thereafter and died in 1991 at age 94.

Erasmus Hall High School and Harvard College

In 1944, when I graduated from elementary school, the Yeshiva of Flatbush did not as yet have a high school, so I went to Erasmus Hall High School, a local public school in Brooklyn that was academically very strong. There I became interested in history, in writing, and in girls. I worked on the school newspaper and became sports editor. I also played soccer and was co-captain of the track team. At the urging of one of my history teachers, John Campagna, a Harvard alumnus, I applied to Harvard College and was one of two students out of my class of about 1,400 to be admitted, both of us on scholarships! Fair Harvard indeed!

Even though I was thrilled by my good fortune, I was apprehensive about leaving Erasmus, convinced that I would never again feel the sheer joy I had experienced there. It was at Erasmus that I first sensed myself emerging from behind the shadow of my brother. I now had distinct interests of my own—jazz, sports, American constitutional history—things that did not interest Lewis. At Harvard I majored in 19th- and 20th-century European history and literature and wrote my honors dissertation on The Attitude Toward National Socialism of Three German Writers: Carl Zuckmayer, Hans Carossa, and Ernst Junger. Each of those writers was still alive, and each represented a different position on the political spectrum of fascism: uncompromising liberal opposition and emigration (Zuckmayer), resigned acceptance and internal (spiritual) emigration (Carossa), and intellectual support (Junger). I came to the rather depressing conclusion that many German artists, intellectuals, and academics had succumbed all too eagerly and opportunistically to the nationalistic fervor and racist propaganda of National Socialism. Later studies have found that Hitler did not have widespread popular support in his first year in office. Had intellectuals mobilized effectively and brought along segments of the general population, Hitler’s government might well have been toppled.

I originally thought of doing graduate work in European intellectual history, along the lines of my undergraduate dissertation. However, in the course of my studies at Harvard I became friends with a fellow student, Anna Kris, who had also emigrated from Vienna with her parents. Anna’s parents, Ernst and Marianne Kris, were both prominent psychoanalysts from Freud’s circle. Anna and her parents were very influential in getting me interested in psychoanalysis.

It is difficult to recapture now the extraordinary fascination that psychoanalysis held for young people in 1950. During the first half of the 20th century, psychoanalysis provided a remarkable set of insights into the human mind—insights about unconscious mental processes, psychic determinism, and perhaps most interesting, the irrationality of human motivation. As a result, psychoanalysis outlined a far more coherent, interesting, and nuanced view of the human mind than any other school of psychology. In addition, Anna’s parents, who represented academic psychoanalysis in its most intellectual and interesting form, were extraordinary people—intelligent, cultured, and filled with enthusiasm. Ernst Kris, a former curator of applied art at the Kunsthistorisches Museum in Vienna, had been a worldclass art historian before becoming a psychoanalyst. After taking up psychoanalysis, he focused on the psychology of art, an area in which he helped train, among others, the great art historian Ernst Gombrich. Marianne Kris, a wonderful therapist, was the daughter of Oskar Rie, a well-known Viennese pediatrician and Freud’s best friend. Marianne, in turn, was a close friend of Freud’s distinguished daughter, Anna.

Both Ernst and Marianne Kris were extremely generous and encouraging to me, as they were to Anna’s other friends. As a result of my frequent interactions with them and their colleagues, I was converted to their view that psychoanalysis offered a fascinating new approach, perhaps the only approach, to understanding the human mind, including the irrational nature of motivation and unconscious and conscious memory. Eventually, psychoanalysis began to seem much more exciting and interesting to me than European literature and intellectual history.

Medical School at New York University

To become a practicing psychoanalyst, it was best to go to medical school, become a physician, and train as a psychiatrist—a course of study I had not previously considered. So in 1951, almost on impulse, I went to summer school at Harvard and took the required course in introductory chemistry. That summer I shared a house with Robert Goldberger, Henry Nunberg, James Schwartz, and Robert Spitzer, and we all became lifelong friends. A few months later, based on this one chemistry course and my overall college record, I was accepted at NYU Medical School, with the proviso that I complete the remaining course requirements before I entered medical school in the fall of 1952.

I entered NYU Medical School dedicated to studying psychiatry and becoming a psychoanalyst. Although I stayed with this career plan through my internship and psychiatric residency, by my senior year in medical school, I had become so interested in the biological basis of medical practice (as had everyone else in my class) that I decided to learn something about the biology of the mind. At the time, most psychoanalysts thought of the mind in nonbiological terms; however, some of them had begun to discuss the potential importance of the biology of the brain for the future of psychoanalysis. Two of these psychoanalysts, whom I got to know personally, were Lawrence Kubie and Mortimer Ostow; both had a background in neurology. After considerable discussion with them and with another biologically oriented psychoanalyst, Sydney Margolin, I decided to take an elective period at Columbia University with Harry Grundfest. In 1955 NYU had no one on the faculty who was doing basic neural science, and Grundfest was the most intellectually interesting neurobiologist in the New York area.

Harry Grundfest’s Laboratory at Columbia University

Grundfest had obtained his PhD in zoology and physiology at Columbia in 1930 and went on to a postdoctoral fellowship there, studying with Selig Hecht, an outstanding psychophysicist who was interested in phototransduction, the transformation of light into neural signals. (Hecht also was the teacher of George Wald, who won the Nobel Prize in 1967 for his discovery of the chemical structure of the visual pigments.) Grundfest joined the Rockefeller Institute in 1935, where he remained for a decade, collaborating with Herbert Gasser. In 1944, while Grundfest was in his lab, Gasser shared the Nobel Prize in Physiology or Medicine with Joseph Erlanger for their introduction of the oscilloscope to neurophysiological studies. The oscilloscope made possible accurate temporal resolution of the waveform and conduction velocities of a propagated action potential. In collaboration with Grundfest, Gasser elaborated on his discovery that the conduction velocity of the action potential is a function of the diameter of the axon. Grundfest also carried out reconstructions of the compound action potential from cross-sectional measurements of axonal diameters in mixed nerves, work that formed much of Gasser’s Nobel Prize Lecture.

In deciding to work with Grundfest, I was strongly encouraged by Denise Bystryn, an extremely attractive and interesting Frenchwoman whom I had just met and would later marry. Denise is also Jewish. Her mother helped her father escape from a French concentration camp, and her parents survived the war by hiding from the Nazis in the southwest of France. During a good part of that time Denise was separated from her parents, hidden in a Catholic convent near Cahors. Denise’s experiences, although more difficult, paralleled mine in a number of ways that seemed significant to her but did not seem at all important to me when we first met. Over the years, however, our shared childhood experiences in Europe have proved to be defining in both our lives.

Denise, her brother Jean-Claude, and her parents emigrated to the United States in 1949. Denise attended the Lycée Français de New York for a year and was admitted at age 17 to Bryn Mawr College as a junior. On graduating from Bryn Mawr at age 19, she enrolled at Columbia University as a graduate student in sociology. When we met, she had just started research for her PhD thesis in medical sociology with Robert Merton. Denise’s father, a gifted mechanical engineer who unfortunately died a year before I met Denise, had advised her to marry a poor intellectual because he would probably be sufficiently ambitious to do interesting scholarship. Denise believed she was following that advice (she certainly married someone who was poor) and always encouraged me to make decisions that favored my doing science.

I spent the first several months in Grundfest’s lab working on a number of projects with Dominick Purpura, an independent young scientist just starting out on his own career of cortical physiology. To my surprise, I found my first experience in a laboratory really interesting, and very different from the classroom. The research questions we were asking fascinated me, and the discussions were penetrating and enjoyable. Dominick was very bright and very entertaining. (I have referred to him as the Woody Allen of neurobiology.) But the actual performance of the experiments was also pleasurable and, when successful, very satisfying. Nevertheless, I began to worry about the methods we were using to address rather sophisticated questions about the electrical properties of dendrites. We were using evoked responses that were initiated by stimulating small areas of the cortex, thereby activating thousands of neurons; I thought these methods too indirect to give easily interpretable results. Grundfest and Purpura, of course, were also concerned and talked repeatedly about doing direct, intracellular recordings from cortical neurons, but neither thought this was likely to succeed.

An Introduction to Stephen Kuffler

It was in this frame of mind that I was introduced to Stephen Kuffler, a Viennese-trained physician-turned-physiologist who, together with Bernard Katz and Grundfest, was to become one of my great neurobiological heroes. One evening Grundfest threw into my lap the September 20, 1955, issue of the Journal of General Physiology, with three of Kuffler’s papers on excitation and inhibition in the dendrites and soma of isolated sensory nerve cells of the lobster and crayfish. Grundfest said something about Kuffler’s being very good and that these papers provided direct evidence of the graded properties of dendrites, evidence that was consistent with what he and Purpura were seeing in cortical neurons. I took the issue home and read the papers as best I could. Although I understood relatively little, one thing stood out immediately: Kuffler was studying dendrites that he could actually see, and he was recording from them directly. He used an invertebrate sensory neuron that sent its dendrites into skeletal muscle that is much like the muscle spindles of vertebrates. In the introduction to the three papers Kuffler wrote:

The greatest advantage of the present preparation lies in its accessibility, since all cellular components can be isolated and visually observed. Further, the state of excitability of the structures could be controlled and graded by utilizing the physiological mechanisms given by the stretch receptor nature of the preparation…. It seems of special interest that the sensory cell of crustacea possessed numerous anatomical features, which bear a striking resemblance to many central nervous system cells of vertebrates (Kuffler and Eyzaguirre 1955).

I learned from Kuffler’s papers a new criterion for good science—the importance of having a preparation suitable for testing the questions to be answered. Kuffler taught me to respect the power of invertebrate neurobiology.

On my graduation from medical school in June 1956, Denise and I married. After a brief honeymoon in Tanglewood, I started an internship at Montefiore Hospital while she continued her thesis research at Columbia. I returned to Grundfest’s lab, spending six weeks with Stanley Crain, who had pioneered the electrophysiological study of nerve cells in tissue culture. Crain taught me how to make microelectrodes and how to obtain and interpret intracellular recordings from the giant axon of the crayfish. These experiments confirmed the insights I had gained from reading Kuffler’s paper. Crain also gave me my first insights into the universality of cellular processes.

Based on my two brief stints in his laboratory, Grundfest offered to nominate me for a position at the National Institutes of Health, an alternative to serving in the physician’s draft, which provided medical personnel for the military during the years following the Korean War. On the basis of Grundfest’s recommendation, I was accepted by Wade Marshall, chief of the Laboratory of Neurophysiology at the National Institute of Mental Health/National Institute of Neurological and Communicative Disorders and Stroke (NIMH/NINCDS).

The Neurophysiology Laboratory at the National Institutes of Health

By the time I arrived in Bethesda, Marshall had passed the peak of what had been a remarkable career. In the 1930s he was arguably the most promising and accomplished young scientist working on the brain in the United States. As a graduate student at the University of Chicago in Ralph Gerard’s lab in 1936, he discovered that he could record electrical deflections in the somatosensory processing area of the cerebral cortex by moving the hairs of a cat’s limb. He appreciated that one might use this electrical signal (the evoked response) to map the brain’s representation of the surface of the body.

To study this further, Marshall joined Phillip Bard, chairman of the department of physiology at the Johns Hopkins Medical School, as a postdoctoral fellow in 1937. Bard was a major presence in American neurophysiology. Together with his student Clinton Woolsey, he had surgically removed the somatosensory cortex of the monkey and studied its effect on the “placing reaction,” a form of tactile behavior. Marshall joined Woolsey and Bard, and together they carried out a classic series of studies in which they mapped sensory inputs from the body surface in the somatosensory cortex and showed that a topographical representation of the entire body is wired into the brain. Today, this map is still shown in every textbook of neural science. Marshall next collaborated with John Talbott and mapped retinal inputs in the striate cortex. Finally, with Harlow W. Ades, he mapped cochlear inputs in the auditory cortex.

These marvelous scientific achievements came at a price, however. Marshall was so psychologically fatigued that he collapsed and left science altogether for a number of years. When he returned, in about 1945, he moved on to a completely new problem: spreading cortical depression, a propagating, reversible silencing of cortical electrical activity. Marshall enjoyed doing occasional experiments, but he had lost his scientific drive and now focused much of his energy and interests on administrative matters, which he did well. Although eccentric, moody, and somewhat unpredictable, he was a wonderful lab chief. In particular, he was supportive and generous to young scientists and gave us a great deal of freedom.

Just before I arrived at the NIH in 1957, the neurosurgeon William Scoville and the cognitive psychologist Brenda Milner had described the nowfamous patient H.M. In order to treat H.M.’s intractable bilateral temporal lobe epilepsy, Scoville had removed the medial temporal lobe on both sides of H.M.’s brain, including the hippocampus, a structure located deep within the temporal lobe. The procedure largely eliminated H.M.’s seizures; however, while retaining all his cognitive functions, he lost the ability to put new information into long-term memory. These findings pinpointed the medial temporal lobe, and especially the hippocampus, as sites specialized for memory storage.

Until the Scoville and Milner paper, the person most closely identified with attempts to localize memory had been Karl Lashley, professor of psychology at Harvard and perhaps the dominant figure in American neuropsychology in the first half of the 20th century. Lashley explored the surface of the cerebral cortex in the rat and systematically removed different areas. In the process, he failed to identify any particular region of the brain that was special to or necessary for the storage of memory. Based on these experiments, he formulated the law of mass action, according to which memory is not localized to any specific region of the cortex but is a distributed property of the cortex as a whole. The extent of any memory defect, Lashley argued, was correlated with the size of the cortical area removed, not with its specific location.

Since I had already begun to think about problems in psychiatry and psychoanalysis in biological terms, the cellular and molecular mechanisms of learning and memory struck me as a wonderful problem to study. I had first become interested in the study of learning at Harvard, where B.F. Skinner, the great behaviorist, was a dominant force in the 1950s. It was clear to me even then that learning and memory are central to behavior, and thus to psychopathology and to psychotherapy. Nothing was known about the cellular mechanisms of learning and memory, and the techniques for studying them, some of which I had learned from Stanley Crain in Grundfest’s lab, were just becoming available.

My initial ideas about how to tackle the biology of memory were confused and vague. Because intracellular recordings seemed such a powerful analytic tool for studying nerve cells, and because the hippocampus seemed particularly important for memory, I wanted to explore the hippocampus in cellular terms. The prospect was even more attractive because, as the great anatomists Santiago Ramón y Cajal and Rafael Lorente de Nó had pointed out, the cellular architecture of the hippocampus is remarkably conserved among mammals, and the main cell type, the pyramidal cell, is found in a discrete layer that is easy to target with microelectrodes. In addition, because the pyramidal cells send their axons into a large fiber tract (the fornix), one could identify individual cells electrophysiologically by stimulating the axons in the fornix, which would then fire signals back to the cell bodies. I thought it would be interesting to compare pyramidal neurons to the only other mammalian neurons that had been well studied at that time, the motor neurons of the spinal cord. I had the idea that the properties of the pyramidal cells themselves might reveal something about memory storage. I was emboldened to try this technically demanding study because Karl Frank was in the laboratory next to ours, pioneering the examination of spinal motor neurons with intracellular recordings in parallel with John Eccles. Although Frank himself thought that studying the hippocampus was chancy, he was not discouraging.

Almost as soon as I began, my research took an extremely fortunate turn in the person of Alden Spencer, who arrived in Marshall’s lab having just graduated from the University of Oregon Medical School. Like me, Alden was becoming interested in the biology of learning and memory. It therefore took little effort to convince him that we should join forces on the hippocampus. Although Alden had no experience with intracellular recordings, he had done electrophysiological research on the brain at the University of Oregon, where he worked with John Brookhardt. Among Alden’s many remarkable talents, he had good surgical skills and a fine knowledge of the anatomical organization of the mammalian brain.

Being both naïve and brash, we were not reluctant to tackle what appeared to Frank and others to be the technically difficult problem of obtaining intracellular recordings from cortical neurons in a pulsating brain. Alden and I developed a simple way of reducing pulsations in the hippocampus that allowed us to obtain, on occasion, high-quality recordings for a long enough period (up to one hour) to carry out an initial analysis of the electrical properties of pyramidal cells. By applying to the hippocampus the powerful methodologies we had learned from Frank, we easily picked some low-hanging intellectual fruit.

First, we found that action potentials in hippocampal neurons are initiated not only at the axon hillock, as they are in motor neurons, but also at a second site, which we inferred to be the apical dendrites. These putative dendritic action potentials, which we called fast prepotentials, appeared to trigger the firing at the axon hillock. Second, we found that hippocampal neurons, unlike motor neurons, are not silent in the absence of synaptic activity; they tend to fire spontaneously, and this firing often takes the form of bursts, or spikes, that are maintained by the summation of depolarizing afterpotentials. Third, we found that hippocampal neurons engage a powerful, recurrent inhibitory system that gives rise to a prolonged inhibitory synaptic action that is several orders of magnitude longer than the recurrent inhibition in the spinal cord.

The mere technical success of obtaining intracellular recordings from hippocampal neurons and the few interesting questions we were able to address caught the enthusiastic attention of, and drew encouragement and help from, our senior colleagues at the NIH: Marshall, Frank, Frank’s gifted colleague Michael Fuortes, and the great biophysicist Ichiji Tasaki. When John Eccles visited the NIH he, too, was generous in his comments. But even in our brashest moments, we both realized that ours was a typical NIH story: in the Intramural Program young, inexperienced people were given the opportunity to try things on their own, knowing that wherever they turned, experienced people were available to help out.

As Alden and I reviewed our work, we realized that the properties of hippocampal neurons are not sufficiently different from those of spinal neurons to explain the ability of the hippocampus to store memory. Thus, it dawned on us what in retrospect is quite obvious: the neuronal mechanisms of learning and memory reside in how neurons are functionally connected. Learning results when connections among neurons are modified by appropriate sensory signals. This conclusion, so clear in retrospect, emerged only gradually as we learned, mostly through reading and discussions with one another, to think more effectively about the biology of learning and memory.

This realization led us to reappraise our strategy. Even though we were now quite familiar with the hippocampus, it was not the place to begin. The hippocampus has a large number of neurons and an immense number of interconnections. We would have great difficulty working out how sensory information specific to learning reaches the hippocampus and how learned information processed by the hippocampus might influence motor output.

Alden and I therefore became convinced that to make headway with the study of learning at the cellular level, we would have to take a very different approach. Alden, a committed mammalian neurophysiologist, turned to the study of the spinal cord, particularly the modifiability of spinal reflexes, and went on to make important contributions in collaboration with Richard Thompson. However, even the spinal cord proved too difficult for a detailed cellular analysis, and both Alden and Thompson ended up abandoning it.

The Search for a Tractable System for Studying Learning

Influenced by Kuffler, Grundfest, and Crain, I yearned for a more radically reductionist approach to the biology of learning and memory. I wanted a system that would serve the cellular study of learning as well as the giant axon of the squid had served the study of the action potential or the nervemuscle synapse of the frog had served the study of synaptic transmission. I wanted to find an experimental animal in which a simple behavior could be modified by learning. Ideally, that behavior should be controlled by only a small number of large, accessible nerve cells; in that way, I could relate the animal’s overt behavior to events occurring in the cells that control that behavior.

Such a reductionist approach is traditional in biology. In neurobiology it is exemplified by the work on the squid’s giant axon by Hodgkin and Huxley, the nerve-muscle synapse of the frog by Bernard Katz, and the eye of Limulus by Keefer Hartline. When it came to the study of behavior, however, most investigators were reluctant to apply a strict reductionist strategy. In the 1950s and 1960s it was often said that behavior was the area of biology in which simple animal models, particularly invertebrate ones, were least likely to produce fruitful results. The brain that really learns—the mammalian brain, especially the human brain—is so complex that inferences from studies of invertebrates would not stand up. It was thought that the human brain, with its higher-order capabilities, must have neuronal organizations that are qualitatively different from those found in invertebrates.

These arguments held some truth, but they overlooked certain critical issues. Work by students of comparative behavior, such as Konrad Lorenz, Niko Tinbergen, and Karl von Frisch, had already shown that certain behavior patterns, including elementary forms of learning, are common to both humans and simple animals. I therefore believed from the outset that the mechanisms of memory storage are likely to be conserved in phylogeny and that a cellular analysis of learning in a simple animal would reveal universal mechanisms that extend to more complex organisms as well.

Not surprisingly, I was strongly discouraged from pursuing this strategy by some senior researchers in neurobiology, particularly Eccles. His concern reflected, in part, the existing hierarchy of acceptable research questions in neurobiology. Few self-respecting neurophysiologists, I was told, would leave the study of learning in mammals to work on an invertebrate. Was I compromising my career? Of even greater concern to me were the doubts expressed by some very knowledgeable psychologists, who were skeptical that anything interesting about learning and memory could be found in a simple invertebrate animal.

I had made up my mind, however. Since we knew nothing about the cell biology of learning and memory, I believed that any insight into the modification of behavior by experience, no matter how simple the animal or the task, would prove to be highly informative.

After an extensive search that included crayfish, lobster, flies, and the nematode worm Ascaris, I settled on Aplysia, the giant marine snail. Aplysia offered three major technical advantages: its nervous system has a small number of cells, the cells are unusually large, and, as I came to realize, many of the cells are invariant and identifiable as unique individuals. The only two people in the world working on Aplysia at this time were French: Ladislav Tauc, in Paris, and Angelique Arvanitaki-Chalazonitis, in Marseilles. So far so good! But Denise’s advice in the matter was decisive: ever the Parisian chauvinist, she thought that living in Marseilles instead of Paris would be like living in Albany instead of New York City. So before leaving the NIH in 1960, I arranged a postdoctoral fellowship with Ladislav Tauc: I was to join him in Paris in September 1962, as soon as I had completed my residency training. It proved an excellent choice.

Residency Training in Psychiatry at Harvard Medical School

I began my psychiatric residency at the Massachusetts Mental Health Center of the Harvard Medical School in the spring of 1960. When I arrived at Harvard, I found an unanticipated bonus. Stephen Kuffler, whose thinking had so influenced my own, had been recruited a year earlier from Johns Hopkins to build up the neurophysiology unit at Harvard. Kuffler brought with him several young postdoctoral fellows—David Hubel, Torsten Wiesel, Ed Furshpan, and David Potter—each of whom was extraordinarily gifted. In this way Kuffler succeeded, in one fell swoop, in setting up at Harvard the premier group of neural scientists in the country. I now had my first opportunity to interact with Kuffler and with the remarkable people he had assembled around him. Even though I was in full-time residency training, Kuffler and his group were extremely accessible, and their generosity allowed me to remain intellectually engaged in neurobiology. Moreover, Jack Ewalt, professor of psychiatry at the Massachusetts Mental Health Center, provided me with funds and space so that I even managed to do some research in my spare time. I obtained the first intracellular recording from hypothalamic neuroendocrine cells and found that these hormonereleasing cells had all the electrical properties of normal nerve cells.

During my residency I began to think about simple forms of learning in preparation for work on Aplysia. I read Kimble’s wonderful revision of Hilgard and Marquis’s classical text Conditioning and Learning, and I reread Skinner’s great book The Behavior of Organisms. This reading made me realize that the paradigms of simple learning articulated by Ivan Pavlov and Edward Thorndyke, describing changes in behavior in response to controlled stimulation, included precise protocols for stimulating experimental animals. It occurred to me that the paradigms they described—habituation, sensitization, classical conditioning, and operant conditioning—could readily be adapted to experiments with an isolated Aplysia ganglion using artificial electrical stimuli rather than natural sensory stimuli. While recording the behavior of a single cell in a ganglion, one nerve axon pathway to the ganglion could be stimulated weakly as a conditioned stimulus while another pathway was stimulated as an unconditioned stimulus, following the exact protocol used for classical conditioning with natural stimuli in intact animals. One could then see whether synapses changed systematically in response to these patterns of stimulation, and if so, whether the synaptic changes in any way paralleled changes in the overt behavior of intact animals that classical psychologists had described.

I soon began to call these patterns of stimulation derived from learning experiments in intact, behaving organisms analogs of learning. It dawned on me that by applying analogs of learning directly to a neuronal system and analyzing the results, I could take an initial step toward the study of learning in the intact animal.

Paris, Aplysia, and Neural Analogs of Learning

Based on this idea, I was awarded an NINCDS postdoctoral fellowship for work to be done in Tauc’s laboratory. In September 1962, about a year after our son, Paul, was born, Denise and I took off for Paris with him. Tauc proved an excellent person to work with; both our interests and our areas of competence complemented each other. He was, of course, completely at home with Aplysia, but he also had a strong background in physics and biophysics, which I lacked. Born in Czechoslovakia, Tauc had originally studied the electrical properties of plant cells. As a result, he had no experience with behavior and had up to this point thought little about the problems of neuronal integration that dominated thinking about the mammalian brain, problems that Alden and I had discussed incessantly. Tauc was quite enthusiastic about my approach, which proved even more effective than I had anticipated. In my cellular studies of analogs of habituation, sensitization, and classical conditioning in Aplysia, I found synaptic changes that parallel the behavioral changes seen in experiments on intact animals. This encouraged Tauc and me to write in our 1965 paper in the British Journal of Physiology:

The fact that the EPSPs (excitatory postsynaptic potentials) can be facilitated for over half-an-hour with an input pattern scheme designed to simulate a behavioral conditioning paradigm also suggests that the concomitant changes in the efficacy of synaptic transmission may underlie certain simple forms of information storage in the intact animal (Kandel alnd Tauc 1965).

A Brief Return to Harvard Medical School

Upon completing a very productive 16-month stay in Tauc’s laboratory, I returned to Harvard in November 1963. In July 1965 our daughter, Minouche, was born, completing our family: one boy, one girl, exactly what we had hoped for.

During this period at Harvard I struggled with three choices that were to have a profound effect on my subsequent career. First, I realized that to do effective science I could not combine basic research and a clinical practice in psychoanalysis, as I had earlier hoped. I therefore decided not to apply to the Boston Psychoanalytic Institute, a decision which meant that I would not attempt to become a psychoanalyst, but would instead devote myself full time to science. It was my strong sense that one of the problems within academic psychiatry, a problem that has only become worse with time, is that young people take on much more than they can handle effectively. I concluded that I could not and would not do that.

The second choice arose a few months later, when Ewalt and Howard Hiatt, then chairman of the department of medicine at Beth Israel Hospital at Harvard, suggested that I take on the newly vacated chairmanship of the department of psychiatry at the hospital. For a moment I was forced to rethink my decision to focus full time on science. The person who had just left that position, Grete Bibring, was a leading psychoanalyst and a colleague of Marianne and Ernst Kris in Vienna. Earlier in my life this position would have represented my highest aspiration. But by 1965 my thinking had moved in a very different direction, and I decided against it, with Denise’s strong encouragement. (Denise summarized it simply: “What?” she asked, “throw your scientific career away?”) Instead, I made my third choice. I decided to leave Harvard and accept an invitation to start a small neurophysiology group focused specifically on the neurobiology of behavior in the departments of physiology and psychiatry at the NYU Medical School.

Harvard was quite wonderful, and it was not easy to leave that intellectually heady neurobiology environment. My interaction with Kuffler had increased after my return from Paris, and until his death in 1980, he proved a marvelous friend and counselor. Moreover, my interactions during this period with members of Kuffler’s group—Hubel, Wiesel, Furshpan, Potter, and Ed Kravitz, a biochemist who joined them later—were extensive, and I learned much from them. Many years later, at a small meeting at the Marine Biological Laboratory at Woods Hole in honor of Steve Kuffler, I was surrounded by Steve’s Harvard entourage, some of whom were struggling with the decision of whether to leave Harvard for attractive positions elsewhere. I could not resist beginning my lecture with the remark, “I am here as living proof that there is life after Harvard.”

New York University and a Focus on the Behavior of Aplysia

The position at NYU had several great attractions that, in the long run, proved critical. First, it brought us back to New York and closer to my parents and to Denise’s mother, all of whom were having medical problems and benefited from our being nearby. Second, NYU gave me the opportunity to recruit an additional senior neurophysiologist, and Alden Spencer agreed to move to NYU from the University of Oregon Medical School, where he had returned after his stay at the NIH. Alden occupied the laboratory next to mine, and although he and I never collaborated experimentally again, we talked daily not only about our science—the neurobiology of behavior—but about almost everything else. He died in 1977, at age 46, from amyotrophic lateral sclerosis, after we had both moved to Columbia University. While he was alive, no one influenced my thinking on matters of science as much as Alden. I still think about him frequently.

Alden and I arrived at NYU together in the winter of 1965. Within a year we were joined by Jimmy Schwartz, whom I had first met in the summer of 1951 at Harvard summer school and who was now a member of the department of microbiology at NYU and was becoming interested in behavior. The three of us formed the nucleus of the Division of Neurobiology and Behavior at NYU.

With several important decisions behind me, I made a strong effort to focus on whole-animal behavior. In France I had found that chemical synapses are remarkably plastic—they readily undergo long-lasting changes in strength—but I had no evidence that the changes were in fact behaviorally meaningful, that they occur when an animal learns something. During my last few weeks in France I had begun to replicate my results by substituting natural stimuli for electrical stimulation of nerves, but I still had not shown that synaptic plasticity occurs during behavioral learning. As a first step I thought it essential to show that Aplysia is capable of learning. With this in mind, I set about recruiting a postdoctoral fellow with a specific interest in behavioral learning. I was fortunate to recruit, first to Harvard and then to NYU, Irving Kupfermann, an extremely critical and thoughtful student of behavior. We were later joined by another learning psychologist, Harold Pinsker, and together we set about delineating a very simple behavior that we could study: the gill-withdrawal reflex. We quickly found that this simple reflex could readily be modified by two forms of learning: habituation and sensitization.

In exploring these two forms of learning, we focused on short-term memory. In 1971 we were joined by another experienced behavioral psychologist, Tom Carew, who brought a new level of energy and insight to our behavioral studies. He arrived as Pinsker was leaving, and soon afterward we shifted from working on short-term memory and started on long-term memory. Tom found that spaced repetition of stimuli converts the memory underlying short-term habituation and sensitization to longer-lasting memories. In 1981, after several unsuccessful attempts, Carew, Terry Walters, Tom Abrams, and Robert Hawkins were able to define the conditions for reliably producing classical conditioning in Aplysia. This was a particularly exciting period; Carew, Walters, Hawkins, and I met regularly to discuss how to explore whether a simple reflex, in a simple invertebrate, could show the higher-order cognitive features of classical conditioning recently demonstrated in mammals by Leo Kamin and somewhat later by Robert Rescorla and Alan Wagner. Soon, Hawkins was indeed able to demonstrate that the gill-withdrawal reflex can undergo second-order conditioning, blocking, overshadowing, and other cognitive aspects of associative learning, features that were surprising to uncover in such a simple behavior.

We thus were able to describe a rather rich repertory of learning in Aplysia. But long before this inventory of the animal’s behavior was complete, we returned to our initial concerns. What happens in the brain of an animal when it learns a task? How does it remember? We proceeded, first with Kupfermann and Vincent Castellucci and then with Jack Byrne and Hawkins, to work out most of the neural circuitry of the gill-withdrawal reflex. We identified the specific sensory neurons and motor cells that produce movements of the gill. Next, we found that the sensory neurons make direct connections to the motor neurons as well as indirect connections through interneurons, both excitatory and inhibitory. The aversive shocks to the tail that produce sensitization of the gill-withdrawal reflex also activate modulatory interneurons that act on terminals of the sensory neurons. We now could turn to thinking about how learning might occur in this reflex.

Cellular Mechanisms of Learning

At the end of the 19th century Ramón y Cajal introduced the principle of connection specificity, which states that during development, a neuron will form connections only with certain neurons and not with others. Kupfermann, Castellucci, and I saw this remarkable regularity of connections in the circuitry of the gill-withdrawal reflex of Aplysia. We also saw, in exquisite detail, that specific, identifiable cells make invariant connections to one another. This invariant organization of neurons presented serious questions: How could we reconcile hardwired circuits in the nervous system and the specificity of connections with an animal’s ability to learn? Once acquired, where or how is learned information retained in the nervous system?

One solution was proposed by Ramón y Cajal in his Croonian Lecture to the Royal Society of London in 1894, when he suggested that “mental exercise facilitates a greater development of the protoplasmic apparatus and of the nervous collaterals in the part of the brain in use. In this way, preexisting connections between groups of cells could be reinforced by multiplication of the terminal branches of protoplasmic appendices and nervous collaterals” (Cajal 1894).

This remarkably prescient idea was by no means generally accepted. On the contrary, different theories of learning held the attention of neural scientists at various times. Two decades after Ramón y Cajal’s proposal, the physiologist Alexander Forbes suggested that memory is sustained not by changes in synaptic strength of the sort suggested by Ramón y Cajal, but by dynamic changes resulting from reverberating activity within a closed loop of self-exciting neurons. This idea was elaborated by Ramón y Cajal’s student Lorente de Nó, who found in his own and in Ramón y Cajal’s analyses of neural circuitry neurons that were interconnected in closed pathways; these neurons could therefore sustain reverberatory activity, thus providing a dynamic mechanism for information storage. In his influential book The Organization of Behavior (1949), D.O. Hebb proposed that a “coincident activity” initiated the growth of new synaptic connections as part of long-term memory storage, but for short-term memory, Hebb invoked a reverberatory circuit:

To account for permanence, some structural change seems necessary, but structural growth presumably would require an appreciable time. If some way can be found of supposing that a reverberatory trace might cooperate with the structural change, and carry the memory until the growth change is made, we should be able to recognize the theoretical value of the trace, which is an activity only without having to ascribe all memory to it. The conception of a transient, unstable reverberatory trace is therefore useful. It is possible to suppose also some more permanent structural change reinforces it.

Similarly, in The Mammalian Cerebral Cortex, an influential book of 1958, B. Deslisle Burns challenged the relevance of synaptic plasticity to memory.

The mechanisms of synaptic facilitation which have been offered as candidates for an explanation of memory … have proven disappointing. Before any of them can be accepted as the cellular changes accompanying conditioned reflex formation, one would have to extend considerably the scale of time on which they have been observed to operate. The persistent failure of synaptic facilitation to explain memory makes one wonder whether neurophysiologists have not been looking for the wrong kind of mechanisms.

Indeed, some scholars even minimized the importance of specific neuronal connections in the brain, advocating instead mechanisms of learning that were partially or even totally independent of “pre-established” conduction pathways. This view was held by Wolfgang Kohler, the famous Gestalt psychologists, and subsequently by the neurophysiologists Ross Adey and Frank Morrell. Adey wrote in 1965:

No neuron in natural or artificial isolation from other neurons has been shown capable of storing information in the usual notion of memory …. In particular, the possibility exists that extraneuronal compartments may participate importantly in the modulation of the wave processes that characterize the intracellular records, and that these wave processes may rank at least equivalently with neuronal firing in the transaction of information and even more importantly in its deposition and recall.

Finally, a macromolecular notion of memory was advocated by Holger Hyden, based upon his finding of changes in the nucleotide composition of RNA. He proposed that learning gives rise to a specific pattern of neural activity, which alters the stability of RNA molecules, enabling the exchange of one base pair for another. In this way, he held, new RNA molecules are formed with new base sequences that are specific to the instructing pattern of neural activity induced by learning. Hyden’s hypothesis implied that the patterns of stimulation activated by learning could introduce changes in RNA.

We were in a position to test experimentally, which, if any, of these ideas had merit. Using the gill-withdrawal reflex we quickly established that memory in the Aplysia nervous system is not represented in self-exciting loops of neurons but in changes in synaptic strength. We found that all three simple forms of learning—habituation, sensitization, and classical conditioning—lead to changes in the synaptic strength of specific sensory pathways and that these changes parallel the time course of the memory process. Our findings, which were fully in line with our earlier studies of analogs of learning, gave rise to one of the major themes in our thinking about the molecular mechanisms of memory storage: although the anatomical connections between neurons develop according to a definite plan, the strength and effectiveness of those connections are not fully determined during development and can be altered by experience.

We therefore concluded the third in a series of papers on the cellular mechanisms of learning, published in Science in 1970, with the following comments:

[T]he data indicate that habituation and dishabituation (sensitization) both involve a change in the functional effectiveness of previously existing excitatory connections. Thus, at least in the simple cases, it seems unnecessary to explain the behavioral modifications by invoking electrical and chemical fields or a unique statistical distribution in a neural aggregate. The capability for behavioral modification seems to be built directly into the neural architecture of the behavioral reflex.

Finally, these studies strengthen the assumption … that a prerequisite for studying behavioral modification is the analysis of the wiring diagram underlying the behavior. We have, indeed, found that once the wiring diagram of the behavior is known, the analysis of its modification becomes greatly simplified. Thus, although this analysis pertains to only relatively simple and short-term behavioral modifications, a similar approach may perhaps also be applied to more complex as well as longer lasting learning processes (Castellucci et al. 1970).

A Beginning Molecular Analysis of Memory Storage

Having defined a critical site of plasticity, we were ready to begin a molecular analysis. Here again I could not have been more fortunate. As I mentioned earlier, soon after I arrived at NYU I ran into Jimmy Schwartz, who had attended NYU Medical School two years behind me. After medical school he obtained a PhD with Fritz Lipmann at the Rockefeller University, studying enzyme mechanisms and protein translation in cell-free bacteria extracts. As Schwartz and I began to talk again, he mentioned that he was thinking of moving from E. coli to the brain. Aplysia seemed ideal for the biochemical study of individual nerve cells, so in 1966, we joined forces to carry out biochemical studies on specific nerve cells of Aplysia.

Schwartz soon found that different kinds of nerve cells in Aplysia have different transmitter biochemistry. Cells that we had presumed on pharmacological grounds to be cholinergic did in fact synthesize and release acetylcholine. With time, he became interested in the molecular mechanisms of synaptic plasticity, and together we began to examine the role of protein synthesis in memory storage. We knew from the work of Louis Flexner and Bernard Agranoff in the mid-1960s that long-term memory in vertebrates requires protein synthesis, whereas short-term memory does not. In our first study together, in 1971, we found that blocking protein synthesis for 24 hours does not prevent the short-term synaptic changes associated with habituation and sensitization. That finding made us think that short-term changes representing memory storage might involve activation of a secondmessenger pathway—for example, the cyclic AMP (cAMP) cascade, whose actions might persist longer than the millisecond of conventional synaptic actions.

In the discussion of our 1971 paper on the role of protein synthesis and synaptic plasticity we wrote:

Alterations in molecular configuration would not be expected to persist for long periods of time, although molecular changes lasting for several minutes have been observed…. Most likely, the biochemical mechanisms underlying these short-term plastic changes are composed of a series of sequential reactions which result in a new distribution of transmitter substance. Mechanisms involving cyclic 3',5' AMP might serve as one example of a series of reactions which result in transient enhancement in the activity of a critical enzyme system. A pathway of this kind might trigger the mobilization of transmitter from one component (a long-term store) to another (an immediately releasable store)….

If our conclusion is correct … rapidly synthesized RNA cannot immediately play a role in neuronal functions; it might, however, be important for long-term neuronal processes (Schwartz et al. 1971).

Earl Wilbur Sutherland and Ted Rall had shown in brain slices that several neurotransmitters known to exist in the brain can increase concentrations of cAMP by activating the enzyme adenylyl cyclase, which converts ATP to cAMP. We appreciated that we had a particularly good experimental preparation for examining, on the cellular level, the role of second-messenger pathways in synaptic transmission, synaptic plasticity, and memory storage. In 1972 Schwartz, Howard Cedar, and I found that stimulation of the pathway involved in sensitization increases the concentration of cAMP in the entire abdominal ganglion. Schwartz and Cedar next found that the transmitter serotonin can also increase cAMP, providing the initial evidence that serotonin might activate an adenylyl cyclase in Aplysia.

Columbia University and the Molecular Analysis of Short-Term Memory

It was at this time that I was invited to move from NYU to Columbia University’s College of Physicians and Surgeons to become the founding director of the Center for Neurobiology and Behavior. I was able to persuade Schwartz, Spencer, and Kupfermann (who had established an independent research program concerned with feeding and motivational state in Aplysia) to join me. This move was attractive for several reasons. Historically, Columbia has had a strong tradition in neurology and psychiatry, and a friend and former clinical teacher, Lewis Rowland, was about to assume the chairmanship of the department of neurology. In addition, I had my first experience in neurobiology at Columbia with Harry Grundfest, who was now retiring and whom I was being recruited to replace. Finally, Denise was on the Columbia faculty and our house in Riverdale was near the College of Physicians and Surgeons, so the move would greatly simplify our lives.

In 1974, just after arriving at Columbia, Castellucci and I went back to the elementary circuit of the gill-withdrawal reflex to determine the exact site of the synaptic change produced by short-term sensitization. We wanted to know which component of the synapse changes. Is it, as we suspected on the basis of indirect evidence, the presynaptic cell, which releases a chemical transmitter, or is it the postsynaptic cell, which contains the receptors that bind and respond to the transmitter? Using a quantal analysis, we found that the synaptic facilitation characteristic of sensitization is presynaptic and that inhibitors of serotonin block this presynaptic facilitation. Later, Hawkins and I found that shocks to Aplysia’s tail, which initiate sensitization, activate a set of modulatory interneurons, the most important of which release serotonin. The serotonergic and other modulatory interneurons all act on the sensory neurons and on their presynaptic terminals to enhance the release of the transmitter glutamate. We could now ask for the first time: Is cAMP directly involved in synaptic facilitation? In 1976 Marcello Brunelli took advantage of the size of the Aplysia neurons and injected cAMP directly into the presynaptic sensory cell; he found clear enhancement of synaptic transmission. This cAMP-induced enhancement parallels the enhancement produced by serotonin and by shocks to Aplysia’s tail.

I now began to interact with Paul Greengard, who was demonstrating that cAMP produces its actions in the brain through the cAMP-dependent protein kinase, or PKA. In 1980 Schwartz, Castellucci, Greengard, and I injected a purified catalytic subunit of bovine PKA into presynaptic sensory neurons and found that it simulates the actions of cAMP and of serotonin. Moreover, we could block the actions of serotonin by injecting into the sensory neuron a specific peptide (PKI) that inhibits PKA. With Steven Siegelbaum we next began to define some of the targets of PKA, focusing on one in particular, a novel potassium channel. Siegelbaum showed that this channel is closed by serotonin and by PKA and that the action is consistent with the channel’s being phosphorylated directly by PKA.

The Howard Hughes Medical Institute and the Molecular Analysis of Long-Term Memory

Just before I arrived at Columbia, Arnold Kriegstein, an MD-PhD student, succeeded in culturing embryonic Aplysia in the laboratory, a quest that had intrigued and eluded biologists for almost a century. Most of us who were there will not readily forget Kriegstein’s extraordinary in-house seminar in December 1973, when he first described his discovery that the red seaweed Laurencia pacifica is required to trigger metamorphosis from a free-swimming veliger larva to a small crawling snail. When he showed the first pictures of the tiny, postmetamorphic juvenile Aplysia I remember saying to myself, “Babies are always so beautiful!” Kriegstein’s work opened up the study of development and cell culture in Aplysia.

Because we now had young animals at all stages of development, we at last had the essential requirements for the generation of dissociated cell culture. This was taken on by Sam Schacher and Eric Proshansky. With the help of Steven Rayport (another MD-PhD student at Columbia), the three soon succeeded in culturing the individual sensory neurons, motor neurons, and serotonergic modulatory interneurons of the gill-withdrawal reflex. The development of the culture system coincided with two other events that enabled me to begin studying the molecular mechanisms of long-term memory storage. The first was my encounter with Richard Axel and my collaboration, in 1979, with him and with Richard Scheller, who became a joint postdoctoral fellow. The second was my being recruited to become a senior investigator at the Howard Hughes Medical Institute.

Axel and Scheller’s success in 1982 in cloning the gene that encodes the egg-laying hormone in Aplysia seeded Axel’s long-term interest in neurobiology and gave me not only a wonderful friend but also an exposure to the methods of recombinant DNA and modern molecular biology. The very next year, Donald Fredrickson, the newly appointed president of the Howard Hughes Medical Institute, asked Schwartz, Axel, and me to form the nucleus of a research institute at Columbia devoted to molecular neural science. This gave us the opportunity to recruit from Harvard both Tom Jessell and Gary Struhl, as well as to keep Siegelbaum at Columbia.

My first goal on becoming a Hughes investigator was to examine the molecular mechanisms underlying the synaptic changes that parallel longterm memory storage. In 1885, Herman Ebbinghaus transformed speculation about memory into a laboratory science by having subjects memorize lists of nonsense syllables. In this way Ebbinghaus generated two basic principles about memory storage. First, the transition from short-term memory to long-term memory is graded: practice makes perfect. Second, there is a fundamental distinction between short-term and long-term memory.

What was the molecular basis of this distinction? Flexner and Agranoff had found that inhibitors of protein synthesis disrupt long-term memory without adversely affecting learning or short-term memory. We found that long-term sensitization in Aplysia is similarly dependent on protein synthesis, whereas short-term sensitization is not. These findings illustrated the generality of the distinction between short-term and longterm memory processes for both invertebrates and vertebrates. In each case, spaced repetition of the learning stimulus transforms a transient memory into a more stable (long-term) memory through a process that depends on the synthesis of new protein. But how this occurred remained a mystery.

We had found earlier in Aplysia that long-term sensitization involves a persistent increase in the strength of the same synaptic connection that is altered by the short-term process—that is, the connection between the sensory and motor neurons of the gill-withdrawal reflex. To study this process more effectively, we turned to dissociated cell culture and found that we could reconstitute both short- and long-term synaptic facilitation in a culture consisting of only a single sensory neuron and a single motor neuron. We did this, together with Sam Schacher, Philip Goelet, and Pier Giorgio Montarolo, by applying either one or five brief, evenly spaced pulses of serotonin to the sensory neuron and motor neuron in the culture dish. Much as we had seen in behavioral long-term memory, long-term synaptic change requires the synthesis of new protein, whereas short-term change does not. We had succeeded in tracking the protein synthesis–dependent component of memory storage in the elementary synaptic connection between two identified cells. We could now address directly several important questions: Why is protein synthesis required for long-term but not short-term facilitation? What are the molecular steps that switch on longterm facilitation? Once switched on, how is it maintained?

We next found that new protein synthesis begins with a flurry of gene activity initiated by PKA. With repeated applications of serotonin, PKA moves to the nucleus of the cell and in so doing activates the mitogenactivated protein (MAP) kinase, another kinase often recruited for growth. Thus, one of the functions of repeated stimulation is to cause both kinases to move into the nucleus. Pramod Dash and Binyamin Hochner, and later Cristina Alberini, Mirella Ghirardi, and Dusan Bartsch, provided the first evidence that in the nucleus, these kinases act on a gene regulator called CREB-1 (the cAMP response element binding protein) to initiate a cascade of gene transcription. With David Glanzman and Craig Bailey, we found that CREB-mediated transcription, which triggers the synthesis of new proteins, is also required for the growth of new synaptic connections—and it is the formation of these new synapses that sustains the long-term change.

This finding explained why long-term memory requires the synthesis of new proteins. It also showed us that since long-term synaptic change relies on the activation of genes in the nucleus, there is ready communication between the synapse and the nucleus. But the finding posed a new problem. Since long-lasting synaptic change requires gene transcription, a process that takes place in the nucleus, and the nucleus is shared by all the synapses of a neuron, is long-term memory storage a cell-wide process? Or can longterm synaptic changes be restricted to individual synapses?

Is Long-Term Facilitation Synapse Specific?

Experiments by Kelsey Martin, based on a beautiful new cell culture system that she developed, revealed that individual synapses or groups of synapses within a cell can be modified independently. Martin cultured one sensory cell with a bifurcating axon that connected with two motor neurons, thus forming two widely separated synapses. A single puff of serotonin applied to one synapse produced transient facilitation at that synapse only, as expected (Bacskai et al. 1993; Casadio et al. 1999). Similarly, five puffs of serotonin produced long-lasting facilitation (more than 72 hours) at the stimulated synapse only. These findings indicated that despite their recruitment of nuclear processes, long-term changes in synaptic function and structure occur only at synapses that have been stimulated by serotonin.

How does this come about? Martin, Andrea Casadio, Bailey, and I found that five puffs of serotonin send a signal to the nucleus to activate CREB-1, which then appears to send proteins to all terminals; however, only those terminals that have been marked by serotonin can use the proteins for synaptic growth. Indeed, we found that marking a previously unstimulated synapse with just one puff of serotonin, which normally produces facilitation lasting a few minutes, was sufficient to produce a weaker version of the long-term facilitation induced by five puffs of serotonin at the other synapse.

These results gave us a new and surprising insight into short-term facilitation. The stimulus that produces the short-term process has two functions. When acting alone, it enhances the strength of a particular synapse, thus contributing to short-term memory. When acting in conjunction with the activation of CREB initiated by a long-term process in either that synapse or any other synapse formed by the neuron, the stimulus marks those particular synapses. Marked synapses can then utilize the proteins activated by CREB for synaptic growth, thus producing a persistent change in synaptic strength.

The finding of long-range signaling between the synapse and the nucleus and between the nucleus and the synapse introduced a new dimension into our understanding of the integrative action of neurons. Long-term facilitation is indeed synapse specific and restricted, but once gene transcription has been activated, the potential for change at all of the synapses of a neuron is altered. As a result, the action of any given synapse is no longer determined simply by the history of that synapse; it is also determined by the history of the transcriptional machinery in the nucleus. Thus, the logic of the long-term process is quite different from that of the short-term process.

The Nature of the Local Marking Signal

How does one puff of serotonin mark a synapse for long-term change? We found that the synapse is marked both for long-term synaptic facilitation and for growth of new synaptic connections by covalent modifications of existing proteins, modifications that are mediated by PKA. For that structural change to persist, however, protein must be synthesized locally (Casadio et al. 1999). Oswald Steward’s important work in the early 1980s had shown that dendrites contain ribosomes and that specific mRNA molecules, or transcripts, are transported to the dendrites and translated into proteins there (Steward 1997). But the function of those locally translated mRNA transcripts was unknown. Our experiments showed that one function of the local mRNAs is to stabilize synapse-specific, long-term functional and structural changes.

What proteins might be important for stabilizing these changes? To answer this question we needed a preparation in which we could study the local mRNA transcripts and proteins in isolation—that is, in the processes (the axon and dendrites) of neurons, with no possible contamination by the cell body or surrounding glial cells. Martin cultured several hundred sensory neurons in a dish and then cut off their cell bodies, thus allowing us to study the mRNA transcripts and how they are regulated (Martin et al. 1998). We found that serotonin stimulates the translation of mRNA into new proteins in these isolated processes. Moreover, the mRNA transcripts in these processes contain regulatory sequences that are consistent with at least two mechanisms for regulating local translation of proteins.

These local mechanisms of translation serve different functions. One mRNA transcript, the elongation factor EF-1α, has an oligopyrimidine tract in the 5' untranslated region. This same tract is found in a small group of mRNA transcripts that are preferentially translated in response to stimulation by growth factors, or mitogens. The ability of growth factors to recruit these mRNA transcripts is blocked selectively by the drug rapamycin (reviewed in Schuman 1997; Steward 1997; Martin et al. 2000). Indeed, we found that rapamycin inhibits both the stabilization of longterm facilitation and the growth of new connections (Casadio et al. 1999). Other mRNA transcripts, which are necessary for initiating long-term facilitation, are not blocked by rapamycin; they are blocked by emetine, a general inhibitor of protein synthesis. These studies thus revealed a new, fourth type of synaptic action that is mediated by neurotransmitter signaling (see Figure 1).

Our understanding of three of the four types of neurotransmitter action emerged, at least in part, from the study of learning and memory. First, in 1951, Fatt and Katz opened up the modern study of chemical transmission with their discovery of ionotropic receptors that regulate ion flux through transmitter-gated channels to produce fast synaptic actions lasting for milliseconds (Fatt and Katz 1951). Second, in the 1970s metabotropic receptors were found to activate second-messenger pathways, such as the cAMP-PKA pathway, to produce slow synaptic activity lasting minutes (Greengard 1976). As we have seen in Aplysia, this slow synaptic action can regulate transmitter release, thereby contributing to short-term memory for sensitization. Third, an even more persistent synaptic action, lasting days, results from the repeated action of a modulatory transmitter such as serotonin. With repeated applications of serotonin, second-messenger kinases move to the nucleus, where they induce a cascade of gene transcription leading to the growth of new synaptic connections. This raises the problem of synapse specificity that we considered earlier. Our experiments in the bifurcated culture system revealed the fourth action of neurotransmitters: the marking of the synapse and the regulation of local protein synthesis, which establishes synapse-specific long-term facilitation and thus contributes to the solution of the specificity problem.

Fig. 1.  Four different consequences of the action of neurotransmitters, showing that the synapses and the nucleus interact readily. 1. Transmitter activation of a ligandgated ion channel leads to a rapid synaptic action. 2. Transmitter activation of a seventransmembrane receptor and a second-messenger kinase leads to a more enduring synaptic action. 3. Repeated transmitter activation of a seven-transmembrane receptor leads to the translocation of the kinase to the nucleus and the activation of mRNA transcription, producing a persistent synaptic action. 4. Transmitter can also activate local protein synthesis to stabilize the synapse-specific facilitation.

A Return to the Hippocampus: Genetically Modified Mice and Complex Spatial Memory

In our studies in Aplysia, we focused on the simplest form of memory: implicit (or procedural) memory. These memories are concerned with the unconscious recall of perceptual and motor skills and do not require a hippocampus. The hippocampus is involved in explicit (or declarative) memory, the memory for people, objects, or places; these memories require conscious recall.

For years I tried to encourage people who left my lab to turn their attention to the hippocampus, but to no avail. Finally in 1990, when I reached my sixtieth birthday, I returned to the study of the hippocampus myself. I was emboldened to do so in great part because of the development of methods for inserting and for knocking out individual genes in mice. This work made it clear to me that mice offer a superb system for examining the role of individual genes in synaptic modification, on the one hand, and intact behavior—explicit memory storage—on the other. Mice have a well-developed medial temporal lobe and hippocampus, and these structures are necessary for explicit memory of objects and space. Moreover, in 1972, Tim Bliss and Terje Lømo, in Per Andersen’s laboratory in Oslo, had discovered that electrically stimulating any one of the three major pathways in the hippocampus gives rise to a synaptic facilitation called long-term potentiation, or LTP. We were interested in two questions: What molecular signaling pathways are important for LTP? Is LTP important for explicit memory storage?

The contributions of Seth Grant and Mark Mayford were particularly influential in these new studies in genetically modified mice. Grant was the driving force in our first studies, in which we showed a role for nonreceptor tyrosine kinases in long-term potentiation and in spatial memory in the hippocampus. Mayford’s critical thinking became important somewhat later, as we began to realize the limitations in the first generation of genetically modified mice. These limitations stimulated Mayford to develop promoters that limit the expression of genes to certain regions of the brain and to devise methods for controlling the timing of gene expression. Those two technical advances proved important in allowing us (as well as Susumu Tonegawa, whose lab was now also studying memory in genetically modified mice) to generate mice with more specific phenotypes. Genetic defects could be more readily interpreted in these mice than in the first generation of mice because we could relate any given defect more directly to specific synaptic changes and to behavior.

Over the next few years Mayford, Ted Abel, Mark Barad, Isabelle Mansuy, Chris Pittenger, Amy Chen, and Angel Barco created a number of regionally restricted and regulated transgenic animals that allowed us to examine the role of the PKA, CREB-1 and CREB-2, and protein synthesis– dependent transcriptional switch within the hippocampus and to determine that it is quite similar in principle to what we had encountered in Aplysia. Our lab and those of Alcino Silva and Dan Storm found that the cAMP, PKA, and CREB switch required for long-term forms of synaptic plasticity in the hippocampus was also required for spatial memory.

The Cognitive Map of Space: Steps toward a Molecular Biology of Attention

With this background information about genes, long-term potentiation, and spatial memory, we now could ask deeper questions: How does an animal learn about extrapersonal space? Why does spatial memory go awry with defects in PKA signaling? What is the function of the transcriptional switch? To address those questions, we began to study how space is represented in the hippocampus.

One of the key insights to emerge from the study of higher cognitive functions is that each perceptual or motor act has an internal representation in the brain. These representations can be simple or complex. The simplest internal representations are those of the sensory systems, whose afferent fibers are arranged as topographic maps of the receptor surface. These are the representations that Wade Marshall, my former mentor at the NIH, had discovered in the 1930s and early 1940s. Marshall showed that this map is most clearly evident in the neural representation of personal space, the representation of touch. The neural representation of extrapersonal space, the space surrounding the body, is far more complex. Here, the representation is encoded in the pattern of firing of neurons that have no topographic relation to one another. This representation was discovered in 1971 by John O’Keefe at University College London, who made the brilliant observation that the hippocampus contains a complete representation of extrapersonal space—a cognitive map.

O’Keefe discovered that all of the pyramidal cells in the hippocampus, the very same cells we had used to study long-term potentiation, form an internal neural representation of the space surrounding an animal (O’Keefe and Nadel 1978). In a familiar environment, different pyramidal cells in the hippocampus fire as the animal traverses from one region to the next. This tendency is so marked that O’Keefe referred to the pyramidal cells as place cells.

Some place cells fire only when an animal’s head enters one position in a given space. Others fire when the animal’s head enters another position in the same space. Thus, a mouse’s brain breaks up the space in which it walks into many small, overlapping fields; each field is assigned to specific cells in the hippocampus, forming a spatial map of the animal’s surroundings. This holistic neural representation is thought to permit the animal to solve spatial problems efficiently. When the animal enters a new environment, a new place map is formed within minutes, in part from some of the pyramidal cells that made up the map of the first environment and in part from pyramidal cells that had been silent previously (reviewed in O’Keefe and Nadel 1978). Each cell will have the same firing field whenever the animal is reintroduced to that environment. Place fields are formed in minutes, and once formed, the map to which they contribute can remain stable for weeks.

The spatial map is the best-understood example of a complex representation in the brain. This true cognitive map differs in several ways from the sensory maps for touch, vision, or hearing. As we have seen, the map of space is not topographic: neighboring cells in the hippocampus do not represent neighboring regions in the environment. Furthermore, a place cell will fire whenever an animal is in a given place, regardless of what the animal is looking at. Finally, the firing of place cells can persist after pertinent sensory cues are removed, even in the dark. Thus, although the activity of a place cell can be modulated by sensory input, it is not determined by sensory input, as the activity of a sensory neuron is. Place cells do not map current sensory input, but the location where the animal thinks it is.

Although place cells had been studied since 1971, nothing was known about the cellular or molecular mechanisms whereby new place fields are formed; specifically, no one had attempted to relate the biology of place cells to the molecular mechanisms of long-term potentiation or hippocampalbased memory. In 1995 it struck me that the formation of a new spatial map is a learning process. The map develops with time as the animal walks around, and once learned, the map is retained for days or weeks. I therefore wondered whether protein synthesis and the synaptic plasticity related to LTP might play a role in the long-term stabilization of the map.

To explore this problem, I was fortunate to start a collaboration with Robert Muller at Downstate Medical Center in Brooklyn, who had pioneered the systematic study of place cells. This problem was taken on by Cliff Kentros, a postdoctoral fellow in my lab; by Naveen Agnihotri, a graduate student; and by Alex Rotenberg, a joint student with Muller and myself. Using a combination of pharmacological and genetic approaches, we demonstrated that recruitment of PKA and protein synthesis is linked to the longterm (but not the short-term) stability of the representation of space in the hippocampus. Thus, PKA and protein synthesis are required for long-term memories of extrapersonal space because such memories are based on a learned representation of space whose long-term stability requires PKA and new protein synthesis (Rotenberg et al. 1996; Kentros et al. 1998; Rotenberg et al. 2000; Agnihotri et al. 2001; Muller 1996).

This raised a final problem. In people, explicit memory differs from implicit memory in requiring conscious attention for recall. How does conscious attention come to bear on explicit memory? Indeed, how can one study consciousness in the mouse? In the course of our work on place fields, Kentros, Agnihotri, Hawkins, and I found that the long-term stability of a spatial map correlates strongly with the degree to which a mouse is required to attend to its environment. Thus the long-term recall of a spatial map is not an implicit, automatic process; rather, it requires that a mouse pay attention to its environment, just as explicit memory in human beings requires conscious attention. The finding that attention, the recruitment of PKA, and new protein synthesis are required for a mouse to form and recall a stable cognitive map of space has opened up a molecular biological approach to attention.

The Late Phase of LTP and Long-Term Memory of Extrapersonal Space

To explore the role of PKA in the late phase of long-term potentiation and to determine its role in memory, Ted Abel, Mark Barad, Rusiko Bourtchouladze, Peter Nguyen, and I generated transgenic mice that express R(AB), a mutant form of the regulatory subunit of PKA that inhibits enzyme activity (Abel et al. 1997). To restrict expression of R(AB) to the postnatal hippocampus and other forebrain regions, we used the promoter from the Ca2+/calmodulin protein kinase IIα (CaMKIIα) gene that Mayford had isolated and characterized. In these R(AB) transgenic mice, the reduction in hippocampal PKA activity is paralleled by a significant decrease in late LTP, whereas basal synaptic transmission and early LTP remain unchanged (see Figure 2). Most interesting, the decrease in late LTP is paralleled by behavioral deficits in hippocampus-dependent long-term memory of context and of extrapersonal space, whereas learning and short-term memory are unimpaired (Figures 3 and 4). Thus, PKA plays a critical role in the transformation of short-term memory of extrapersonal space into long-term memory in the mammalian hippocampus, much as it does in the storage of implicit memory in Aplysia and Drosophila.

Fig. 2.  A comparison of LTP in wild-type mice (WT) and two lines of mutant mice [R(AB)-1 and R(AB)-2] in which PKA has been compromised by the expression in the hippocampus of a transgene, a dominant negative inhibitor of PKA. This inhibitor, R(AB), is a mutated form of the regulatory subunit of PKA that inhibits the catalytic subunit but does not recognize cAMP. Early LTP is comparable in mutant and wildtype mice, but mutations that block PKA or CREB reduce or eliminate late LTP in the mutant mice. From Abel et al. 1997.

Fig. 3.  Mice that express R(AB) were conditioned to freeze in the context of a box. They first walked around the box for a brief period and became familiar with the context. They then heard a sound (CS, conditioned stimulus) followed by a shock (US, unconditioned stimulus) delivered through the electrified grid in the floor. As a result, the animals learned to associate being in the box with the shock, and they froze when put in the box. The mice were then tested 1 hour and 24 hours after training. From Abel et al. 1997.

PKA and the Internal Representation of Extrapersonal Space: Toward a Molecular Biology of Cognition

Using R(AB) mice we could now ask, What are the specific functions of PKA and the late phase of LTP in spatial memory? Why do animals with compromised PKA signaling have difficulty with space (Abel et al. 1997)?

When an animal moves within an enclosed space, a particular subset of pyramidal cells becomes active (Muller 1996). When the animal is in a different space, a different set of pyramidal cells becomes active (see Figure 5). In one of our initial experiments, Kentros, Muller, Hawkins, and I simply blocked LTP pharmacologically, using an NMDA receptor antagonist (Kentros et al. 1998). We found that when placed in a new environment, animals with blocked NMDA receptors formed a good spatial map that was stable an hour later. However, after 24 hours the map had become completely unstable: most pyramidal cells no longer retained the initial representation of their place field. This suggested that activation of NMDA receptors—perhaps a step in modifying the strength of the synapse—is required for the long-term stabilization of a spatial map, a result consistent with the role of the late phase of LTP in the stabilization of such maps.

Fig. 4.  Mutant mice that express the R(AB) gene in the hippocampus, blocking the action of PKA, underwent contextual conditioning and were tested after 1 hour and 24 hours (see Fig. 3). The mice learned well and froze when put in the box an hour after conditioning. However, they no longer froze when put in the box 24 hours after conditioning, indicating a defect in long-term explicit memory, which requires the hippocampus (A). Wild-type mice exposed to anisomycin, an inhibitor of protein synthesis, during training show a similar defect in long-term memory 24 hours after conditioning (B), also indicating a defect in long-term memory that requires the hippocampus. From Abel et al. 1997.

We next asked: Does a selective deficit—one that affects only the late phase of LTP and leaves the early phase intact—cause a selective abnormality in the long-term stability of place cells? Since only the late phase of LTP requires PKA, Alex Rotenberg, Muller, Abel, Hawkins, and I returned to the R(AB) transgenic mice, which have diminished PKA activity and a diminished form of late LTP (Rotenberg et al. 2000). If reduced activity of PKA affects the stability of place cells, R(AB) mice should be able to form a stable map of space in a novel environment, as normal animals do, and the map should remain stable for at least an hour. However, the map should be unstable 24 hours later. This is precisely what we found (see Figure 6).

Fig. 5.  Spatial memory can be studied in the mouse by recording from individual pyramidal cells in the hippocampus. The firing pattern of these place cells creates an internal representation of the animal’s location in its surroundings. A mouse is attached to a recording cable and placed inside a cylinder (49 cm in diameter by 34 cm high). The other end of the cable goes to a 235-channel commutator attached to a computer-based spike-discrimination system. The cable is also used to supply power to a light-emitting diode mounted on the headstage the mouse carries. The entire apparatus is viewed with an overhead TV camera whose output goes to a tracking device that detects the position of the mouse. The output of the tracker is sent to the same computer used to detect spikes, so that parallel time series of positions and spikes are recorded. The occurrence of spikes as a function of positions is extracted from the basic data and is used to form two-dimensional firing-rate patterns that can be analyzed numerically or visualized as color-coded firing-rate maps. Dark areas indicate regions in the circular enclosure in which a given pyramidal cell fires at high rates. Based on Kandel 2000.

The fact that long-term instability in the spatial map and the deficit in long-term memory parallel the deficit in the late phase of LTP suggested that PKA-mediated gene activation and the synthesis of new protein might be essential for the stabilization of the spatial map. Naveen Agnihotri, Kentros, Hawkins, and I tested this idea and found that inhibiting protein synthesis destabilizes place fields in the long term, much as inhibiting PKA does (see Figure 7; Rotenberg et al. 2000; Agnihotri et al. 2001).

Fig. 6.  The long-term stability of the place field of a pyramidal cell, as shown in two simultaneous recordings from pyramidal cells in the hippocampus of a wild-type mouse and a mutant mouse. In the wild-type mouse, the spatial fields form and are stable when the mouse is taken out of the test environment and put back one hour later. When the wild-type mouse is taken out and put back 24 hours later, the fields of the pyramidal cells are still quite stable. By contrast, pyramidal cells in the R(AB) mice, in which PKA has been compromised, form good fields that are stable an hour later, but do not remain stable after 24 hours.

In the course of this work we discovered, as mentioned earlier, that attention is a key feature in the formation of a stable place map in mice (Kentros et al. 2001). When a mouse does not attend to the space it walks through, the map forms but is unstable after three to six hours. When the mouse is forced to pay attention to the space, however, the map is invariably stable for days. How does this attentional mechanism work? Our recent work suggests that one necessary component is mediated by the dopaminergic modulatory system, acting through a D1/D5 receptor that activates adenylyl cyclase, cAMP, and PKA. The actions of dopamine and other modulatory transmitters might, among other things, trigger the protein synthesis–dependent steps that stabilize the map.

Fig. 7.  Group data for R(AB) mice, with compromised PKA, and wild-type mice in which protein synthesis is inhibited. The top graph shows the group data for R(AB) and wildtype mice; the bottom graph shows that similar effects can be obtained by inhibiting protein synthesis with anisomycin. From Rotenberg et al. 2000; Agnihotri et al. 2001.

Constraints on LTP and Explicit Memory Storage

My colleagues and I (Mallaret et al. 2001) and Emmanuel Landau (Blitzer et al. 1998) and his colleagues found that the threshold for hippocampal synaptic plasticity and memory storage is determined by the balance between protein phosphorylation and dephosphorylation. This balance involves PKA and the Ca2+-sensitive phosphatase calcineurin, the initial step in a phosphatase cascade (Mansuy et al. 1998; Mallaret et al. 2001). To determine whether endogenous calcineurin acts as a constraint in this balance, we inhibited calcineurin and examined the effects on synaptic plasticity and memory storage. Using the CaM kinase promoter and the doxycyclinedependent rtTA system that Mayford had first successfully applied to the brain, Isabelle Mansuy, Gael Malleret, Danny Winder, Tim Bliss, and I found that a transient reduction of calcineurin activity facilitates LTP both in vitro and in vivo (see Figure 8) (Mallaret et al. 2001). This facilitation persists for several days in the intact animal, and it is accompanied by enhanced learning and strengthening of shortand long-term memory on several spatial and nonspatial tasks requiring the hippocampus. The LTP activity and memory improvements were reversed when we suppressed the expression of the transgene by withdrawing doxycycline. These results, together with previous findings by Winder and Mansuy showing that overexpression of calcineurin impairs PKA-dependent components of LTP and memory (Mansuy et al. 1998; Winder et al., 1998), demonstrate that endogenous calcineurin negatively affects synaptic plasticity, learning, and memory (Figure 8).

There Is Life after the Nobel Prize

Since my residency in psychiatry at Harvard in the early 1960s, Denise and I have spent much of each August in the town of Wellfleet on Cape Cod, and since 1972, in our summer home in South Wellfleet. The house has a beautiful view of Wellfleet Bay and is a lovely place for boating and swimming. There are also superb clay tennis courts at Oliver’s, a five-minute drive away, where I enjoy playing. Most important, this is an opportunity for Denise and me to have a peaceful vacation and to get together with our two children, Paul and Minouche, and their families, who come for at least a part of the month.

Fig. 8.  Long-term potentiation requires regulation not only of kinases but also of phosphatases. The phosphatase cascade initiated by calcineurin shuts off a phosphatase inhibitor, thereby removing constraints on the protein phosphatase 1, which then proceeds to inhibit the kinase cascade. Based on Mallaret et al. 2001.

Outside the house Denise has strung some clotheslines; being Frenchborn, she likes the smell of laundry dried in the fresh air and sunshine. One day in August 1996 she and I were hanging the laundry when the phone rang inside the house. I went to answer it, and found Stephen Koslow, my project officer from the NIMH, on the line. He told me that the grant I applied for had been awarded and should be funded within a reasonable period of time. He then added that he and a number of people at NIMH thought I would get the Nobel Prize.

After I hung up the phone, I went outside and continued to hang the laundry. I told Denise that Koslow thought I was going to get the Nobel Prize. She responded, to my astonishment, “I hope not soon.” I turned to her and said, “What do you mean ‘not soon’? How could you, my wife, say that?” She answered, “As you know, I worked with Robert Merton and Harriet Zuckerman when I was a graduate student in sociology at Columbia, and they studied people who had won the Nobel Prize. They found that, by and large, after someone has won the Nobel Prize he or she did not contribute more to science. You still have a few ideas. Play them out. There is lots of time for the Nobel Prize later on.”

So when I heard from the Nobel committee on Yom Kippur, October 9, 2000, that I was to be awarded the Nobel Prize in Physiology or Medicine, I realized that in addition to the pleasures and gratification of this remarkable award, I now had a challenge on my hands: I had to prove to Denise that I was not completely intellectually dead.

As a result of a number of fortunate circumstances, including sustained support from the Howard Hughes Medical Institute, I have continued to have a very enjoyable and productive scientific career. This was in important part made possible by several outstanding postdoctoral fellows and graduate students with whom it has been my privilege to work over the last 15 years.

A Functional Prion in the Maintenance of Long-Term Memory

Once we realized that there are separate processes for the initiation and maintenance of memory, we asked the question, How does the second mechanism work? Kausik Si, who joined my lab in 1999, addressed this question in a remarkably original and effective set of experiments.

Kausik argued that if the neuron sends mRNA transcripts to all of its terminals and only those terminals that are marked can use the transcripts productively, then presumably the transcripts must be dormant before being activated in some way. He thought that one way of activating protein synthesis at the synapse would be to recruit a regulator of gene translation that is capable of activating dormant mRNA. In Xenopus oocytes, there is an example of this. Here, the maternal RNA is silent until activated by a regulator of protein synthesis known as CPEB, the cytoplasmic polyadenylation element binding protein (Richter 1999). Kausik searched for a homolog in Aplysia and found, in addition to the developmental form of CPEB, a new form that had novel properties (Si et al. 2003a, 2003b, 2010). Blocking this form of CPEB at a marked (active) synapse prevents the maintenance, but not the initiation, of long-term synaptic facilitation for a day or more after the memory is formed.

A remarkable feature of the Aplysia form of CPEB is that its N-terminus resembles the prion domain of yeast prion proteins and endows the Aplysia CPEB with self-sustaining properties. But unlike other prions that are pathogenic, the Aplysia CPEB appears to be functional: the active, selfperpetuating form of the protein does not kill cells, but rather controls synapse-specific translation. Notably, the persistence of long-term memory in Drosophila and in mice has also been found to involve CPEB (Keleman et al. 2007; Majumdar et al. 2012; Rajasethupathy et al. 2012; Pavlopoulos et al. 2013; Fioriti et al. 2014, 2015; Stephan et al. 2015; Drisaldi et al. 2015).

Based on the prion-like persistent properties of CPEB in Aplysia neurons, Kausik and I (Si et al. 2010) proposed a model for the persistence of memory storage in Aplysia. CPEB activates the translation of dormant mRNA transcripts by elongating their poly-A tail. Aplysia CPEB has two states: one is inactive and acts as a repressor, while the other is active. In an unmarked synapse, the basal level of CPEB expression is low, and the protein is inactive or repressive. According to the model, serotonin induces an increase in CPEB. When a given threshold is reached, CPEB is converted to the prion-like state, which is more active and lacks the inhibitory function of the basal state.

Once the prion state is established at an activated synapse, dormant mRNA transcripts, made in the cell body and distributed throughout the cell, are translated—but only at that activated synapse. Because the activated CPEB is self-perpetuating, it is capable of contributing to synapsespecific, long-term molecular change, thus providing a mechanism for the stabilization of learning-related synaptic growth and the persistence of memory storage in stable periods of normal growth, when very low levels of protein synthesis are required.

Animal Models of Drug Abuse: Molecular Mechanisms in the Gateway Effect

In a return to my clinical roots, I have begun to study disorders of memory in three contexts: drug abuse, age-related memory loss, and schizophrenia.

In 2010 Amir Levine and I collaborated with my wife, Denise, to explore the molecular mechanism for a gateway drug. Denise pioneered the epidemiology of the Gateway Effect in a paper she published in Science in 1975. She found that in human populations, cigarettes and alcohol generally serve as gateway drugs: people use them before progressing to marijuana, cocaine, or other illicit substances.

To understand the biological basis of the gateway sequence of drug use, we developed a mouse model and used it to study the effects of nicotine on subsequent responses to cocaine. We found that giving the mice nicotine increases their response to cocaine, as assessed by addiction-related behaviors and reduced LTP-related synaptic plasticity in the striatum, a brain region critical for addiction-related reward. The responses to cocaine were enhanced only when we administered nicotine first, followed by nicotine and cocaine concurrently. Reversing the order of administration showed that cocaine has no effect on nicotine-induced behaviors or LTP in the striatum. We concluded that nicotine primes the response to cocaine by enhancing cocaine’s ability to induce expression of the FosB gene. We found that this gene is activated through inhibition of histone deacetylase, which results in histone acetylation thereby enhancing gene expression throughout the striatum.

We tested this conclusion further and found that a histone deacetylase inhibitor simulates the actions of nicotine, priming the response to cocaine and enhancing FosB gene expression and depressed LTP in the nucleus accumbens. Conversely, in a genetically modified mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens.

The epidemiological data—which indicate that most cocaine users start using the drug after having begun to smoke and while still smoking, and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine—are consistent with our findings in mice. If the findings in mice apply to humans, a decrease in smoking rates among young people would be expected to lead to a decrease in cocaine addiction.

Molecular Mechanism for Age-Related Memory Loss

To distinguish age-related memory loss more explicitly from Alzheimer’s disease, Scott Small, Elias Pavlopoulos, and I explored its molecular underpinnings in the dentate gyrus, a subregion of the hippocampal formation found by Scott Small to be targeted by aging. We carried out a gene expression study in human tissue harvested postmortem from both the dentate gyrus and the entorhinal cortex, a neighboring subregion that is unaffected by aging and is known to be the site of onset of Alzheimer’s disease. Using expression in the entorhinal cortex for normalization, we identified 17 genes that manifest reliable age-related changes in the dentate gyrus. The most significant change was an age-related decline in RbAp48, a protein that binds to CREB and to the CREB binding protein and acts to modify histone acetylation. To test whether the decline in this protein could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, the RbAp48 protein is less abundant in the dentate gyrus of old mice than in young mice.

We next generated a transgenic mouse that expressed a dominant-negative inhibitor of the RbAp48 protein in the adult forebrain. Inhibition of the protein in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. fMRI showed that within the hippocampal formation, dysfunction occurs only in the dentate gyrus and corresponds to a selective decrease in histone acetylation in this region of the brain. Upregulation of the RbAp48 protein in the dentate gyrus of old wild-type mice ameliorated age-related hippocampusbased memory loss and age-related abnormalities in histone acetylation.

Together, these findings show that the dentate gyrus is targeted by aging, and they identify a molecular mechanisms that contributes importantly to cognitive aging that could be useful therapeutically.

Animal Model of Schizophrenia: Transient and Selective Overexpression of Dopamine D2 Receptors in the Striatum Causes Persistent Abnormalities in Prefrontal Cortex Functioning

Eleanor Simpson and Christoph Kellendonk in my laboratory have developed a new animal model of the cognitive and negative symptoms of schizophrenia. Increased activity of D2 receptors in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of such increased receptor function, we generated mice with reversibly increased levels of D2 receptors only in the striatum. These mice exhibit cognitive impairments in working memory tasks and behavioral flexibility but not more general cognitive deficits. Moreover, the deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2 receptors but from excess expression during development.

To determine what may mediate these cognitive deficits, we analyzed the prefrontal cortex, the brain structure importantly associated with working memory. We found that overexpression of D2 receptors in the striatum affects concentrations of dopamine, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.

Life Is a Circle

But life is a circle. As I have continued to enjoy doing science, I have also, surprisingly, ended up where I began—as a would-be intellectual historian. In so doing I have essentially picked up where I left off on graduating from Harvard in 1952.

First in 2006 I published a scientific autobiography entitled In Search of Memory. This book went on to win both the Los Angeles Times and The National Academy of Science Book Awards in the Science category. Based on that book, the filmmaker Petra Seeger made a film also entitled “In Search of Memory” based on a sentimental journey that my family and I made to Europe on the occasion of our 50th wedding anniversary. Together with our children and grandchildren we traveled to the South of France and visited the convent where Denise was in hiding during the war years. We then went on to Paris where she was born and to Vienna where I lived.

More recently, in 2012 I wrote a second book, this one about Science and Art entitled The Age of Insight: The Quest to Understand the Unconscious in Art, Mind, and Brain from Vienna 1900 to the Present. This book won the Bruno Keisky Prize, Austria’s most important literary award.

In thinking of these endeavors in the context of my science, which I am continuing to do with great pleasure, I am reminded that in 1959, at the beginning of our career, my colleague Alden Spencer and I formulated a hierarchy of the four levels that define an academic life of a neural scientist. At that time, we saw this hierarchy as a series of descending degenerative steps in an intellectual carrier:

First, the most important level, is the working Neuroscientist—the person who works at the bench, does everything with their own hands.

One step down on the second rung is the Neuroleader—the scientist who runs a lab.

Third is the Neuropolitician—the scientist who runs a department.

Fourth is the Neurohistorian—the scientist who writes a textbook.

In the last several years I have had the privilege of working with Charlie Rose and we have so far put together 30 programs on Brain Science with 8 still to come—designed for the general viewer.

Thus in my return to intellectual history since the year 2000 I have gone on to define a new category, a fifth category of degeneracy, that of the Neuroentertainer.

I assure you: je regret pas: Indeed, I want to assure those of you who are in the running: There is life after the Nobel Prize. In fact a most enjoyable life.

My research has been generously supported by the Howard Hughes Medical Institute, the National Institutes of Health, the Mathers Foundation, FRAXA, and The Lieber Trust. I am particularly indebted to the Howard Hughes Medical Institute and its leaders, both former and current: Donald Fredrickson, George Cahill, Purnell Chopin, Tom Cech, Robert Tjian, and Gerry Rubin and Erin O’Shea. Their farsighted vision has encouraged Hughes investigators to take a long-term perspective and to tackle challenging problems. Research on learning and memory certainly meets both of these criteria!

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The Nobel Prize Committee asks each awardee to prepare both an autobiographical essay and a scientific lecture (Kandel 2000). In this chapter, I have combined parts of my essay and my lecture and added a brief summary of my scientific and extrascientific activities since the year 2000.

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Nancy Kopell

BORN:

New York City, New York

November 8, 1942

EDUCATION:

Cornell University, Ithaca, NY, BA (1963)

University of California, Berkeley, MA (1965)

University of California, Berkeley, PhD (1967)

APPOINTMENTS:

C.L.E. Moore Instructor of Mathematics, M.I.T. (1967–1969)

Assistant Professor of Mathematics, Northeastern University (1969–1972)

Associate Professor of Mathematics, Northeastern University (1972–1978)

Professor of Mathematics, Northeastern University (1978–1986)

Professor of Mathematics, Boston University (1986–present)

William Goodwin Aurelio Professor of Mathematics and Science, Boston University (2000–2009)

William Fairfield Warren Distinguished Professor, Boston University (2009–present)

HONORS AND AWARD (SELECTED)

Mathematical Neuroscience Prize, Israel Brain Technologies, 2015

Moser Prize Lecture, SIAM Annual Meeting, Snowbird, 2013

Elected to Honorary Membership of London Mathematical Society (one or two such awarded worldwide each year), 2011

SIAM Fellow, 2009

Massachusetts Academy of Sciences, Fellow, 2008

Von Neumann Prize/Lecture, SIAM Annual Meeting, Zurich, 2007

Weldon Memorial Prize, Oxford University, 2006

Honorary Doctorate, New Jersey Institute of Technology, May 2006

H. Dudley Wright Prize, Harvey Mudd College, 2001

Josiah Willard Gibbs Lecturer, Annual Meeting of the AMS, San Antonio, 1999

Elected to National Academy of Sciences, 1996

Elected to American Academy of Arts and Sciences, 1996

John D. and Catherine T. MacArthur Fellow, 1990–1995

J. S. Guggenheim Fellowship, 1984–1985

Alfred P. Sloan Fellow, 1975–1977

Nancy Kopell has been a pioneer in the analysis of networks of oscillators and applications to areas of chemistry and biology. Trained in pure mathematics, she switched to applied math shortly after receiving her degree and has focused mainly on neuroscience for the last three decades. She has made significant contributions to the understanding of synchronization and phase-locking of oscillators, both in abstract settings and in the context of brain rhythms. In neuroscience, she first applied her knowledge to the study of central pattern generators, especially lamprey swimming and the crustacean stomatogastric ganglion. She then began an ongoing series of papers on the physiological origins of the various brain rhythms in various parts of the neocortex as well as hippocampus, thalamus and striatum. The detailed study of the mechanism of rhythms led her to projects on the effects of rhythms in both normal cognition and disease. She has investigated how changes in rhythms due to anesthesia leads to loss of consciousness, and how pathologies of rhythms in Parkinson’s disease and schizophrenia lead to abnormal coordination and cognition. She has also studied how rhythms affect gating and routing of signals in the context of normal cognition, including attention.

Nancy Kopell

Beginner Mind: A Scientific Autobiography

It seems that I’ve always been a beginner. Almost none of the things I’ve done professionally have been built on material I studied formally. Almost every major interest led to other interests about which I started off clueless, and there were many times I asked myself “am I really doing this?” As someone who did not formally train to be a neuroscientist, and spent much of her career as a mathematician, I’m especially honored to be included in this series.

Early Years

I was born in 1942. My earliest years were not promising. According to family lore, I spent much of my first years drooling, and my parents were convinced that I was developmentally delayed (then known as “retarded”). This started changing when I was about five years old. An eye test revealed that I needed glasses and eye exercises (both provided), and I started picking out tunes on our home piano, all of which added to my interaction with the world. Another probe, some form of IQ testing, revealed that I was not, indeed, mentally challenged.

Early school years went better. I grew up in a part of the Bronx known as Pelham Parkway. It was then a solidly middle-class neighborhood; I once saw it described in a newspaper as “the last of the old-time Jewish ghettos.” As I grew up, I got used to all the old people sitting on the stoops of the low-rise apartment buildings, and I joined the bands of kids that played in the street. Bronx Park was near enough to walk to, and I spent a lot of time with friends playing there. I also became a voracious reader—anything with print, including the backs of cereal boxes, was fair game. We did not have an extensive home library (ours consisted mostly of Reader’s Digest condensed books), so I was a regular at the public library. My father was an accountant and mother did not work outside the house, though she volunteered for many things and helped my father with his accounting work. I walked to school by myself from an early age, as did my classmates; this was a simpler time when kids had less supervision, and needed it less. We did not have a television until I was a teenager, though we bought one for my grandmother, who lived for many years in a small apartment near us. The family gathered to watch Milton Berle, (known in a Yiddish accent as Milton Boyle). I studied piano for about five years.

By the time I got to junior high school, I was considered smart. I was part of a program known as Rapid Advance, which allowed selected kids to do three years of junior high school (grades seven to nine) in two, and then enter high school as a sophomore. (As I understand it, this program was formed because schools were overcrowded. My older (by three years) sister had been part of this program, and also an earlier program allowing her to skip second grade, so she was under 16 when she graduated high school.) I don’t remember learning much in junior high school besides the sociology of early teenage interactions; I vividly remember which kids were cool (not me) and which were picked on (not me either), and one boy I admired who bravely stood up for the most bullied girl. Whatever we learned seemed very easy to me, especially math, and I remember talking to one of my teachers about arithmetic mod 2, which I had rediscovered for myself. The school wasn’t walking distance from my house, and it was then that I became a regular subway-goer.

For high school (grades 10–12), there was a choice. I took and passed the entrance exam to the Bronx High School of Science, but my parents were opposed to my attending there. The issue was not the distance, since I was used to being a straphanger. My parents thought that Bronx Science would be too competitive for me. Later, it became clear to me that their decision was based more on the personality of my older sister, but I didn’t protest it. Ever after, I’ve had to correct people who simply assumed that I went there. In the end, this may have been a good choice: I seem to thrive more when the motivation is mostly internal, rather than competition or trying to live up to other people’s expectation.

Though the neighborhood school (Christopher Columbus High School) didn’t teach very much (every semester in English class, we started with the definition of a noun, and never got much beyond that), there were a lot of smart kids from the neighborhood, and I didn’t feel bored or out of place. I think I just never expected very much from school. I did have an outstanding math teacher (Mrs. Chad, who became very well known, and moved to Bronx Science sometime after I graduated). She was my first mentor and active supporter, and I didn’t mind the reputation of “teacher’s pet.”

My vivid memories of high school were less about intellectual matters than about interactions with people. Chemistry class provided the most adventures. The labs were an hour or under, which made it impossible to complete anything, and the exercises were designed to be carried out over several classes. One such involved heating something and having whatever came off as vapor to be cooled and collected. For this, we needed to set up the glassware, including the corks that connected the tubes to the glassware and the sinks that provided the cold water. Unfortunately, the corks were rarely of the right size, and I had to go to the teacher several times to replace a cork that was too small to hold or too large to fit in, a task I found embarrassing. After a few iterations, I got a cork that was just slightly too large and I wedged it in. It held just until the teacher came around to look at the setups and then blew out, drenching him head to toe. In another unforgettable incident, we were playing with aqua regia, a potent combination of nitric acid and hydrochloric acid, known to be able to dissolve almost anything, including gold. It was safely held in test-tubes, until one boy in the class poked a bit too strongly and the liquid fell in his lap. The other boys in the class immediately formed a circle around him and his damaged clothes, and march-stepped him to the boys’ room. It was never talked about if the damage went beyond his clothes. The classroom was also engaging: All the glassware was marked with what it would cost if we broke it, and some of the more elaborate pieces were marked “you can’t afford it.”

During that time, I continued to read prolifically, with no particular theme. I recall that I did read some math and science books, beyond the curriculum. At one point, I attempted to help my sister, then in college, with a take-home algebra exam. Unfortunately, I hadn’t read the relevant book, and “we” got a C. I spent Saturdays or Sundays ice skating in Central Park with a friend or going to museums in Manhattan. The trip was an hour in each direction and we were young, but this was considerably before those trains became active sites of mugging, and kids weren’t chauffeured around; in fact, my family didn’t have a car until my late teenage years. We played stickball and catch in the street, and a game that involved aiming a Spaulding rubber ball at a brick that extended out from the wall and getting the ball to pop up. It was not the purpose of the game, but when done exactly right, the ball would go directly into my first-floor bedroom window. I had the largest collection of these balls in the neighborhood, and also an occasional visit from a neighborhood kid trying to climb through the window to retrieve his property. I went to a full-summer sleep-away camp every summer (starting from the time I was under three) and liked athletics, which I played in after-school programs.

There was one intellectually stimulating experience that I remember from my high school days. Columbia University had a program for high school kids from schools all over the city, with classes taught by Columbia professors. I took a class in population genetics from the eminent geneticist Theodosius Dobzhansky. It had a lab component, which was to breed generations of fruit flies to have more (or less) bristles on their backs. I understood quickly the hazards of working with experimental animals: To transfer the flies from the breeding jars to the place where they could be examined under a microscope, the animals were anesthetized, but not too much or they would die and not be available to breed. However, too little and the flies would wake up while being counted and fly off. Several of my prize specimens joined the outside world instead of breeding for science. I don’t know how that affected the statistics of the class experiment.

College Years

When it came time for college, it was at first expected that I would go to a New York city school and live at home, as had my sister. In fact the city schools were then very good, and graduated people who became highly successful. Like many in their generation, my parents felt that it was a waste to spend money on the college education of a girl (who would get married and have children and not make use of it), but they were persuaded by family (and perhaps my teachers) to let me go away to college. Since I had a small but significant scholarship from New York State, I ended up at Cornell. My parents hoped I would join one of the free land-grant schools within Cornell (such as Agriculture), but it was not possible to major in math in those schools, so I was permitted to go to Arts and Sciences. We had a family tradition of math: Both my mother and sister majored in math, though both were happy to drop it instantly at the end of college, and I believe that was expected of me as well.

At Cornell, I toyed with becoming a chemistry major. However, I had been placed in an honors class in which the major difference was that we got pop quizzes much harder than those in the regular classes. I associated chemistry with anxiety, and stuck with math. After one semester of beginning calculus, I got placed in a math honors program. The half-dozen or so in this program were given standard textbooks for the next three semesters of calculus and told to learn it on our own. Meanwhile, our classes were on much more advanced, graduate-level material. There was far too much to cram into the class hours, so the classes were scheduled before a lunch hour and went far into the latter; I associate those classes with growling stomachs. Another notable feature were our tests, which started after dinner and went on until my curfew time (as the only woman, I was the only one with a curfew). The pressure was intense, but not over grades, and there was more bonding than competition. Some of the bonding was over bad behavior: I recall that before one of the tests, we threw many of the classroom chairs out the second-floor window, for reasons I can’t remember, but which likely involved tension. After three semesters of this program, most of my classes were graduate classes, and I was hanging out with the graduate students.

At that time, Cornell considered itself in loco parentis, especially for the women. There were separate dorms for the sexes, and a formal atmosphere: At every Sunday lunch, we dressed in our best, sat down to tables with cloths, and began the ritual with the singing of the campus alma mater. Women wore girdles, skirts, and heels; pantyhose were just beginning to be in style, but were considered expensive, since you had to replace the entire garment if one leg had a tear. Knee-length boots were beginning to be adopted, much better adapted to the cold and snow of Ithaca. All of us got a lot of exercise walking around the many hills of the campus; it was said that you could tell what year a coed (aka female student) was in by looking at the size of her calves (which were indeed much looked at). I joined a sorority and several singing groups (singing alto in one and soprano in another) and had the usual college experiences. I remember my classes as excellent; a professor who I later knew as a friend described the years I was at Cornell as its golden age.

I took the differences in policy for men and women for granted except for one incident. In my junior year, all the undergraduate math majors were sent a letter from IBM inviting them to interview for a summer job. I put on my girdle and heels and suitably tight skirt and hobbled my way up the hill for my appointment. My interviewer displayed great embarrassment when he saw me; it appeared that the job in question was only for men. Since it was very clear that I was not going to be offered the job, I decided to have some fun with the interview. For example, I asked why the jobs at IBM were categorized according to gender. His answer, with a straight face, was that the women preferred it that way. I must have impressed him, since they offered me another summer position, which I declined.

Instead of working at IBM, I accepted a summer fellowship in Illinois to learn to work with computers. Those were early days for computing. The machine we kids had access to was an early ILLIAC (Illinois Automatic Computer)—not the most current one, which was being used by grownups who presumably knew what they were doing, but the previous model that was then considered somewhat obsolete. It filled an entire large room and was programmed in machine language using paper tape; if a mistake was made, the tape had to be punched again from the beginning. Luckily, there was a machine that would copy the tape up to before the mistake. Later I remember working with decks of punch cards. These were more forgiving about mistakes, since individual cards could be replaced. But if the deck was accidentally dropped and fell out of order, the game was up. We spent most of our time in that room, since it was the only air-conditioned space and the summer was hot. I helped produce a program on “spin glasses” that was used by local physicists, and I was very proud. However, I stayed away from computers after that, doing all my computing through a human interface. In retrospect, this is astonishing for a computational neuroscientist. But by the time I got to the point where computers were essential, my students and postdocs were better prepared than I was, and had much more time. In general, my collaborators, students, and postdocs have been much earlier adopters of technology than I have been. I recall a lecture I gave in California, invited by David Kleinfeld. In his introduction, he told students to pay careful attention to my talk. I expected him to then tell the students why the work was important. Instead, he told them that this was perhaps the first and last time they would see a talk given with transparencies on an overhead projector. That embarrassed me enough to overcome my fear of PowerPoint and start using it. Thanks, David!

Graduate School

I had not entered college thinking about going to graduate school. But when my senior year arrived, I was not married and had nothing specific I wanted to do, so graduate school seemed like a good option. With some parental pressure to stay close to home, I applied to excellent schools up and down the east coast, and was admitted to almost all of them. But near the last minute, I got some seductive advice from a Cornell math grad student: Wherever you come from, go far away. I had an NSF Fellowship that was applicable to any school, so I applied and was admitted to Berkeley. There was more than a little parental upset when I decided to accept that offer. When I now work with students to decide about graduate schools, I’m aghast at my memory of how little thought I gave to what I would find there. I knew almost nothing about the faculty, which wouldn’t have helped anyway, since I didn’t have a clear idea of what I would specialize in. At Cornell, I was generally trained in pure mathematics and had thoughts of being an algebraist, the most pure of the mathematical disciplines. I also thought I might do geometry or topology, other fairly pure subjects. Other possibilities, like applied math, were never even on the radar screen.

Berkeley at that time was a huge and confusing macrocosm. In the math department, it was said that it was not known to within a hundred how many grad students there were; many graduate students had stopped taking courses or otherwise participating in the mathematical life of the mind, but were still officially on the rolls. There were very few women students, and (I recall) no women faculty. For better or worse, I stood out. I stood out more when I did well in my classes and then passed the oral qualifying exam with honors. (In spite of studying hard, I was asked questions I didn’t know, but I was very good at thinking on my feet.) This led one professor to woo me to work with him in algebraic topology, and I immediately accepted; at Berkeley, with all the grad students, finding a thesis advisor was not said to be routine. Unfortunately, he turned out to be not very interested in the question he started me on, and I saw him rarely, mostly at parties. This was, to say the least, anxiety provoking. But I had other ways to fill my time: I dated, learned to play the guitar, did folk-dancing, went on hikes—and stayed intensely anxious.

There were other distractions as well: This was the era of the free speech movement, a student-led uprising stemming originally from Freedom Summer, the months that many students rode buses in the south as part of the civil rights movement. The free speech movement (FSM) was triggered when the Berkeley Admin refused to let returning students set up information tables in Sproul Plaza, the center of campus life. The FSM essentially took over the campus for a year or more, and politicized much of the student body, leading into the Berkeley protests over the war in Vietnam. I took part, but did not put myself in a position to be arrested, as did many of my friends.

This was also the first time I was really aware of sexism in the sciences. The kind of sexism I experienced from graduate school through my early career was not harassment (though there was sometimes intense sexual tension, not acted on). Rather, it was the unspoken but very widespread assumption that women in math were like dancing bears—perhaps they could do it, but not very well, and the attempt was an amusing spectacle. I was young and reasonably attractive, so I got a fair share of attention, especially in situations in which women other than administrative assistants were barely visible. I was already highly insecure about my ability (in spite of lots of encouragement from teachers from junior high school on), and any encouragement I got in grad school could easily be interpreted, at least by me, as sexual rather than scientific interest. Thus, though I had the reputation for being among the best students of my class, I did not have any of the confidence to match. Of course, this is now an old story that many institutions have since tried to remedy, with mixed success. At the time, nobody recognized it as a problem, and I was not about to tell.

My period of mathematical limbo lasted more than a year. I was rescued by another professor, Steven Smale, near the end of my third year. As he passed me in the hall, he would suggest other problems I might work on (as I said, I was known, for better or worse). All of them were far from anything I knew, and I let him know that. Luckily for me, Steve was known for being tenacious, as well as very smart (in the next year or two, he was given the Fields medal, the math equivalent of the Nobel prize). After a number of such iterations, I agreed to work on a problem that appeared very elementary. It was both elementary and hard for the same reason: There were apparently no tools that were relevant to solve it. The good news was that there was not very much to learn before I could attack it. I worked away at it for a while, mostly by myself, but at least getting somewhere. Steve was away most of the time (he was visiting at Princeton), but he had other students who were very close and who included me in the group. The main two were Mike Shub and Jacob Palis. They welcomed me graciously and proceeded to teach me the field in which I was supposed to be an expert. We formed a close-knit band, asking each other almost every day about results since the last conversation. I had found an intellectual home, and loved it. Ironically, during this time, my first advisor changed his field and joined our group. There were also other faculty members loosely affiliated. Though Steve was famous, he had moved around enough that Mike, Jacob, and I were his first students.

The field that I joined was called “dynamical systems.” It was the study of the properties of differential equations. Smale had begun to revolutionize this field by introducing ways to classify the geometric properties of the equations, and he introduced methods for studying how robust those properties were to perturbations. The solutions to differential equations provide a set of transformations of the underlying space, one for each time point. I was tasked with showing that, under some conditions, almost any transformation of the space comes from a differential equation. I got my first results very quickly, over the first summer. I showed that this hypothesis was in fact completely wrong; almost all transformations do not come from differential equations, and the ones that do can easily be perturbed so that they don’t. I showed it in the context of equations on a very simple space, a one-dimensional interval. This surprised a lot of people, including those in a field I didn’t even know about called foliation theory; that hypothesis was assumed by the field to be correct, and many other results were implicitly built on it.

The following fall I visited Steve at Princeton and showed him my results. He said something like, “Well, you have a thesis!” Since the proof of my first result was somewhat under three pages (and later got shorter), I was dubious. But he was convinced it would now grow quickly and planned my graduation for the next spring. So there I was, with an unfinished thesis in a field (dynamical systems) I didn’t yet know, and a deadline not that many months away. I remember some all-nighters, but by the end, I had a thesis written up with more results and a respectable number of pages. I was less than 25 when I got my PhD degree. I’ve never since been able to do math (or science) at that intensity; I look back on that year with wonder and gratitude.

The year was not easy going. I remember one time being in despair about whether I could finish my thesis, and slumped into the office of a faculty friend, Bernard Kripke. I told him that I couldn’t stand it and was going to quit. While I was there, his new wife Margaret, a grad student in biology, called him and said, essentially, “I can’t stand it, I’m going to quit.” Ber had an instant inspiration: He took me back to his house, mixed up a large batch of margaritas, and sat back while she and I drank and commiserated. The next day, she went back to her thesis and I to mine, and both of us got through very well.

MIT and Depression

Though I was quite successful throughout school, I had been struggling with large emotional ups and downs, partly due to family issues and likely partly due to chemical imbalances. Neither of those was acknowledged within my family, and kept as repressed as I could manage. After graduate school, these struggles caught up with me. My thesis was good enough (and my thesis advisor famous enough) to win for me a C.L.E. Moore Instructorship at MIT. This was a nontenured but fancy position for which I was the first woman. The position had very little teaching, a huge amount of freedom, and no mentoring. In spite of the academic success I enjoyed up till that point, I was very shy and highly insecure, and those years were extremely hard for me. I had chosen MIT over other options partly because I sensed a depression coming on, and preferred to be at a place in which no one would notice. (I think I was mostly right about MIT and this.) I had gone from a position in which I had a collegial nest to one in which the doors were wide open and I had no idea where I wanted to go. There were plenty of good problems that had arisen from my thesis (and which other people followed up). But I found myself not wanting to work on any of them. Indeed, during my two years at MIT, I didn’t even publish the work from my thesis, which later went into a conference volume in honor of my thesis advisor; he told me later I could have published it in the Annals of Mathematics, one of the most prestigious math journals.

MIT was both welcoming and a center for the kind of unexamined sexism that was almost universal at that time. I vividly remember one time in the math common room in which some math graduate student asked me, “Why aren’t there any good women in mathematics?” (He did not say “present company excluded.”) So now I was supposed not only to succeed on my own, but also defend the successes of my scientific sisters. As I recall, I was not up to it, and fled. I did a lot of hiding during those two years. My colleagues from dynamical systems continued to invite me to many conferences and workshops, and I attended some of them. They did their best to encourage me and get me to start working again and were all very kind. But I knew that I didn’t want to stay in that field and was unsure about mathematics as well. I knew I could love doing it, as I loved doing my thesis. But math can be very narrow as well as very deep, and as I looked forward, the idea of doing similar things in 10 or 20 years was claustrophobic. I knew I had to change fields and had no idea how.

During that time, I was not entirely inert. I was reading lots of theoretical literature about self-organization, hoping it would be relevant to issues of pattern formation (development) in biology. There were two thenfashionable gurus that I tried to follow. One was Ilya Prigogine, who had developed a theory of “dissipative structures,” or self-organization far from equilibrium. This became the body of work that developed my allergy to “theories of everything”: abstract declamations that didn’t quite illuminate anything, though they could be said to apply to many things. I read and read and couldn’t find what I considered content. This experience helped shape my understanding about the politics of prizes: Prigogine got a Nobel prize for that work (and one of his colleagues, on being asked to comment, said, “It was only to be expected”).

The second major guru I tried to understand was Rene Thom, a very distinguished mathematician who had developed a mathematical body of work known as catastrophe theory. This work was an extension of what is called bifurcation theory, a study of how the qualitative properties of systems can change dramatically when some parameters of the system are changed just a bit. Thom focused on systems of a particular kind (so-called “gradient systems”) and classified the bifurcations within them. The work was justly praised for its elegance and depth, but it was being marketed as relevant to understanding changes in the world. Unfortunately, no one could come up with a convincing example that followed his theory. There were several of us from the Boston area who were interested in learning the mathematics (including Gabe Stolzenberg, who much later became my husband), and we had an ongoing working group. We became experts, which turned out to be highly important for my career, but not in a straightforward manner (more below).

My First Faculty Job: Northeastern University

My position at MIT was not tenure track, and I certainly had not distinguished myself there. What to do next? There were several things that helped. First, the times were much more forgiving than now. I suspect that someone with no publications in the two years after graduation would now not be able to get any faculty positions. Second, my (then still unpublished) thesis was a kind of underground classic, and that made me desirable, even if somewhat damaged. I had several possibilities, none at the level (or close) to MIT. I took the offer at Northeastern, partly so I wouldn’t have to move. (The depression was still with me.)

The math department at Northeastern was totally different from MIT, in ways that turned out to be very good for me at that time. At MIT, common room conversation was often about ranking living mathematicians: who was the best, the second best etc. As can be imagined, I did not find this conducive to happiness. I also didn’t want to compete according to the standard rules: Mathematics is very hierarchical, and problems are often considered interesting because X, who is very famous, pronounces that it is. There was a clear notion of what is math and what isn’t, and the things I was starting to get interested in were not on the radar of my MIT pure-math colleagues. The Northeastern math department, by contrast, was then an intellectual free-for-all. People were not competing with one another, and their interests varied widely. The expectations about publishing were low, so all pressure was internal. Since I’m very good at generating internal pressure, and not so comfortable with rigid external pressure, this was a good situation for me. I could breathe out and try to find out who I wanted to be when I grew up.

The sexism that was endemic in math was not absent from Northeastern, but it had a different flavor. There were then a fair number of quite strange people in that department and an acceptance of this state of affairs. So, in that department, a dancing bear did not stand out that much, even if she was experimenting with topics that would not be welcomed in most traditional math departments (and most math departments are still traditional). If I was going to be eccentric, at least I had company. However, the lack of women was perceived to allow bad behavior: Once, in a later meeting of full professors, administrative people (female, of course) were brought in to maintain a civilizing effect on the discourse.

Within the Boston and more general math community, I still had to cope with attention of the wrong kind. There were many incidents that fell short of what can be called harassment but still set a tone about interactions. In one, I gave an invited talk at Brandeis, at which some audience member continually asked pointedly pointless questions; I finally assigned him a quota, and kept hash marks on the board for each. At an invited talk at a Midwestern school, the entire hiring committee showed up, though I hadn’t applied; at the colloquium party later that evening, a well-lubricated faculty member confessed to me that the department had had to fill out a form about how many women they intended to hire in the next five years, and he proudly reported: 0,0,0,0,0. At one point after I was tenured, I got a letter from a faculty member at Berkeley inviting me to apply for an assistant professor position, though I was already an associate professor. I wrote back inviting him to apply for a similar position at Northeastern. That letter was posted on the door of many people at Berkeley, becoming part of my publication oeuvre. I grew to have a thicker skin, something that was invaluable when I found myself in similar outsider positions for scientific, rather than gender, reasons.

One story I love is less about me than about my husband, and beautifully illustrates the atmosphere of the time. Gabe had given a Boston areawide math colloquium at Harvard and was being taken out to dinner, as was the custom. I came along as significant other. There were four of us in a car, the other two being famous Harvard mathematicians. With Gabe and me in the back seat, the others had an animated discussion of why there were no women in the world good enough to be at Harvard, oblivious to the potential reactions of the young woman mathematician in the back seat. “Well,” said one (roughly), “maybe there is someone, but she is in a remote part of the Soviet Union and we can’t get her.” After a long and uncomfortable time, Gabe piped up and said, “George, according to your criteria, many of the people currently in your department don’t deserve to be there.” George thought about this and then allowed that this might be so. “Well,” said Gabe, “so why aren’t any of those people women?” George later had a talented daughter, and changed his attitude.

During that time, I also started my career as a serial hobbyist. Northeastern had an excellent early music group, and I joined it, playing recorders and krummhorns, capped-reed instruments that buzz. We had access to instruments from the New England Conservatory and were given the use of instruments, provided we agreed to play them in the next concert (free at Northeastern, not at the conservatory). I agreed to learn the racket, a precursor to a bassoon that looked like a coffee can with a pig’s tail. I did, barely, manage to get out a simple base line for the next concert, which was difficult since the finger holes did not match my fingers (a friend created a pinky extension for me).

My other hobby was various versions of art. My partner in crime was Harriet Fell, who was a grad student at MIT when I was an instructor. We did some photography together, and took a class in pottery at MIT. She made small beautiful things and I made large “interesting” ones. One of the things I tried to do was produce a good pyramid, using slabs of clay. Unfortunately, I couldn’t get the slabs to stay upright for the pyramid, and it was quite sorry looking. Harriet confiscated my work in progress and transformed it: She cut a hole on the back slab which we later corked, and added a very large nose on the front two angled slabs. There was also a very large tongue emerging from another hole. We glazed it a Pepto-Bismol pink (except for the tongue, which was rough and red instead of smooth and pink) and named it The Nose. Now what to do with it? MIT had a glass case with a lot of models of mathematical objects, including spheres and pyramids. We decided that would be a perfect place for The Nose and presented it to the then chair of the math dept. He accepted it with perfect solemnity and promised it would be put on a rotating stand to best exhibit its fine features. Shortly thereafter, some administrative assistant with less of a sense of humor disappeared it, and it has never since been seen. Harriet and I also hung around at a lab at MIT that had previously produced submarines for the Korean War and now ran courses with names like “metal sculpting for students.” We were by then no longer at MIT, but we were female, and that was enough to get us the privilege of hanging out after hours and on weekends. I learned just enough about welding to not kill myself or others. That avocation stopped abruptly when someone at MIT did kill himself by walking into a laser that had not been properly shielded; a subsequent safety crackdown throughout the Institute made it very uncomfortable for the head of that lab to allow noninsured people to play with dangerous toys. Many years later, I ran into him, and he invited me to come back. I tried, but never found the same communication with metal that had been effortless before. My mind had moved on. I also entertained myself during that time with sailing and rowing on the Charles River.

Oscillating Chemical Reactions

I’m not finding it easy to make a clear date-based story of my career, and part of the reason is that, usually, many things were happening at once. My interest in catastrophe theory continued into the Northeastern days, and I was known as a local expert. One day I got a visit from a graduate student in chemistry who was concerned with what would later become famous as the Belousov-Zhabotinsky (BZ) reaction. This was a chemical reaction that turned red and blue about every second if continually stirred. If left in a thin sheet and covered (to prevent fluid motion via convection), it formed complex patterns of interacting rings. The student was sure that catastrophe theory could explain this. So we had many sessions in which we went through catastrophe theory (and some of the Prigogine work), trying to see the relevance to the BZ patterns. Finally, I told him that I thought that catastrophe theory would not be of any use. Disappointed, he dropped the project in my lap (metaphorically speaking: a main ingredient was sulfuric acid) and went off to work with Prigogine.

Once I saw that system, and weaned myself from the expectation that the tools to understand it were available, I realized that this provided a concrete example of the kind of self-organization I wanted to study. But how to do it? It occurred to me that, though there was no fluid motion involved, the theory of pattern formation in fluid dynamics would give me some clues to the relevant mathematics I could use. So I set out to learn about patterns in fluids. This, of course, was pre-Web days; you found things out from painful days in the library and/or finding the right people to guide you. MIT was then (and still is) an active leader in fluid dynamics, so I walked across the river from my apartment in Boston and knocked on the door of one wellknown expert. I regard it as one of the luckiest events of my life that he wasn’t there, because then I walked down a few more doors and knocked at the door of Lou Howard, another renowned fluids expert, who was also wellknown for his wide-ranging intellectual curiosity. It appeared that I arrived at the right time for Lou. For whatever reasons in his life, he was ready for something new, and after questioning me closely about the reasons for my interest and the BZ system, he mostly dropped his fluids work and became my collaborator for the next seven or eight years. This did not make me popular with his other collaborators!

Those were my real postdoc days. It was during this time that I turned myself (with his help) into an applied mathematician. Though I had worked in dynamical systems, which involve differential equations, my work had not required me to actually learn to solve them. (I did that for the first time teaching an elementary version of the topic at MIT.) Applied math has a large number of computational techniques that tend not to get taught in pure math classes, partly because they don’t necessarily end up with a proof of something. But those techniques are extremely valuable in getting intuition, and that’s when I started to learn them. By computation, I don’t mean computers—these were the days of pads and pencils and many scrawled pages of formulae trying to lead to a comprehensible formula for something. There could be bugs, but the software was the human brain, not a code.

The patterns formed in the BZ system were very complex and never the same from experiment to experiment. But they had common features: Bright blue spots appeared in the deep red medium, propagating outward in a ring, and then another spot would appear in the center of the ring. This created locally a set of concentric rings we called a “target pattern” (not unlike the logo of Target, but with more rings). Adjacent target patterns crashed into one another in a manner reminiscent of abrupt shocks. Applied mathematicians work in a similar way to experimental scientists: They focus on some repeatable aspects of behavior and try to explain them. Lou and I started by looking at a thin radial strip within a target pattern, in which the behavior was essentially that of a periodic traveling wave: a pattern that would be stationary if the observer ran alongside at the appropriate speed. We were interested in the mechanistic origin of those traveling waves. There are many ways of describing what a “mechanism” is, a lesson that was very useful to me as a neuroscientist. A standard applied math method would be to create a fairly complex model of the chemistry that displayed the periodic changes in color while stirred, add in the spatial interactions (via diffusion), and then see if that model displayed traveling waves. I had a different idea: Perhaps (almost) any system that produced an oscillation when stirred would produce these patterns when ions were allowed to diffuse without gross fluid motion. My abstract math background allowed me to formulate and prove such a result, and Lou’s background enabled us to see appropriate simplifications and produce helpful calculations. The generalization, and others we were able to make, was highly useful because it made strong predictions. Any system that could oscillate, and had a couple of other properties, should produce these patterns. Later, Irv Epstein of the Brandeis chemistry department was able to construct families of oscillating reactions, and they did indeed form these patterns.

One of the papers we did was an attempt at explaining the origin of the interaction among the target patterns, with something like shocks between adjacent target patterns. We came up with a simple (“caricature”) mathematical model in which we could reproduce those shocks and understand (within that system) what caused them to form. A question that always arises (or should arise) when using a highly simplified description of some phenomenon is whether the results will be the same in more realistic versions of the system with many more details; that is, does the simplification merely allow us to see the essence of a phenomenon more clearly, or do the results of the study depend on removing the complexities? To answer this in the shock case, Lou and I made a stab at the problem in the general setting of reactiondiffusion equations (Howard and Kopell 1977). We used some classic applied math techniques, which were calculations known in some cases to yield good approximations to answers that were hard to compute. But we used them in what was regarded as a very weird way: In a coordinate system corresponding to running along a traveling wave, we looked at how phases at a given spatial point affected the phases nearby in space, something that was wholly uncausal. The computations we did showed how the general case mimicked the much simpler case, but there was no way to prove that the computations were anywhere near correct. In the current publishing climate, this likely would have remained in a drawer. But then, though we got some teasing for this strange work, we were able to publish it in an MIT-run journal. Recently, I learned that the work was a precursor to a now-hot field in math known as spatial dynamics, in which the work is far more rigorous, but in the same spirit as our early computations.

The work we did revealed principles that went beyond the BZ system that we were studying. These included pure math papers on general observations (theorems) about bifurcations that were useful in the application to the BZ patterns. So, in the end, I was indeed doing things related to catastrophe theory. I laughed when, long after my episode learning about catastrophe theory, I got a note from Rene Thom saying that my BZ work would help to extend catastrophe theory. Throughout my career there has been a tension between abstraction and detail. I sometimes refer to this tension as finding “which differences make a difference.” My mathematical background leads me to try to explain phenomena in a very general way, but as I later got deeper into biology, the specificity of various phenomena stared me in the face and changed some of my working methods. More of this is described below.

Throughout the series of papers that we wrote together on many aspects of the patterns, Lou and I had highly different styles of working: He grabbed a pad and starting computing, while I sat on what he called my three-legged stool and stared out into the distance. I tend to work by visualizing the geometry of the solutions and then trying to get down on paper the results of the visualization (which does involve some calculation); he worked entirely by calculating. At the end of a session, we would compare notes. They were usually in the same direction. But after one session, we diverged, and I insisted I was right; he later found an error in a 15-page calculation. That never happened again, but I was very proud for one day, since Lou almost never made mistakes, and I had found that there was an error without actually looking at the calculation. Though we worked differently and separately, we found it helpful to do the work together in some unused room that MIT let us use. It had a fridge that was stocked with Lou’s favorites: oranges and pickles, consumed with a lot of bad coffee.

The working atmosphere was very different from current times in multiple ways, one of which concerned time frames and expectations about productivity. This was an unavoidable consequence of differences in technology. There were no word processors, so multiple drafts were retyped multiple times, or written out in long-hand multiple times. Manuscripts could not be e-mailed to colleagues or put on a Web site. If you wanted your colleagues to see your work in less than the year or so it would take for publication, you sent out preprints. The papers I wrote with Lou tended to be generous in length. I vividly remember a day in the 1970s in which I had about 100 copies of some long paper reproduced at a local printer, page by page separately, and then spent hours collating the copies and stapling. Then there was collecting a list of recipients, stuffing large envelopes, and addressing them. Of course, sending out 100 copies was a form of hubris, but the hope was that a significant subset of recipients would at least read the abstract or perhaps save the paper in a file cabinet.

In addition to the mathematical work we did, we had an experimental component. We played with the patterns in a tiny lab in the MIT basement that used to be part of a men’s room before it became part of the fluid dynamics lab, and then ours. Our first paper described patterns that formed when the concentrated sulfuric acid was poured gently into a test tube in which the other ingredients were well mixed (Kopell and Howard 1973). The patterns were waves of blue propagating upward in a red medium, but not at uniform speeds or distances. We came up with a reason for it that did not involve any fluid motion. To test this idea, Lou created a camera that could take space-time pictures of a vertical slit of the test tube by moving the camera slowly across the test tube as the pattern unfolded. It proved our hypothesis. We later built a demonstration using compound pendula, showing the same space-time behavior due to a gradient in frequency rather than any actual coupling. We built it out of wooden rods, cut-up lengths of metal rods, straight pins to pivot on and shrink wrap, and displayed it many places. The math for that (unlike for the complex target patterns) was very simple and earned me some disapproval from someone who had a more restricted view of what math was (or was for). But it got into Science, my first and only research paper in that journal. We also produced various versions of the target patterns and related spiral patterns, used mainly for demonstrations in talks; it was still possible at that time to take concentrated sulfuric acid on a plane and keep it under the seat. I was not a very careful experimentalist, and small drops of the acid too often met my attire. One time after a stint in the lab, my fortune cookie at a Chinese restaurant announced “you will get new clothes.”

In addition to working together at MIT, I visited Lou in the summer when he was a part of the computational fluids course at Woods Hole Oceanographic Institute. I was not a student in that course, though I was included in the annual picture the years I was around at the right moment. In other years, I was included in a head shot mounted on a picture of the cover of a garbage can. I stayed with him and his family at a small cottage on Crooked Pond. The property had a “little house” (barely big enough for a bunk bed) that I occupied for the few days I visited. The “big house” was sufficiently small that his four kids all slept on the porch; none of them wanted to bunk with the many spiders that inhabited the little house. Crooked Pond was wonderful to swim in except that its shores had many snakes, to be avoided while entering and leaving. This was nature, if not red in tooth and claw.

Continuing to be a (Pure) Mathematician

During this time and continuing thru the next decades, I was also working on questions that were purely mathematical. In general, I’m attracted to questions that have a strong geometric component, where I can visualize what the mathematical behavior might be. Many such systems are singular: This means that there are multiple time scales and, in a limit in which the ratio of these scales is infinite (or zero), the system has fewer variables. Almost all models describing neural systems have such multiple time scales associated with the multiple kinetics of intrinsic and synaptic currents.

One of the first of these papers I did on singular systems (Kopell 1979) was about “resonance,” used in a different way than matching frequencies of input and a target. As a parameter in a system is varied, there is a sequence of discrete values at which there is a solution to the problem. Looked at in the right coordinates, I could see that the solution corresponded to a pair of surfaces being rotated with respect to one another as the parameter varied. I used this to describe (and prove) what this form of resonance was (Kopell 1979). I emphasize the sole authorship because of one of the reviews I got when I used this to apply for an NSF math grant. The review said, approximately, “She has never done anything before working with Lou Howard and will not do anything after.” Both statements, of course, were untrue, and ignored by NSF: I got the grant. I later visited Caltech, where some people had done related work using very different ideas. When I got there, I was greeted by someone who told me (the first minute he saw me): “X tells me I don’t have to read your paper, since he can prove this in a much easier way.” A scientific boxing match was then set up, in which we hurled questions at each other in the presence of a completely male audience clearly rooting for the home team. I was happy enough with my performance; I definitely held my own, especially considering I had no time for preparation. At the end, I chided the audience for the unregulated level of testosterone and hostility in the room, and after that they were nicer to me, maybe because I had survived the hazing initiation and could now be considered one of the boys. This was one more incident leading to a thicker skin.

In general, singularly perturbed systems display invariant manifolds (potentially higher dimensional surfaces with the property that a trajectory starting on such a surface stays there). Much of the behavior of the full system can be understood from the geometry of the invariant manifolds. Thus, being able to track invariant manifolds from a set of initial conditions is a highly useful tool. With Chris Jones, I invented a new technique for doing this (Jones and Kopell 1994). It used what is known as differential forms, a set of ideas from differential geometry (which I had never formally studied). Instead of following individual trajectories, one could follow whole surfaces by following the planes tangent to them. We used this to understand and bring some mathematical rigor to trajectories near singular solutions, which often make sharp angles at points in the trajectory. Methods following one trajectory at a time could not handle this, but methods looking for intersecting surfaces, such as the use of differential forms, could do so. This method was picked up by others as well and used widely.

The methods I used for my mathematical work were constructive, meaning roughly that any item I claimed to exist was conjured up using an explicit construction, rather than a double negative. (“Suppose not. Then there is a contradiction.”) Gabe was a standard-bearer of the constructive school of mathematical thought, which was not (then or now) in ascendency. One mathematical friend remarked he thought that I used this approach “to keep peace in the family.” In fact, I used it because it made much more sense to me than the mystery of mathematical objects that couldn’t not exist but were wholly undefined. In general, I tend to question most things I come in contact with; another mathematical friend said that the sentence he most associates with me is “Why?”

Following invariant surfaces turns out to be a powerful method for applications to specific equations. After the work on tracking invariant manifolds (early 1990s), I was drawn to see if such ideas could be applied to a well-known and open problem of “blow-up,” or the focusing singularity of the nonlinear Schrodinger equation. The problem had been much investigated by standard tools of applied math, including “matching asymptotic expansions,” in which calculations are made separately for regions governed by different times scales, and then these are somehow put together in ways that constrain the individual calculations. Everyone agreed that this was likely to give correct intuition, but there were holes in the argument that kept the calculation from being considered a proof of the existence of the desired solution. I had a sense that combining the calculations with geometry could produce a proof, and this problem, acknowledged to be very hard, could be a proof of principle about the importance of geometry. The role of the calculations was to suggest the right variables in which to look for the geometry, and then dynamical systems methods using invariant manifolds could be used. To make it work, I needed a collaborator who knew the asymptotics of this set of equations. I approached one such well-known person, who did not have time, but he recommended Michael Landman, a younger investigator who was in Australia. This was way before Skype. I had never met him (and met him briefly only once in Paris, when we were almost done with the paper). Nevertheless, it was possible to send ideas back and forth by e-mail and solve the problem. This time I managed to please those working in different ways: The project showed that both applied math techniques and pure math techniques could be combined to do something that neither had been able to accomplish (Kopell and Landman 1995). It might have been a coincidence, but shortly thereafter I was elected to the National Academy of Sciences (1996) in both pure math and applied math. At that point, I was deep into trying to understand neuroscience, so I signed up for the neuroscience section.

Even when my primary interest has been neuroscience, as it has been for the past decades, I’ve been continuing to make occasional forays into purely mathematical questions that arise from the neuroscience. One such set of papers I did with Horacio Rotstein and others was on “canards.” These are sets of solutions that arise in the transition from a subthreshold oscillation to a full “relaxation oscillator,” a system of equations with a periodic trajectory that has slowly changing plateaus and fast transitions among them; canards are important in neuroscience in understanding so-called “mixed mode” oscillations, in which full spiking or bursting alternates with subthreshold behavior (Rotstein et al. 2008). In general, I think that almost all simulations give rise to interesting mathematical issues, but I haven’t had the time to follow up any but a few. But trying to understand why simulations behave the way they do can lead to new mathematics (Kramer et al. 2008). Currently, I’m most interested in interactions of rhythms, or effects of temporally structured input to networks that have multiple time scales; these areas are still mathematically almost virgin.

Introduction to Mathematical Biology: Oscillators and Bard Ermentrout

The work I did with Lou on pattern formation in chemistry was inspired by pattern formation in biology and extended by others in that direction. It was not about biology, but it was close enough that I got invited to the Gordon Research Theoretical Biology Conferences. This was in the 1970s, the early days of the field of mathematical biology (not counting a much earlier era that had not left much of a mark on biology). There were few enough people in this field that we could all go to the same conference, whose talks (in each conference) ranged from ecology to genetics to immunology to all forms of physiology and any kinds of mathematics that might be relevant to any of the above. The conferences, which started in the early 1970s, were the place to go to network with others and find out the general state of the art. Compared to now, that state was pretty primitive and not accorded much respect; we went as much for comfort and fellowship as for the science. Over time, that yearly conference went to every two years, and eventually ended. As mathematical biology got more and more tied to cutting-edge biology, people wanted to go to the relevant biology conferences, not ones that were only “theoretical.” But in the 1970s, the conference served an important purpose of creating a community that has remained and encouraging many collaborations.

My first such Gordon conference was in July, and my talk was on the Fourth of July. Lou and I prepared carefully for that talk. We made a filter for a slide machine that was red except for a vertical bright blue stripe in the middle. We shined this edge-on to the contraption that had the swinging pendula: Every time a pendulum swung through the middle, it turned blue, and the rest of the time, it was red. Thus, we mimicked the red stripes propagating through a blue medium in a test tube. It was a big success with the crowd. It seems to me that it was easier to have fun with science way back then; science has gotten a lot more competitive and that makes it harder to enjoy it in simple ways.

Mathematical biology in the 1970s and 1980s was more mathematical than biology. I didn’t start considering myself working in this field until the 1980s, and then with much more of a focus on mathematics. My collaboration with Bard Ermentrout started with intestines and peristalsis, a very Bardish topic. Bard had initially corresponded with me about some simulations done with Lou in the late 1970s. In the early 1980s, he initiated an interaction by calling me about a paper he was working on concerning traveling waves associated with peristalsis. In the simulations he was doing, the waves did not travel down the entire length of the model intestine; instead, they broke up into apparently decoupled waves, though there was no break in the coupling. Bard had computations suggesting that this was to be expected, but no clear intuition for why. I was a reasonable person to contact, since the work I had done with Lou included analysis of traveling waves in a locally periodic environment, and I had geometric tools with which to think about his question; this complemented his expertise on computation and linear algebra. He recalls that I said it should be easy—and then called back a week later to say it wasn’t easy (see below).

Bard and I were an odd couple: We met in person for the first time in Washington when he was a postdoc working with John Rinzel and I had come for a NSF review panel. I was dressed as I thought a panelist should present herself, in a skirt and heels and neat grooming. Bard walked into my hotel lobby in cutoffs and a t-shirt with holes. He suggested we go to a bar, where he gave what I learned was his standard opening with a new person: a description of why he had only pieces of various fingers (answer: an explosion when he was trying to make bombs to give to the Black Panthers, who didn’t want them; explanation of the explosion: not enough cornstarch). In later years, every time he introduced me, he claimed that he had picked me up at a bar.

At this point, Lou and I both felt that we had done what we wanted with the BZ reaction, and he went back to fluids, while I was back to (mainly) pure math. In spite of the obvious personality differences, the collaboration with Bard lasted over two decades and produced over 25 papers, most of them in pre-Internet days, and so with work carried out by handwritten letters and telephone calls. Much of the work that Bard and I did was on oscillators that were coupled to one another with weak signals. For such coupling, it turned out that there is a general theory that could be developed that is not dependent much on the details of the oscillator or the coupling, and there was a way to condense the effects of each oscillator on the other in a function we called “the H-function,” from our notation (Kopell and Ermentrout 2002). A version of such a theory had been previously published in Russian and had been unknown to us; we developed a more geometric and intuitive version, and later showed the equivalence of the theories. The theory allowed us to make many inferences about interactions of networks of such oscillators from just one computation about each. That is, any changes in physiology that made a difference to how neural oscillators would synchronize or lock with a nonzero phase lag showed up as a change in the H-function. This was very similar in spirit to the work I had done about patterns in reactiondiffusion equations, in which the details of the reactions were shown to (mostly) not matter to the outcome. I learned this lesson very well, and then had to partly unlearn it.

The early work that Bard and I did was mostly about chains of oscillators, not all relevant to intestines. It was necessary to produce new mathematical tools, since almost all the voluminous literature about oscillators dealt with linear oscillators. In biology (and in the BZ reaction), the relevant systems are nonlinear oscillators that have a single periodic solution to which other solutions approach in time. These are called limit cycle oscillators. The first significant paper we did was motivated by intestines, in which the length of gut could be conceptualized as a chain of oscillators with a gradient in frequency along the chain, producing peristaltic waves. This was the problem Bard had called me about. We showed that the waves were a consequence of a frequency gradient (Ermentrout and Kopell 1984). We worked with weakly coupled oscillators, so (as in the BZ study), we did not have to specify the details of the oscillators. Our work showed that when the gradient is too steep to allow phaselocking at a single frequency (with a single wave), there are “frequency plateaus,” or sequences of oscillators having the same frequency, with a jump in frequency from one plateau to another. The work showed unexpected geometry in the solutions; we rediscovered, in the context of networks of oscillators, a kind of “bifurcation” (qualitative change of behavior do to a small change in some parameter). The work has been cited many hundreds of times, though I doubt by any biologists.

Bard and I went on to do other papers as well about chains of oscillators, some of which were related to our later work on lamprey, though we were motivated at that time just by the mathematics. In Kopell and Ermentrout (1986), we looked at chains of oscillators that may or may not have a frequency gradient, and asked what produced synchrony or waves or any other dynamical behavior. Again, with weak coupling, the setting was very general. If a finite chain of identical oscillators is connected in a way mathematically equivalent to diffusion (e.g., with coupling from gap junctions), they tend to synchronize. The central insight of the new work was a mathematical generalization of properties of chemical synapses: They do not behave like diffusion, and because of that, even if the oscillators are identical, they can speed each other up or slow one another down. (Cells connected by standard gap junctions ignore one another if they have the same voltage.) This speeding up or slowing down could give rise to waves along the chain. Such waves were very different from those associated with a frequency gradient, as in peristalsis. It was that insight that later got us started on lamprey swimming. We also extended the work in many ways, including looking at behavior as the number of oscillators increased without bound (Kopell and Ermentrout 1990). This connected us with a community of physicists, including David Ruelle, who were looking at large ensembles of particles, again in the limit of numbers of particles. I went to some conferences and wrote some papers because of this, but it was not a lasting interest.

Another early paper of ours made a big splash for something we thought was a minor point in the paper. We were investigating a kind of “bursting” pattern in which there are multiple spikes within a longer time period, and the spikes are faster in the middle of the burst. This was again a subject that Bard started and brought to me. He had shown, using Lou-type standard applied math calculations, how the solutions are forced to behave. However, the calculations did not satisfy the reviewers, who didn’t believe the results at all. With geometric methods that were very different from the standard calculations, we were able to reframe the questions, using a change of variables that amounted to a different perspective (Ermentrout and Kopell 1986). In this new perspective, we had a simpler model that was easy to analyze. The most noticed point was our proof that anything in a large class of models could be turned into this simple one by a change of coordinates. In general, simple models may be easy to analyze, but their relationship to ones of interest may be unknown. By establishing this relationship, we could know when our analyses applied to much more complex models. The simple model has been called “the theta model,” after the notation we used, and is now showing up all over in work on mathematical neuroscience.

Bard and I also worked on many other questions associated with oscillators, including how interactions could change amplitude of the oscillations (Aronson et al. 1990; Ermentrout and Kopell 1990). We also wrote many reviews on oscillators, some of which appeared in dark places, but which seem to have been found by interested readers (Kopell and Ermentrout 2002).

In 1990, I was awarded a prestigious MacArthur (“genius”) Fellowship. Though they never identify the basis for the award (and the use is unrestricted), it seemed likely that the work with Bard was involved. I had remembered it as connected with work on lampreys (below), but the first paper on that came out in 1990.

Going to Boston University

In 1986, I moved to the Boston University (BU) Mathematics Department. Northeastern has since become a very good and very popular school, but in the mid-1980s the department was in turmoil. I had appreciated the wildwest atmosphere of the Northeastern Math Department, but it had gotten out of hand, and I was ready for more stability. When BU approached me, I was very receptive. The fact that I could continue to live in the same place and just take a different subway was certainly a plus. This has turned out to be a wonderful decision for me. I often refer to my department as the most collegial and functional group I’ve ever had the pleasure to work with (I was very familiar with dysfunction). We have made hard decisions together without recriminations and supported each other’s attempts to both develop a top group in pure mathematics but also to connect mathematics to the rest of the university and the rest of science.

The department is now a combined math–stat group, something that has fostered important collaborations. It has been very easy within BU to form collaborations in multiple departments. Within the BU Biomedical Engineering Department, I worked with Jim Collins on genetic oscillators and John White on networks of neural oscillators (more below). I now work with Xue Han (also with biomedical engineering) on pharmacological and optogenetic projects associated with basal ganglia and Parkinson’s disease (PD; below), as well as Tim Gardner (biology) on oscillations in songbirds and Howard Eichenbaum and Mike Hasselmo (psychology) on hippocampal rhythms. There are also others, such as Barb Shinn-Cunningham and Helen Barbas, who share mentoring of students with me. I have had and still have collaborators in the math department (Tasso Kaper, Uri Eden, Mark Kramer), but don’t feel pressure to restrict interactions to that group. Indeed, BU has strongly encouraged interdisciplinary outreach. BU has also been very generous to me. In 2000 I was given a chair (William Goodwin Aurelio Professor of Mathematics and Science), upgraded in 2009 to another (William Fairfield Warren Distinguished Professor). These positions came with a huge amount of freedom, which I gratefully took advantage of. The freedom, including much less formal teaching (but much informal teaching and mentoring, which I love), allowed me to do lots of community building, described below.

Lampreys

Most of the things in which I became interested showed up in my life by accident. I met Avis Cohen for the first time in the late 1970s when she was a grad student and I was a young professor. She had invited me to speak at a conference in honor of Eric Lenneberg, a mentor of hers who had recently committed suicide. The eclectic group of invitees, who included Ursula Bellugi and Noam Chomsky and my future husband Gabe, consisted of those who had been on the mind of Lenneberg, and I was apparently among them. The work with Bard, plus the earlier work with Lou, earned me a reputation as “the oscillator lady.” That meant that I was fair game for those who had questions about anything periodic. Within neuroscience, the most obvious and accessible networks involving things periodic were central pattern generators (CPGs), networks of neurons involved in periodic motor activity. Much later, Avis, who was working on lamprey locomotion, recruited me to write a pedagogical chapter (Kopell 1988) about oscillators for a book she was editing on central pattern generators.

There is a huge amount that can be said about oscillators, and many books have been written. The chapter had to be much more specific: What do people who work on CPGs need to know about this topic? Unfortunately, though I knew a lot about oscillators, at the time, I knew almost nothing about how CPGs might involve and use oscillators. I had a Sloan Fellowship at the time, which relieved me from teaching, so I decided to dig into this. This was (again) before PubMed, so I clearly needed help and guidance. Avis sent me a large box of reprints (yes, people made reprints then), and I went through all of them, at first understanding a small subset of the words. She very patiently put up with all my extremely naïve questions. And then she sent me a second large box of reprints to absorb. My paper was only a book chapter, and most of the other participants could knock off their contributions in a short time. Mine took almost a year as I learned a field, figured out what people in that field needed to know, figured out what I could say that would be useful to them, and learned to write it in a way that would be accessible. I recall the chapter was about 60 typed pages, done before word processors, and Avis made me rewrite it six times. Each time, I learned something about communication with people who collect data and think about them in a way that was very foreign to me. Avis was more scientifically junior than me, but she was an essential mentor in allowing me to transition from thinking about abstract oscillators to thinking about important biological examples.

Avis also invited me to give a poster at a conference in Stockholm (home of Sten Grillner, then the most well-known scientist working on lamprey locomotion). I realized that previous work with Bard (Kopell and Ermentrout 1986) gave us a central insight into what might produce the traveling wave of electrical activity that is the basis for swimming in various kinds of fish and other vertebrates, such as lampreys. This was one of the few vertebrate preparations that were being explored, and the electrical behavior could be reproduced in an isolated spinal cord (“fictive swimming”), making it especially attractive as an experimental preparation. As described above, the fact that chemical synapses could speed up or slow down oscillations could give rise to waves in a chain of oscillators, such as a lamprey spinal cord. I discussed this work in a poster.

I remember vividly how strange it was to present a poster (mathy people rarely did that at the time). What do I put for materials and methods? (Answer: pencil and paper, the method of thinking.) This was a smallish conference, in which everyone seemed to know almost everyone else, and I knew only Avis. Of course, people went first to the posters of their friends, and I stood around feeling very much the wallflower. After a while Karen Sigvardt and Thelma Williams appeared at my poster, and sniffed around suspiciously. But they engaged with this strange interloper, and after a while, even got interested. This was the start of a multiyear, multipaper collaboration with me and Bard (and sometimes Avis). Avis hosted several lamprey meetings at Ithaca, with the small group of people actively working on this subject. It was there that I saw how these animals were kept in captivity: Many of these long, slim animals were attached by their suckers to a host fish, prompting Bard to remark about the resemblance to Rastafarian locks.

The central work that we did was related to trying to prove experimentally that the “fictive locomotion” in the lamprey spinal cord was indeed this new kind of wave, powered by chemical synapses, not diffusion or gradients in frequency. The mathematics had shown that, unless the coupling in the two directions was identical, one of the two directions was dominant in the sense that it determined the phase relationships between the neighboring oscillators, almost independently of the other coupling. However, the nondominant coupling did have an effect: It changed the phase relationships at the edge corresponding to the origin of the nondominant direction. From our work on weakly coupled oscillators, we were able to use our H-functions to figure out what properties would lead one edge or the other to be “dominant” and control the propagation; this dominant direction need not be same as the direction of the wave (Kopell et al. 1991).

It was unclear if such a description of propagation actually applied to the lamprey. My first attempts to come up with reasonable experiments were laughable. So how could we prove that the fictive locomotion was indeed guided by this new kind of wave? It occurred to us all that we could do this only by somehow demonstrating the existence of the “edge effect.” Technically, this was hard to do with the whole lamprey cord. Karen came up with the idea of cutting the cord and looking at the two new edges created. But look at what? It was very hard to measure the actual phase lags near the edges to enough accuracy. Here was where the mathematics helped again. Bard and I had analyzed what happens when a chain of oscillators is “forced” with a periodic input, that is, is given periodic input at one end. The analysis showed that there is a difference in outcomes depending on whether the end receiving the periodic input was the dominant end or not. More specifically, the math showed that, with periodic input at the dominant end, the chain could be made to oscillate at frequencies above and below the natural chain frequency. But with periodic input at the nondominant end, the chain would respond only to frequencies above or below the natural frequency.

Karen and Thelma were game to try this out. To do this, they developed a rig in which a tiny motor was attached to one of the two newly created edges and wiggled the end of the cord, with most of the cord pinned down. Because the cord has mechanoreceptors, wiggling created a periodic signal at that edge of the cord. They then measured the range of frequencies at which the activity of the motor could entrain the whole piece of spinal cord. From a biological point of view, the experiment was very strange; as Karen liked to say, there was absolutely no biological reason apart from the mathematics for wiggling a cord with a motor. But the experiment worked (Williams et al. 1990): It produced the effects that were predicted and taught us a few biological things we didn’t know before: (1) ascending coupling sets the intersegmental phase lags, whereas descending coupling changes the frequency of the coupled oscillators; (2) there are differences in the ascending and descending coupling other than strength; and (3) coupling slows down the oscillators, suggesting it is primarily inhibition-based. I recall that Karen and Thelma presented this before publication at SfN, and I was bursting with pride. At this time, there was still not much attention paid to mathematics, and being able to make highly unintuitive predictions from mathematics was not very frequent.

The lamprey work that we did was thought to be a paradigmatic example of collaboration between experiments and theory, and so Karen and I were booked yearly at the Woods Hole course on Methods in Computational Neuroscience. This went on for a significant number of years after both Karen and I stopped working on lamprey. It was a popular gig, since we did a dog and pony show alternating back and forth in the one to two hours we had and setting up punch lines for the other. I did get tired of that talk after a while (and was released from what one course director called “fish duty”), but it was a tremendous amount of fun while it lasted. It was also wonderful to spend informal time with Karen and other scientists over multiple days. The talks we gave together were a challenge for me, since the audience was so broad and the some of the mathematics quite technical. I recall some mathematicians from the Oceanographic Institute dropping in on one of these talks and listening to me try to get the essence of the ideas across. After, one said “but surely there are hypotheses?”

Another Kind of Modeling: Turning Physiology into Mathematics

At some point around the early 1990s, the direction in which Bard and I were taking the lamprey work became less exciting to us. We had explored many nuances of how chains of oscillators give rise to patterned activity, without going into any depth about the nature of the oscillators or the nature of synaptic coupling. The questions we had asked had answers that did not depend on those details, and as I was in my mathematical mode, that made me happy. Other people continued to explore questions about swimming in vertebrates, notably Sten Grillner’s group working on the structure of individual lamprey segments, and Thelma Williams and collaborators, who put together the original insights with work involving the mechanical structures of the animal that constrain movement.

This was also around the time that Bard and I got divorced (amicably) as a mathematical couple. At the beginning of our collaboration, essentially all of our papers had the other as an author. But after a decade or so, Bard said to me “I don’t want to be married any more, I want to be promiscuous.” After I got over being jilted, I decided that this was a very good decision for both of us, and it started an era in which I was also scientifically promiscuous, continuing to occasionally write papers with Bard.

By this time, I had become something of an expert on a variety of central pattern generators and decided to look more closely at some of them. An obvious mentor for me was Eve Marder, who was doing very interesting work on crustacean networks (lobsters and crabs). With her encouragement, I started hanging out at Brandeis and picking up more of the culture of biological experimentation. The work she was doing was producing data showing complex patterns of activity among small networks of neurons; these patterns could be changed by application of neuromodulators. The central questions for me were: What caused these patterns to emerge? And how did the modulation change the interactions? These were clear mathematical questions.

The mathematics needed to address these questions had a very different flavor from what I had done before. In working on the lamprey and the BZ chemical reaction, it was possible to use weak coupling to abstract out most of the details behind the local behavior (such as within an individual lamprey segments), and the segments were (reasonably) treated as the same. In going from a network of networks (i.e., chains of segments) to the lobster stomatogastric ganglion (STG), more detail needed to be considered. Though each of the cells in the STG was capable of oscillating in the right circumstances, each had its own dynamical personality, its own set of intrinsic currents, and its own set of connections with other cells in the network. It was not possible to understand the network without making a detailed acquaintance with each of the network participants. Eve was an excellent mentor over that period, which included times in which she was totally baffled by my various turns of mind, some of which were not good ideas, as she let me know. Another scientist I hung out with during that time was Ed Kravitz, then working with crustaceans, and now with fighting flies. In addition to his science, Ed was known for his elaborate jokes and the great parties that he gave for students at Woods Hole.

The 1990s was a transitional time for mathematical biology. There was still not very much work being doing on networks of real neurons, as opposed to “neural networks,” which were artificial networks whose connectivity could be changed by an artificial plasticity to “learn” certain behaviors, but whose connection to biology was still being gingerly investigated. In 1984, John Hopfield had published a very influential paper on what came to be called “Hopfield networks.” These were abstract networks of nodes that were connected by symmetrical weights. Such networks, started at random initial conditions, would converge to an “attractor” and could be “trained” to learn specific attractors, which was conceived as a model of associative memory, and later (with David Tank) as a way to do fast “neural” computations. There were a lot of interesting math/physics questions that could be investigated about these networks, and physicists flocked in droves. People who picked up that thread and carried it far included Haim Sompolinsky and Larry Abbott. The study of these networks, which could be done analytically, was the starting point for much speculation about cognitive function that could be conceptualized as network properties. It was also the beginnings of a different kind of thread, one that focused more on physiology and the dynamics properties of single cells. John Rinzel and his colleagues were pioneers of this direction, producing many modeling papers on ionic currents (Sherman and Rinzel 1992; Wang and Rinzel 1993), cable properties (based on earlier work of Wilfred Rall), and effects of electrical coupling. Those two threads in computational neuroscience stayed mostly apart for many decades; I believe that much more than the current overlap is going to be needed to understand cognition. One continuing gulf between those communities is about what constitutes an “explanation.” In writing this mini-bio, I came upon a chapter I wrote in the 1970s (Kopell 1978) before I was working in neuroscience and found that, even then, I was preoccupied by how differently people thought about intellectual issues and what they find satisfying.

Of course, the 1990s was also a time when computer simulation became available, and the study of more complex problems became possible. The number of people interested in computational neuroscience grew and new journals appeared: Neural Network in 1988, Neural Computation in 1989, and Journal of Computational Neuroscience in 1994. Around this time, many groups were starting to work on biophysical oscillators, not necessarily neural. There was work on respiratory oscillators (Butera et al. 1999). Mathematical work, such as that of Eugene Izhikevich on bursting (Izhikevich 2000), was getting a lot of attention. X. J. Wang, with Gyorgi Buzsaki and others, were working on synchronization (see below). My work with Eve and her group fit well with the zeitgeist.

This was also a transitional period for me, in which I was still very focused on mathematical structure and how one could understand interactions of network participants by using abstractions of cells. (I did not publish in a biology journal until 1990.) For example, a bursting cell was described by a relaxation oscillator. Some of the cells were “bistable,” with ability to remain stably at a fixed low or high voltage. I became interested in how elements with these mathematical properties could interact, and whether such a study could give insights into the workings of CPGs, especially the crustacean STG. The experiments in Eve’s lab provided many projects for me and introduced me to intrinsic conductances, such as the hyperpolarization-activated inward conductance h-current, which provided a slow time constant and which opposed both excitation and inhibition, shaping the interactions of cells having those conductances. I turned these physiological properties into mathematical ones that I could play with. Izhikevich later wrote a book on dynamical systems and properties of intrinsic and synaptic currents, taking this very useful theme much further (Izhikevich 2007). During this time, I was also much influenced by the work of John Rinzel. John and collaborators were studying a variety of specific biophysical systems, notably thalamocortical networks (Wang et al. 1995), as was Alain Destexhe (Destexhe 1998). John was working in a more biophysical way, while I tried to use abstractions of the biophysical properties. His work was also a big influence on me as I later turned to more biophysical descriptions and simulations, going even farther away from the abstractions of Hopfield networks.

The crustacean STG network has a small number of cells, most of which are not intrinsic oscillators. Though the interaction of oscillators was wellstudied (especially if the coupling was weak and the oscillators were not of relaxation type), the interaction among periodically bursting cells and nonperiodic cells was not well understood. With my students (Tom LoFaro and Christina Soto-Trevino) and members of Eve’s extended group (Larry Abbott, then doing a lot of joint work with Eve; Farzan Nadim, a former student of mine; and Yair Manor, Gwen LeMasson, Scott Hooper, and others), I wrote a series of papers on subsets of the STG network, and how the multiple time scales associated with intrinsic and synaptic currents could give rise to oscillating networks (Skinner et al. 1994; Marder et al. 1998). Some of the behavior was complicated, such as subharmonic coordination, in which one cell could participate on a fraction of the cycles of the other (LoFaro et al. 1994). Others were unintuitive: for example, how electrical coupling between a bistable element and a burster could create a network oscillator (Kopell et al. 1998). Farzan had done a very theoretical thesis for his math PhD, which had nothing to do with oscillators or physiology, and then did a postdoc with Ron Calabrese. He was the first of my students and postdocs to turn themselves into experimentalists. I recall telephoning Ron (over some holiday) and discussing the possibility that Farzan might join him to get a bit of experimental experience. Ron said “why not a full postdoc”—and a career was born. This was a time when it was rare for people with theoretical backgrounds to be welcomed into labs (and supported!), and I was happy at Ron’s prescience in seeing the possibilities. And I was delighted to be able to work with Farzan again in Eve’s lab over very different questions.

The cells of the STG that oscillate are bursters, which can be described, as above, as relaxation oscillators. One theme I explored with another student, David Somers, was the differences between coupled relaxation oscillators and coupled nonrelaxation oscillators. These projects were inspired by Eve’s work, but not directly connected to them. I had not fully taken in how different the network outcomes could be, and David had to work hard to convince me. One of our papers, on chains of relaxation oscillators, showed why such chains could synchronize much faster than chains of nonrelaxation ones. The work (Somers and Kopell 1993), in the end analytical, started with a huge amount of simulations. Now I take it for granted that doing large quantities of simulations is likely to be an important precursor to seeing interesting results, but then I was computationally naïve and not at all used to working that way. Another major insight that came out of David’s work was that phase relationships among coupled relaxation oscillators are generally much more rigid than among nonrelaxation oscillators: They like to synchronize or antisynchronize and don’t like anything in between. Two relaxation oscillators, coupled by excitation, can synchronize in antiphase (Kopell and Somers 1995), depending on the duty cycle of the oscillator. The rigidity of the phases was a big surprise, and I’ve continued to use that insight in thinking about very complex networks in which the phase relationships seem rigid.

One of the themes I’ve been interested in, starting from the days in Eve’s lab, has been ways in which small changes in some parameters in a network can make very large differences. This is closely related to bifurcation theory, except that the bifurcations, or switches, were not ones that had previously been described and were “global” rather than local. By global, I mean that one couldn’t understand the switching behavior by looking in a small range of the variables, since it depends on the large ranges of the variables. There are many slow variables that can trigger a switch, and synaptic depression or facilitation is among them; the STG network provides examples of these and one of the papers I did with Farzan and Eve’s group was on switches due to synaptic depression (Nadim et al. 1999). Large switches in network behavior occur in large mammalian networks as well. But because of the general complexity, it is harder to find them, and even harder to analyze. One early foray into this was a paper I did with David Terman and Amit Bose on transitions between spindling and delta sleep rhythms (Terman et al. 1996). These ideas are now reappearing as I try to understand interacting rhythms that appear with various kinds of anesthesia (see below).

Synchronization of Neuronal Oscillators

In the 1990s, studying synchronization of neural oscillators was an industry. The circumstances under which even a pair of neuronal oscillators would synchronize were not at all understood. Bard and I had done a lot of work on this using our “weak coupling” methods. Other people, notably Carmen Canavier (Achuthan and Canavier 2009) and going back to work by Art Winfree, had produced and exploited methods called “phase response curves” (PRC), which are applicable to larger coupling among elements. These are mathematical descriptions of how much an external input to an oscillator changes the phase of that oscillator. Such PRCs can be used to predict when two oscillators will synchronize or lock in antiphase or some other phase relationship, or not lock at all. It can also be used to understand if an oscillator will entrain to a periodic external input. The PRC depends on the specific input and the details of the oscillator, but it can be computed once and used to understand interactions in multiple circumstances. New technology, such as the dynamic clamp pioneered by Eve’s group (Sharp et al. 1993), made it possible to measure PRCs for specific neurons with inputs that were designed to represent specific, and measured, synaptic currents. This helped to make the study of synchronization a more experimental quantitative study.

Synchronization can be achieved in many ways; even for a pair of cells, the coupling can be excitatory, inhibitory, or electrical (gap junctions), as well as mixtures. It seems to have been assumed that excitation would be good for synchronization, so it came as a surprise when people started showing that mutual inhibition could also synchronize. Some of this interest came from physiological networks that were entirely inhibitory, such as the thalamic reticular nucleus; other interest came from the suspicion that oscillating networks of neurons that contained both excitatory (E) and inhibitory (I) cells were paced by the inhibitory components. X. J. Wang and John Rinzel (Wang and Rinzel 1993) were among the early contributors to this industry, showing numerically, for a biophysically based model of spindles in the reticular nucleus, that inhibition with a long enough decay time could synchronize cells. This whetted the appetites of the theoretically minded to try to understand how this could happen. Bard, Larry Abbott, and Carl van Vreeswijk (Van Vreeswijk et al. 1994) wrote a very influential paper about inhibition and synchronization. In their hands (i.e., for their models and techniques), a conclusion was that decay time of the inhibition had to be longer than a spike to get stable synchronization. It seemed to some of us that this was not the whole story (Gerstner et al. 1996), and I was involved in various papers trying to tease this out (Kopell and Ermentrout 2002).

Inhibition between cells, especially relaxation oscillators (bursting cells) could produce also antiphase behavior. John Rinzel and collaborators had pointed out two mechanisms by which this could occur, which they called “release and “escape.” In the first, one cell is held down until the other stops firing and releases it from inhibition, while in the latter, a cell starts to burst on its own time scale and inhibits its partner. With Frances Skinner, then of Eve’s group, I explored mutually inhibitory relaxation oscillators. We looked deeper into the mathematics and saw how the mechanisms affect the overall frequency of the network (Skinner et al. 1994). The issue of what controls the frequency of neural oscillators was also a large theme then, studied mostly in connection with small networks (e.g., two cells; Kopell and Ermentrout 2002), and is still open for large networks. In general, everything turned out to be more complicated than it seemed. Other papers showed that excitatory coupling might or might not produce synchronization (Bose et al. 2000). Even gap junction coupling, assumed by almost everyone to be synchronizing, provided some surprises: At least for a pair of cells, the shape of the spike and the after-hyperpolarization helped determine if the cells would synchronize or go into antiphase or something else (Chow and Kopell 2000).

There was also work on networks with larger numbers of cells. John White was a major experimental collaborator I had on issues involving synchronization. John worked on slices of hippocampus using the dynamic clamp invented in the Marder lab; he was interested in theoretical ideas as well as direct experimental verification of such ideas. The first paper we did together, with Carson Chow and students Jason Ritt and Christina SotoTrevino (White et al. 1998) concerned a model of a mildly heterogeneous inhibitory network. Synchrony in wholly inhibitory networks can be very fragile in the absence of gap junctions. This paper showed that the ways in which synchrony can break depends on the parameter regimes, including strong vs. weak drive and long vs. shorter decay time of inhibition. In some regimes, the more strongly driven cells suppress their neighbors while staying coherent with one another; in other regimes, the cells become more free running with respect to their network partners. In a follow-up paper, we looked at frequency control in reduced models and showed that only in the portion of the phase space associated with suppression and coherence of the remaining cells is the frequency of the network determined by the decay time of the inhibition (Chow et al. 1998). This work connected the behavior of the network in the presence of heterogeneity to the mechanisms that control the frequency of the network. Though the paper was analytical and computational, we were able to replot data of Whittington and his group (Whittington et al. 1996) concerning inhibitory gamma rhythms (30–90 Hz) to support our conclusions.

Though both inhibition and gap junctional coupling could provide synchronization, work with Bard on larger networks showed that they do this in different ways (Kopell and Ermentrout 2004). The inhibitory synapses act to eliminate the effects of different initial conditions, whereas the electrical synapses mitigate suppression of firing due to heterogeneity in the network. A single pulse of inhibition to a homogeneous group of cells can synchronize them by preventing them from spiking until the inhibition wears off for all of them. But when there is heterogeneity, a pulse of inhibition will not do that, and even a small amount of electrical coupling can overcome the tendency to become asynchronous.

Just when the community was beginning to get good intuitions about the mechanisms of synchronization in fairly simple cells (caricatures of standard Hodgkin–Huxley equations or relaxation oscillators), it began to be understood that adding nonspiking intrinsic currents to the description of the cells could completely change their synchronization behavior. The currents most associated with this anti-intuitive (given our then-current intuition) behavior were the M-current and h-current, which Eugene Izhikevich calls “resonant currents” for their involvement in some kinds of oscillations. Each of these currents opposes the inputs that give rise to them. An M-current turns on with excitation and then provides a hyperpolarizing current, while the h-current turns on with inhibition and then provides a depolarizing current. With these currents in cells, the effects of inhibition or excitation could be reversed (Crook et al. 1998; Ermentrout et al. 2001; Acker et al. 2003).

A paper with John White’s group (Netoff et al. 2005) and experimental involvement from Matt Banks tested some of these ideas about synchronization, using O-LM cells in the hippocampus, which interact via inhibition, but which have an h-current. Tay Netoff measured both the PRC and the synchronization in hybrid networks associated with one real cell and one cell “in silico.” The synchronization results matched the theory from the PRCs and showed that these O-LM cells would not synchronize with their natural transmitter, GABA, but would synchronize with excitation. The explanation for this behavior came from the above intrinsic currents whose effect could be seen in the PRC. The study produced many insights into synchronization with inhibition or excitation, but they were complex enough that even I got a headache thinking about them. Eventually, the goal of getting a definitive answer to exactly when inhibition or excitation could synchronize was apparently dropped by the community.

Inhibition could not always synchronize inhibitory cells (O-LM) yet those cells participate in rhythms in which they do synchronize; this raises the question of how such synchronization comes about. That was a fairly clear mathematical question, but the intuition for an answer came from looking at the actual physiological networks involving multiple simultaneous rhythms (see Gamma/Theta below). Other questions, such as effects of noise on synchronization, continued to be studied by others, notably Bard (Ermentrout et al. 2008). There was also a cadre of mathematicians, including Steve Strogatz (formerly a postdoc of mine), who were investigating synchronization in more abstract networks of oscillators. Much of the abstract work was done on networks (sometimes called Kuromoto systems) that had special properties allowing the use of various tools for analysis. Unfortunately, many of the results (not just the methods) depended critically on the simplifications; they would disappear with small perturbation to the systems and were therefore not relevant to most applications. Awareness of this phenomenon increased my sensitivity to the issues surrounding making reduced models.

Gamma, Beta, Hippocampus, Traub, and Whittington

In the late 1990s, my perspective started to shift, and I found myself at least as interested in the physiological phenomena as the mathematics problems that they generated. I didn’t stop thinking mathematically, but problems interested me less if I didn’t see the relevance to specific biological networks. This shift was likely associated with two collaborations. One was with John White of the Biomedical Engineering department of BU, the other with Roger Traub and Miles Whittington. In general, the networks I started to focus on were larger, more heterogeneous and altogether more messy. It was clear that pencil and paper were no longer going to be the only—and perhaps not even the primary—tools of the trade.

I had met Roger decades earlier (around 1967) when I was an instructor at MIT, and he did his first and only year of graduate school in math. (He then went to medical school.) He attended a course I taught in differential topology, and for many years into our collaboration (and maybe still), he referred to me as a topologist. It was not until 1997–1998 that we met again at a conference in Minnesota, in the dead of winter in an unusually cold year. This time we connected over biology and modeling, rather than pure math. Roger talked about his work on “doublets” (Traub et al. 1996), a pair of spikes in a fast-spiking (FS) interneuron. Roger had shown experiments and simulations demonstrating that two areas of a hippocampal slice between which there was a conduction delay could synchronize with no phase difference if the interneurons involved in the gamma produced doublets.

Roger has a completely different style of modeling than I do, one I often refer to as “traubian.” He works with extremely large and detailed models, needing supercomputers before the rest of us. This style works for him since he is very careful and self-critical; he wouldn’t believe a result of a simulation until he had tried every way he could think of to break it and failed. With the level of complexity he used, he could reproduce fine details and make very strong predictions. Among them is the still controversial statement that axo-axonic gap junctions among pyramidal cells are critical to the formation of some brain rhythms, including the gamma rhythm (30–90 Hz); Roger has amassed a large amount of evidence in favor of this hypothesis. Later on, I was asked to do a short piece on Roger’s massive model of a thalamocortical column (Traub et al. 2005), and I called it “Does it have to be this complicated?” My answer was that, at least in Roger’s hands, it does, to get the unexpected and game-changing hypotheses that he could produce.

I recall that Roger suggested to me that there might be an interesting mathematical project associated with the doublets. (It was clearly different from any of the other mechanisms for synchrony that Bard and I had investigated.) The obvious question was: How does it work to produce the zero-phase lag? In general, traubian models could reproduce experimental details in ways that were impossible for more pared-down models. However, the downside of this ability was that the great complexity of the models made it very hard to understand how the model did what it did. I felt commissioned to try to find out how doublets produce synchronization, and recruited Bard to help me with it. The model we came up with was simple and surprising (Ermentrout and Kopell 1998). We considered a pair of E/I circuits, connected with conduction delays; each cell was described by a basic Hodgkin–Huxley model, but the actual analysis abstracted the details of the voltage and gating variables to times of cells firing. A doublet was the consequence of the inhibitory cells getting excitation from both its own pair and the other pair; because of the conduction delay, the inputs are separated. We calculated the timing of the spikes of the cells of both pairs, and how they influenced one another, and showed that if the E-cells start off unsynchronized, it affected the timing within the doublets, which then pushed the pair toward stable synchrony. I liked that paper because it showed how thinking conceptually could provide insight into very messy simulations. I was also involved in a paper (Fuchs et al. 2001) from Hannah Monyer’s group, which used genetically engineered mice to break the doublets and destroy synchrony. The model had predicted that the time course of the AMPAmediated excitation onto inhibitory cells had to be significantly faster than that of the decay of inhibition. Fuchs and colleagues slowed down this excitation in mutant mice; though the gamma oscillations remained, the synchrony among distant areas was disrupted.

Roger introduced me to Miles, who was his closest experimental collaborator; they had a long-standing collaboration relating to work on epilepsy. Later, when I did work with Miles without Roger, I experienced this as an act of great generosity by Roger: When Miles worked with me, he had less time for Roger. But there were lots papers that we did together, along with various collaborators. The first papers, including the doublets paper, were all set in the hippocampus. Miles was focusing there because, around that time, that’s where the action was in brain rhythms (though mostly about theta, which is still true for most hippocampal researchers). Miles had been heavily influenced by some of the Hungarian researchers who had/have cornered much of the important field of interneuron research, especially in the hippocampus. Notably, Gyorgy Buzsaki, with collaborators such as Csicsvari, had seeded the interest of many people in hippocampal rhythms in the mid-1980s. Miles was partnering with Eberhard Buhl (who died tragically of a chronic disease in 2003 at the age of 43) to do in vitro physiology of hippocampal slices; together they pioneered methodology to make slices behave like in vivo rhythms under a variety of different modulatory conditions. Miles told me that his partial pivot from epilepsy to brain rhythms dates to a talk he heard from Rudolfo Llinas in the early 1990s on sleep rhythms; he and Roger Traub each was reminded of data (experimental and unrelated simulations) which had the signature of gamma oscillations, leading to their famous 1995 Nature paper with John Jefferys on gamma in interneuronal networks (Whittington et al. 1995), which came to be called ING (interneuronal network gamma).

Miles and Roger, with other collaborators, together produced and simulated multiple different rhythms. In another seminal paper (Traub et al. 1996), they investigated gamma rhythms in networks for which the excitatory to inhibitory connections were intact (unlike the 1995 paper), and they originated what has come to be called pyramidal interneuron network gamma (PING). In addition to the hippocampal gamma rhythm, they discovered a rhythm in the beta frequency range that we came to call “beatskipping beta”: There was an underlying gamma rhythm, sustained by the FS interneurons, but pyramidal cells fired on every other cycle, and more cells fired in one cycle than the other (Traub et al. 1999). The beta rhythm made use of slow potassium conductances, and this was not just a sloweddown version of gamma. One of the first papers I did with Miles and Roger concerned the different synchronization properties of gamma rhythms and beta rhythms, building on the doublet ideas in both the massive simulations and simplified models. As we were to find out later, there are many (!) different mechanisms that produce beta rhythms (12–30 Hz). In the hippocampal beta, the doublets work predicted that the conduction delay must be bounded (e.g., by 8–10 ms) for the doublets mechanism to work. The new work, with Bard (Kopell et al. 2000), used that paradigm to show why the slower rhythm could tolerate longer conduction delays and still produce synchrony. Though the work was motivated by the hippocampal beta, our aim was to suggest why beta oscillations would be good for synchronization between regions of the neocortex. I still believe the title of that paper (“Gamma Rhythms and Beta Rhythms Have Different Synchronization Properties”), but the methods by which this happens in the neocortex now seem unlikely to be the same as in a hippocampal slice. This gang, along with Eberhard Buhl, also did a review paper on inhibition-based rhythms, including gamma and this beta (Whittington et al. 2000).

Roger continued to expand my synchronization horizons by producing examples of phenomena that challenged my intuitions. In a complex model of interneuron gamma synchrony (Traub et al. 2001), he showed that gap junctions were important for synchrony in spatially distributed networks; experimental support for this work had come from Gabor Tamas. That gap junctions should enable synchrony was not surprising; the surprising thing was that the gap junctions could be very local and still create global synchrony across a chain; this was a very different mechanism from the previous work Bard and I had done on chains of oscillators. I didn’t do any of the modeling in that, but I earned my authorship by musing on mechanisms that then enabled Roger to make his simulations work.

The experimental hippocampal slice work of Whittington inspired me about other questions as well. After we had shown that gamma and beta rhythms have different synchronization properties, I started thinking about gamma, beta, and cell assemblies, with postdoc Mette Olufsen. The first part of our work (Olufsen et al. 2003) looked at gamma and cell assemblies, and showed that the physiological properties of gamma (feedback inhibition, time scale determined by the decay time of inhibition), was perfect for creating cell assemblies and protecting those assemblies against distractors (whose inputs go to cells that are inhibited via lateral inhibition.) We then looked at what happens to cell assemblies in the transition from the gamma to the beat-skipping beta, which involves a decay of excitation and an activation of a slow outward potassium current. The modeling predicted that Hebbian changes of connections among pyramidal cells occurring during the gamma rhythm help to give rise to the beta rhythm. Furthermore, two different inputs at different strengths could now create cell assemblies that fire at different times in the beta cycles (on different cycles of the underlying gamma rhythm). This was a very strong prediction, and one that Miles was able to check: By using tiny excitatory inputs to areas of a hippocampal slice close enough to share a set of interneurons, he was able to confirm the surprising prediction. We thus had a mechanism that turned a difference in magnitude in inputs into a discrete temporal difference.

In this work, as in much of the other work I’ve done, I was swimming against the tide (or maybe just “a” tide): The experimental work was in vitro and members of the in vivo community often discount in vitro work. Though Miles and Roger have discussed in detail why in vivo rhythms share the properties of in vitro ones (Traub et al. 1999; Traub and Whittington 2010), some members of the community continue to focus more on the undeniable differences (e.g., there are many more connections in vivo and therefore far more inputs without pharmacological intervention). The devaluation of in vitro work is a significant problem for modelers trying to connect physiology to behavior, since biophysical modeling requires a level of detail that is rarely obtainable from in vivo work. For example, it has become very clear from in vitro work that different rhythms can be associated with different layers (more below); but primate physiologists have been reluctant to accept that because it has been so difficult to be sure of layer information. Now that electrodes with the ability to measure at multiple layers are in more widespread use, there may be less reluctance to accept the insights that have come out of the in vitro work about the differences in physiology of the different layers (as well as different regions of the brain) and potential functional implications (more below). The most important lessons I’ve learned from the in vitro work concern how to think about the effects of signals to local regions of the brain. There is unavoidable complexity in physiology, anatomy, and the effects of neuromodulation, much of which cannot be ignored in trying to understand how incoming signals are processed. I now try to form collaborations that involve multiple experimentalists covering both in vivo and in vitro recordings.

Of course, another opposing tide has been the opposition to the idea that brain rhythms are anything more than the “exhaust fumes” of cognition. As one of the pioneers in the study of rhythms, Charlie Gray has been especially eloquent about the challenges of working in such an intellectual environment. For me, the experience of hearing such strong and (to my mind) unsupported convictions about the irrelevance of rhythms has helped to strengthen my own resolve to pay more attention to evidence and less to fashionable currents of thought. Also, there has been and continues to be very distinguished work on both oscillators and/or in vitro preparations, so there are allies.

A Deeper Look at Gamma Rhythms

By the early 2000s, I had written many papers related to gamma rhythms. But questions about the mechanisms of gamma kept coming up. At its simplest, PING rhythms are interactions of excitatory and inhibitory cells, in which the decay time of the inhibition plus the excitability of the pyramidal cells determine the period: The excitatory cells fire and make the inhibitory cells fire; the E-cells fire again when the inhibition wears off sufficiently. But for networks having large number of cells, the circumstances under which the cells would self-organize into a rhythm, or be asynchronous, or display other dynamical behavior, was not well understood.

Parallel to the time I was working with Miles and Roger, I also started collaborating with Christoph Borgers, a mathematician interested in brain dynamics. From 2003 through 2008, we had a series of paper addressing basic properties of this rhythm and potential functional implications. The papers were influenced by the work of Roger and Miles, but also by the growing impact of the papers of Wolf Singer, including the first major paper on gamma in the neocortex with Charlie Gray in 1989 (Gray et al. 1989). Those papers hypothesized that the gamma rhythm was important for “binding” the activity of local neurons; among other consequences, such binding would make downstream effects stronger via synchronizing the input to neurons. Among the open questions was why gamma, as opposed to any other rhythm, should be associated with binding. Another major influence was the work of Bob Desimone and collaborators (especially, at that time, John Reynolds) on gamma rhythms and attention (Reynolds et al. 1999).

Our first papers addressed aspects of how a network of excitatory and inhibitory cells could synchronize, especially if the number of connections from I- to E-cells or E- to I-cells was sparse. There had previously been substantial work about oscillations in networks of excitatory and inhibitory cells, including the work of Walter Freeman in the 1970s and spikerate models, such as the Wilson Cowan model of 1972. None of the previous models took into account the specific physiological properties of the PING gamma rhythms. We used a network of simplified “theta” model (no connection to the theta rhythm) that Bard and I had invented to see what was needed in the way of connectivity. Our main conclusion was that the connectivity could be very sparse and still get synchrony, and we explained how this worked (Borgers and Kopell 2003). A later paper (Borgers and Kopell 2005) extended our modeling to networks with noisy drive. One question was why the synchronization mechanism of the gamma rhythms, involving feedback inhibition, seemed to work well mostly in the gamma range, since it was possible to get much higher or lower frequencies in a small network of one E- and one I-cell. We looked computationally and analytically at where synchronization failed, especially when there was noise. Although each of the cells could fire at almost any frequency, the E/I network synchronized only in the gamma range, justifying the “G” in PING. The period was determined by the decay time of the inhibition; the same mechanism could produce a slower rhythm if the inhibition had a slower decay (e.g., if it was mediated by dendrite targeting interneurons such as low-threshold spike [LTS] cells.)

We then started considering gamma in the context of cognition, especially attention, partly with Steve Epstein. Here the focus was on a different variation of gamma, called “background gamma,” “sparse gamma,” or “noise-driven gamma.” In this rhythm, the pyramidal cells fire at a rate much lower than that of the population; the inhibitory cells fire close to the population rate. Noise is essential for this kind of gamma: Tonic excitation is not enough to push the pyramidal cells over threshold, even when the inhibition is at its lowest, but noise at the right phases can do so. Our model was a seriously simplified version of a model introduced by Roger Traub (Traub et al. 2005) to account for this kind of gamma rhythm in superficial cortical layers: In Roger’s version, the noise comes from ectopic spikes in pyramidal axons, spread around by axo-axonic gap junctions; in ours, the noise is put in by hand. In this and another paper, we asked what attention was doing physiologically that could be important cognitively. In another paper (Borgers et al. 2005), we focused on inputs to networks that were either asynchronous or displayed a background gamma rhythm. We showed that the transition to rhythmicity within the target network could happen by cholinergic modulation (associated with attention) by reducing the outward M-currents in principal cells; such rhythms accompany states of preparatory attention or vigilance. Furthermore, when the target network is rhythmic, the inhibition is concentrated in some windows, leaving other windows in which weak signals could have an effect on the target, allowing detection of weaker signals in the presence of gamma rhythms than otherwise. Experimental confirmation of this idea came from recent work of Siegle and colleagues (2014).

There are other versions of sparse gamma that make use of adaptation currents, such as the M-current or the closely related hyperpolarizationactivated inward h-current (Kopell and LeMasson 1994; Kilpatrick and Ermentrout 2011). Kopell and LeMasson (1994) may have been the first paper to note that the gamma rhythms enable “windows of opportunity” for excitatory cells to fire. It’s still not well understood in what ways this version of low-firing rate gamma differs from noise-driven gamma, and how it might contribute to attention or other cognitively important states.

I recall (perhaps falsely), that in the mid-2000s, Wolf backed off from saying there was anything special about gamma, and what was really important was synchrony. I disagreed: Our gang thought that gamma was special because its specific physiological bases gave it functionally important properties. Christoph, Steve and I continued to think about the relevance of gamma papers to attention (Borgers et al. 2008), inspired by work of Desimone and colleagues. Reynolds and colleagues (1999) had found that simultaneous presentation of multiple stimuli can reduce the firing rates of neurons in extrastriate visual cortex below the rate elicited by a single preferred stimulus, an effect that was corrected by attention. Our simulations showed how this effect may arise from strong excitatory drive to a substantial local population of FS inhibitory interneurons. With enough drive, the FS cells are excited enough to spike by themselves, without direction from the pyramidal cells; this can lead to a loss of coherence in that population, which in turn can be shown to raise the effectiveness of inhibition. We proposed that, in attentional states, FS interneurons may be subject to a bath of inhibition resulting from cholinergic activation of a second class of inhibitory interneurons (such as LTS cells), restoring conditions needed for gamma rhythmicity. The cholinergic modulation of other classes of interneurons became a theme that I used for later work on attention with Jung Lee (discussed below). Christoph, Steve, and I also showed that, in the context of the gamma in the target network, more input to one subset of pyramidal cells leads that subset to take over control of interneurons and suppress cells reacting to other inputs via lateral inhibition. Although lateral inhibition works in the absence of gamma rhythmicity, simulations showed that the ambient rhythms significantly increased its efficiency. One main point that I cite over and over is that, in a network displaying this kind of gamma, as long as cells share the same interneurons, multiple inputs will produce a winner-take-all outcome of a single assembly. That result is special to gamma, and later work (Kopell et al. 2011) showed a different result for one kind of beta rhythm (15 Hz in slice) because of different underlying physiology.

The final paper in that series (Borgers and Kopell 2008) focused on the rhythmicity of the input rather than the state of the target. More coherent excitatory stimuli were known to have a competitive advantage over less coherent ones (Singer 1999). We showed that this advantage is amplified greatly when the target includes inhibitory interneurons acting via GABAareceptor-mediated synapses and the coherent input oscillates at gamma frequency: A coherent input oscillating at gamma frequency can be highly effective at preventing less coherent competing inputs from being noticed when the target network includes inhibitory interneurons acting via GABAareceptor-mediated synapses. Two factors contribute to this effect. First, inhibition in effect raises the leakiness of the target neurons, thereby greatly amplifying the known advantage of a more coherent excitatory input over a less coherent competitor. A highly coherent stimulus can break through the inhibition generated in the target network, while less coherent competitors cannot. Second, when a gamma frequency train of excitatory input pulses entrains a target network of excitatory and inhibitory model neurons, the timing of the inhibitory spike volleys in the target favors that train over any competing pulse train that has a different frequency or phase. That paper inspired work of Pascal Fries (Bosman et al. 2012) that corroborated our ideas. In an earlier paper (Borgers et al. 2008), we had proposed a different way in which gamma rhythmicity may play a role in stimulus selection; there we showed that gamma rhythmicity helps a strongly driven assembly suppress activity in a less strongly driven one if the two assemblies share a single interneuron network. Thus, the competition was between two assemblies in Borgers and colleagues (2008), whereas in Borgers and Kopell (2008), the competition was between two stimuli competing for control over a single assembly. Combinations of the two scenarios are possible and plausible; for instance, two different stimuli might drive two different but overlapping assemblies within a larger network. Paul Tiesinga, David Golomb, and David Hansel were doing related work around that time, and I recall closely studying their papers to see how our ideas overlapped or were complementary.

More recently, Christoph and I used the insights of our 2008 papers to think about sizes of cell assemblies in the neocortex. The work came out of a collaboration with Ed Boyden and his student Giovanni Talei Franzesi. The experiments concerned optogenetic manipulation of slices to form cell assemblies. We were especially interested in weak (sparse or noise driven) gamma vs. strong gamma. An experimental observation that surprised us was that low-power optogenetic stimulation of pyramidal cells lowers gamma power, while high-power stimulation raises it. Our guess was that low-power stimulation excites too small a number of pyramidal cells to generate strong gamma, but on the other hand disrupts background weak gamma. That led us to do modeling on whether there needs to be a minimum number of pyramidal cells (depending on other parameters) receiving drive for them to form a cell assembly displaying gamma (Borgers et al. 2012). We showed that, when the number of cells is too small, the synaptic interactions may not be strong or homogeneous enough to support the mechanisms we had previously described underlying the rhythm, especially when there is heterogeneity in the synaptic strengths. Furthermore, when there is heterogeneity, the model showed that the synchronization could not happen over many cycles (as is often the case with networks of oscillators); because of the mathematical structure associated with feedback inhibition, they were forced to synchronize in a cycle or two or not at all. The work explained aspects of the optogenetic recordings and also gave reasons why attention experiments in monkeys with very focused stimuli do not give rise to added gamma power (Chalk et al. 2010). Ed’s technological inventions were also the inspiration for other work with Christoph, Giovanni and Annabelle Singer on gamma oscillations; in current work, we are using Ed’s robo-patcher to do intracellular recordings in awake behaving rodents, and finding surprises about the relationship of single cell spiking to LFPs.

Gamma and Theta, Mostly Hippocampus

John White got me interested in networks that were much more complex than pairs of cells. Some work involving networks with multiple different kinds of interneurons had been done by Matt Banks and Bob Pearce (Banks et al. 1998), who showed that there were (at least) two classes of interneurons in hippocampal slices that mediate GABAa inhibition with two different time scales: fast (the usual, around 8 ms) and slow (around 50 ms). With John, Matt and Bob, I wrote a paper about a much more complex network that had multiple time scales associated with both gamma and theta (4–12 Hz) rhythms (White et al. 2000). The motivation was to understand more about the interaction of these rhythms, as often observed by multiple experimental groups, notably Buzsaki and his collaborators and students. In particular, we were interested in the different roles of intrinsic rhythms within the hippocampus vs. effects of input from extrinsic sources such as the septum, especially since the cells in the septum did not necessarily fire on the same phase. There was a very surprising result in our simulations, which used the fast inhibition to get a gamma rhythm (ING) and the slow one to mediate the theta time scale. The very surprising result concerned phase-dispersed external drive at theta frequencies to either class of interneurons; that is, different cells got input at different phases. The simulations showed that, under a broader range of conditions, including heterogeneity in drive, the networks can amplify and resynchronize phasic responses to the external drive. I was involved in doing the project, but I never really understood how that happened until a graduate student of mine (Amanda Serenevy) started to study a much simpler version that had only one class of interneurons with a theta time scale but still had phase dispersed input to a large collection of cells. She was able to prove (Serenevy and Kopell 2013) that the phase dispersion could sometimes lead to a more powerful gamma than synchronous input, and could allow a larger range of input frequencies to entrain the target network. The main idea is that the period of the drive has to be close to that of the target, and the more cells participate, the more inhibition there is and the slower the rhythms of the target network. Heterogeneity in the phase of the drive can enable the target network to dynamically select the appropriate number of neurons for participation in spiking episodes, thereby creating the right amount of inhibition in the network to facilitate locking to the period of the drive. This didn’t account for all the results in the White et al. paper, but it made me a lot more comfortable with the earlier simulations.

John had another big influence in my life: especially in the first half of my career, I was highly reactive to adverse outcomes (e.g., rejected papers and grant proposals). John was far more laid-back, and I took him as my role model in learning how to roll with the punches. Of course, it helped to learn more about grantsmanship in neuroscience and how to frame papers to be attractive to audiences.

I was also influenced by work done in the Whittington lab by Martin Gillies (Gillies et al. 2002) on atropine-resistant theta in the hippocampus. Roger had done a traubian model of experimental results in which theta was produced in response to metabotropic glutamate receptor activation under conditions of reduced AMPA receptor activation. This had far more biophysical detail than anything I was considering. It led John and me to work with Miles and others to understand in our simpler terms what was going on to produce the rhythmicity. In a paper by Horacio Rotstein (Rotstein et al. 2005), we looked at networks of O-LM cells (which produce the slower GABAa-mediated inhibition) and FS cells (no AMPAergic excitation, as in Gillies et al. 2002). Earlier work (above) had suggested that individual O-LM cells, by themselves, are capable of producing a single-cell theta-frequency firing, but coupled O-LM cells are not capable of producing a coherent population theta. By including in the model FS interneurons, which give rise to inhibitory post-synaptic potentials (IPSPs) that decay faster than those of the O-LM cells, coherent theta rhythms are produced. Reciprocal connections from the O-LM cells to the FS cells serve to parse the FS cell firing into theta bursts, which then can synchronize the O-LM cells. The model reproduces relative phases of theta frequency activity in O-LM and FS cells in the Gillies data, and the hyperpolarization-activated h-current in the O-LM cells is critical to the synchronization mechanisms. The interaction between the h-current and inhibition is at the heart of rebound from inhibition and has turned up in multiple later papers (McCarthy et al. 2006; McCarthy and Kopell 2012). The Rotstein et al. (2005) paper answered questions about how cells that don’t synchronize with their natural transmitters can synchronize when other kinds of cells are in the network. In related work (Pervouchine et al. 2006), Dmitri Pervouchine showed how excitatory entorinal cortex (EC) stellate cells, which synchronize with excitation, can desynchronize in the presence of other cells types, such as FS cells.

The paper on gamma and theta that I most like to cite was done with Tengis Gloveli (Gloveli et al. 2005). I think it was Tengis who initiated this collaboration, perhaps with some encouragement from Roger and Miles, who were also involved. This was a hippocampal in vitro paper, in which the slices were cut in multiple ways: the usual transverse way (which I describe as slicing a banana for breakfast), the longitudinal way (bananas Foster), and a coronal section (Chinese stir fry). With exactly the same fluid bathing the slices, the rhythms that appeared depended on the angle of the cut. The transverse one produced gamma rhythms, the longitudinal slices produce theta rhythms, and the coronal slices produced gamma-nested theta rhythms. How could this happen? This was clearly a modeling problem, and Horacio Rotstein and I addressed it. At first, it seemed as if it was important to make a very large three-dimensional model that could accommodate the ability to make slices through the network. However, Horacio and I realized that the central issue was not the geometry per se but which connections were preserved by the various cuts. We made a relatively simple model with only two of each kind of cell (FS, O-LM and pyramidal), and modeled the slices as cutting some connections and preserving others. With strong connections among the pyramidal and FS cells as occurs in the transverse slice, we got gamma; when the connections from the O-LM cells were relatively strengthened, as happened in the longitudinal slice, the network switched to a theta. And intermediate parameters produced the nesting. A central new understanding was that which rhythms manifested depended on which cells controlled the activity of the FS cells. This understanding has shaped other work of mine on interacting rhythms.

A follow-up modeling paper (Tort et al. 2007) considered the interaction of gamma and theta in large networks. We were attempting to understand how the existence of the theta rhythm in a network could affect synchronization among cell assemblies that formed with the help of gamma (see above). This time the network was much larger, with lots of pyramidal cells, so we could look at cell assemblies. The modeling showed that the slower theta rhythm was able to coordinate assemblies that were displaying gamma. There could be coordination even if the members of separate assemblies had no connections to one another and were connected only via O-LM cells. An underlying idea, that coordination can be done by periodic reset at a slower frequency, has been very valuable in thinking about other situations and rhythms.

Now that our group was more comfortable with large and complex models, we did other gamma/theta models as well. A previous model by Hasselmo and colleagues (2002) suggested that some fundamental tasks are better accomplished if memories are encoded and recovered in the hippocampus during different parts of the theta cycle. This model was very influential and insightful, but it was less tightly tied to biophysics than I would have liked. So Mike, postdoc Steve Kunec, and I decided to try a more downand-dirty model to make specific suggestions about the underlying circuitry from the physiological data that Mike had acquired. We were able to suggest networks, including pyramidal cells, FS and O-LM cells, inputs from the septum, dentate, and entorhinal cortex, that could perform the separation (Kunec et al. 2005). At the time, I was still giving lots of talks to mathematical audiences, but I was trying to give them a flavor for what real physiological networks were like, and what kinds of questions and challenges they posed. It was hopeless to try to explain this model, so I flashed it up in one slide, with the take-home message that real physiology could be very complicated.

Frances Skinner made things more complicated with different physiological models of the hippocampal O-LM cells, making use of still more biophysics than we had (Saraga et al. 2003), and followed up related results in a series of papers. I made a stab at simplifying things in the context of understanding why frequencies of theta and nested gamma oscillations tend to change together (Malerba and Kopell 2013). Working on both small abstract models and large detailed ones was one reaction to the tension between abstraction and a more fleshed out description of the world. With my theta/gamma collaborators, I tried to review what I knew by the end of 2000s about this interaction (Kopell et al. 2010).

Sleep and Anesthesia: Work with Emery Brown

I have met a substantial number of collaborators and potential collaborators at conferences. One such collaboration that has stuck over more than a decade was with Emery Brown, who is both a PhD statistician and a cardcarrying working MD anesthesiologist. We got to talking at a conference in Pucon, Chile, in 2002 on computational neuroscience. (Emery remembers that we walked around in fields full of large steers protective of their space; I remember evening drinks and intense conversation). At that time, Emery’s research was mainly on statistics, rather than anesthesia, but he was interested in starting research on anesthesia. We know that anesthesia changes brain rhythms, and I was hooked; we decided to collaborate.

Shortly thereafter, two people who were excellent candidates for carrying out joint work arrived at my lab. Cecilia Diniz Behn had a master’s degree in (pure) mathematics, but a strong interest in applied math, and we started her on sleep circuits. The motivation was to understand the effects of dexmedetomidine, an anesthetic that works through sleep pathways. In the end, there was a lot to learn and work on just focusing on normal sleep, and our collaboration hadn’t gotten back to dex until the last year. The second person was Michelle McCarthy, an MD PhD student who had completed her MD work and wanted to do her PhD in applied math. For various personal and professional reasons, it was decided by her UCLA department to ship Michelle east and have her work with Emery, who asked me to participate. Of course I was delighted. Michelle worked on GABAa circuits, with propofol as the prototype. For the next four years, we met almost every Wednesday at BU. After that, Emery moved from the Martinos Center for Biomedical Imaging (a less accessible place) to MIT, and I became the commuter, though our meetings were less often by then.

Cecilia’s work was to understand what controls switches between sleep and wake, focusing on the mouse, which has multiple such switches during each day, including brief awakenings as well as sustained sleep. When we started, I did not know anything about sleep (or anesthesia), but I did know a lot about relaxation oscillators, and our first go at this problem considered the network as coupled relaxation oscillators. The previous models of deep/slow wave sleep had not considered the microstructure represented by the brief awakenings, which were often just considered noise. However, to get at that microstructure, we needed detailed information about many parts of the sleep network. By classifying various structures as sleep active, wake active and REM active, and using knowledge about anatomical connectivity of these structures, she was able to reproduce the microstructure (Behn et al. 2007). This, along with statistical analyses that she did, earned her a prize for the best thesis that year about circadian rhythms. Emery and I were off to a good start! (And so was Cecilia, who became an expert on circadian rhythms, later getting deeply involved in the underlying physiology and doing a postdoc with Beth Klerman and Tom Scammell.)

Michelle arrived about the same time as Cecilia, and worked on a phenomenon known as “paradoxical excitation”: With low doses of the much-used anesthetic propofol, the subject is often excited rather than sedated, in a manner similar to someone who is drunk with alcohol. One important physiological correlate of paradoxical excitation was an increase in power in a broad range of beta frequencies (12–20 Hz). Michelle’s project was to understand what it was about propofol that caused the increase in beta power. It took another decade (current work) until we began to understand why the increased beta rhythms might cause the motor disorientation associated with this phenomenon.

Michelle and Cecilia were the first of my students to work on projects that required them to do detailed and broad biological literature searches. As an MD–PhD student, Michelle was in a good position to do this for propofol. She determined that, though propofol is a “dirty” drug, at least at physiologically relevant doses, the main effect was on the kinetics and size of synaptic inhibition: Propofol increased both the amplitude and duration of IPSPs. Our question then was: could those physiological effects cause the increase in power in the beta frequency band? Michelle’s modeling suggested that the beta power might arise from a membrane level interaction between the GABAa current and an intrinsic membrane slow potassium current (M-current). In a multicellular network, this interaction can enable a switch from baseline interneuron synchrony to propofol-induced interneuron antisynchrony (McCarthy et al. 2008). In later work, Michelle dissected the mathematical mechanism by which this can happen (McCarthy and Kopell 2012). Importantly, this mechanism for beta gave Michelle a very original idea about the origin of pathological beta in Parkinson’s disease, an idea that opened up an entirely new line of research in my group, with new collaborators (more below).

As the dose of propofol is increased, a subject experiences changes in brain rhythms associated with the degree of anesthesia (Brown et al. 2011). Emery and I worked systematically through these different levels with a succession of trainees. Loss of consciousness is associated with the onset of the alpha rhythm (9–11 Hz), coexistent with a slow oscillation (1–4 Hz or even slower). ShiNung Ching, our next joint trainee, was delegated to figure out how this level of anesthesia, associated with a larger change in inhibitory kinetics, could lead to such changes in brain rhythms. ShiNung had a background in control theory, rather than neuroscience or dynamical systems, but got into the project very quickly. He created models of thalamocortical networks, using a longer decay time for the inhibition (in both structures) than in Michelle’s work. He found that the lengthening of the time scale did two things that worked together to produce a pathological alpha rhythm: It slowed down the rhythms in the cortex, and it enhanced and lengthened bouts of spindling in the thalamus via inhibitory rebound (Ching et al. 2010). The two effects together led to a pathologically ongoing alpha activity that locked the activity of the cortex. This suggested that, rather than shutting down activity, the propofol was creating activity that was dysfunctional for normal cognitive activities. This suggestion, which was later confirmed experimentally, led to the overall hypothesis of our collaboration: Changes in brain rhythms due to physiological changes by anesthetics alter the interaction of regions (and the dynamics within a region) in such a way as to prevent normal cognition. There is now a hotbed of experimental and computational activity in Emery’s universe aimed at understanding the effects of multiple different kinds of anesthetics from the point of view of our system-level hypothesis. This point of view, which focuses on pathologies in brain rhythms, is relevant to a variety of neurological diseases (Cannon et al. 2014; Pittman-Polletta et al. 2015).

ShiNung also looked at still higher doses of propofol, which produce so-called “burst suppression,” in which neural activity is flat-lined in between bursts of activity. The effects of the higher dose are similar to those found in the context of other conditions, such as hypothermia and coma. With Emery, we proposed a unifying mechanism for burst suppression that accounts for all of these conditions, suggesting how the features of burst suppression may arise through the interaction between neuronal dynamics and brain metabolism, including ATP-gated potassium channels (Ching et al. 2012). ShiNung went on, with Emery and others, to get a closedloop control system for delivering anesthetics in such a way as to prevent excessive burst suppression in an ICU setting, when some deliberate burst suppression is desired (Ching et al. 2013). For his work, he was awarded a prestigious career grant from the Burroughs Wellcome Fund (BWF).

It seems to me that almost everything I’ve done or thought about turns up as relevant in some other project. (I recall Sidney Coleman, a friend and famous physicist, once remarking that his big breakthrough on some project was remembering something he had done decades before.) In this case, the other relevant project was with Sujith Vijayan, who was working with me on alpha oscillations associated with the awake state, rather than the spindling of falling asleep or the alpha in loss of consciousness. Using work of M. L. Lorincz, S. W. Hughes, and V. Crunelli (Lorincz et al. 2008), Sujith created a model of awake alpha. ShiNung and Sujith then worked together to explain the classic and not understood phenomenon of “anteriorization,” in which the normal alpha in the occipital cortex disappears and a frontal alpha rhythm emerges. They showed that anteriorization can be understood as a differential effect of anesthetic drugs on thalamic nuclei with disparate spatial projections, i.e., the drugs disrupt the normal, depolarized alpha in posterior-projecting thalamic nuclei while they engage a new, hyperpolarized alpha in frontothalamic nuclei (Vijayan et al. 2013). Thus, the modeling work on awake-state alpha was able to give insight into detailed phenomenology of anesthesia. Sujith was also able to use this model to understand sleep disorders related to fibromyalgia, specifically the injection of episodes of alpha rhythm during periods of slow wave (deep) sleep (Vijayan et al. 2015). Ironically, he had just started working on fibromyalgia when I was diagnosed with chronic fatigue syndrome (see below), a closely related disorder.

Among the most useful translational things done so far by our group was the work of Patrick Purdon (Purdon et al. 2013) concerning EEG signatures of loss and recovery of consciousness under propofol. This followed up on earlier work showing that loss of consciousness (LOC) is associated with the onset of alpha and slow rhythms. Patrick and gang showed that the faster alpha rhythm nests inside the delta rhythm (in the same way that gamma nests inside theta rhythms in the hippocampus). What was surprising, and extremely useful, was the observation that the way in which the alpha nests in the slow rhythm depends on the level of anesthesia: Near LOC, the alpha is found in the trough of the slow rhythm, while in deep anesthesia, it is at the peak of the slow rhythm. This gives a way to measure, online during an operation, how deep is the level of anesthesia. Since an overdose of anesthesia can lead to major postsurgical problems, especially for elderly patients, accurate measurement of the affects of anesthesia is an important clinical problem. The paradigm of Purdon and colleagues, which gives a much better way than previous methods for monitoring appropriate dosage, is currently being used clinically at Massachusetts General Hospital. Current modeling work is analyzing how the trough-peak switch comes about, with the possibility of being able to manipulate effects of the anesthetics. Emery’s gang, which includes many experimentalists, is now also investigating other kinds of anesthesia, including ketamine, dex, and inhalation anesthetics (e.g., sevoflurane). They appear to have different underlying mechanisms and to change brain rhythms in different ways; all, we believe, disrupt normal interactions of regions of the brain. Lots to figure out!

Parkinson’s Disease and Beta Oscillations

It was Michelle McCarthy who got me interested in PD, which is now a major part of the work of my group. After she had done the work with Emery on paradoxical excitation and beta rhythms under propofol, she had the idea that the beta oscillations in PD associated with inability to initiate movement might come about from similar mechanisms. I was skeptical. I already knew of many mechanisms for producing rhythms in the beta frequency band (more below) and didn’t see why the parkinsonian beta should have any relationship to any of the ones I already knew about. But Michelle was ahead of me; she had carefully read a huge amount of the literature about PD and had an argument: The central idea came from the fact that levels of dopamine and acetylcholine often move in opposite directions. Thus, when dopamine levels drop due to losses of dopamine-producing cells, the level of cholinergic tone can increase. (Indeed, therapy with cholinergic antagonists predated dopamine therapy.) In the modeling of the beta due to propofol, the beta frequency rhythms come from an interaction of the inhibition and the M-current, an intrinsic current that is lowered in the presence of cholinergic muscarinic agonists. Michelle started with a model of a network of the main type of striatal cells, the medium spiny neurons (MSNs), in a “normal” state in which the spiking rate was low and beta power was very low. By adding acetylcholine agonists (modeled as reducing the M-current), the firing rate went up and so did the beta power. Mechanistically, this formed a beta rhythm with antiphase behavior of the MSNs as in the propofol model.

The relationship of theory/computation and experiment is very chicken and egg. In many cases, computation comes after some experiments to explain the details of what happened in that experiment. In other cases, as in this one, the theory is motivated by a largish body of previous work, and there may be no initial experimental component. I sometimes think of those papers as bait: The hope (sometimes realized, sometimes not) is that the paper will get some experimentalist to sniff around and decide that it would really be interesting to follow the ideas. In the PD case, we were extremely lucky. We happened to talk with Xue Han, who was then a postdoc in the lab of Ed Boyden at MIT and working also with Bob Desimone. She said it would be easy (for her!) to design an experiment to look for the beta oscillations in the striatum by injecting carbachol, a cholinergic agonist, while using controls to make sure the carbachol was localized there. The very first mouse was a success, with results obvious even without statistics! The recordings from the mouse showed bouts of beautiful beta oscillations interrupted by artifacts associated with trembling (though not at the PD tremor rate). The rest of the mice followed suit, and we had our first paper (McCarthy et al. 2011).

The question of where the parkinsonian beta originates is a complicated one, since the beta oscillation traverses the entire basal ganglia loop. Our suggestion that the striatum might be a central player was controversial from the start. Indeed, the first few experimentalists that we approached were not interested in testing Michelle’s model, because they didn’t think it could be right (a very good reason for not spending time on something!). There were several good reasons for this skepticism. One is that the striatum is almost completely inert as a slice; it is hard to make it do anything. Even in vivo, the firing rate is low in normal animals, far from the beta frequencies (there is evidence that it is significantly higher in a parkinsonian animal). Another is that the cells of the striatum are almost completely inhibitory, even the MSNs, the projection neurons. Though there is precedent for completely inhibitory rhythms (e.g., ING), for some, this made a striatal beta less plausible. Finally, there were other candidates for the origin of PD beta that seemed more plausible to others. One such is the motor cortex, which can produce beta rhythms in slice (Yamawaki et al. 2008), and which projects to the striatum (more or less everything projects to the striatum). The second is a pair of structures in the so-called indirect pathway, the subthalamic nucleus (STN) and external globus palladus (GPe). In vitro, the STN-GPe pair can produce oscillations (Plenz and Kitai 1999), though the published experiments did not show them at a beta frequency. There were well-established computational models of the oscillations (Terman et al. 2002) showing that STN-GPE could, with various parameter tweaks, produce a beta frequency oscillation. We found the striatal model more plausible because the striatum is among the first places to lose dopaminergic tone when dopamine cells are destroyed, because cholinergic agonists were a form of treatment before current dopaminergic treatments, and because we had a clear mechanistic account of where the beta was coming from that was tied to PD changes.

I expected that our experimental paper would have a large impact on the PD modeling community (it has had an effect on some of the experimental community, including surgeons). It was (but perhaps shouldn’t be) surprising to me how strong a pushback we got. By this point in my career, I’m good at thinking for myself, listening hard to what others are saying so I can learn from it, but not swayed by either numbers or another’s force of conviction. I don’t find convincing any arguments I’ve heard against our point of view, nor the experimental evidence that is proposed to support the other points of view. Indeed, sometimes it’s hard for me to understand how others can find those experiments convincing, even when faced with arguments against them that seem obvious to us. But science, as everyone says, is conservative, and those points of view predate ours.

We now have many more experiments, looking at motor cortex and STN and their interactions with striatum, done with both pharmacology and optogenetics. This work is slowly making its way toward publication, along with other modeling papers that I believe give deep mechanistic insight into why pathological beta oscillations are associated with inability to move. As usually happens in science, further work injected more complications in the story (though we still believe, and have more evidence for, the gist of the story). We’ve partnered with Sri Sarma and her group (Johns Hopkins) to think about mechanisms of deep brain stimulation (Santaniello et al. 2015), which are complementary to ones our modeling has suggested. (New experimental results, not yet published, support our ideas.) We have started a collaboration with Emad Eskandar, a neurosurgeon who does deep brain stimulation, to test our theories about the interaction of beta and delta rhythms in the basal ganglia, and we have ongoing conversations with others with whom we may collaborate. I hope that the larger body of work will change minds.

Schizophrenia

Many of the things I now consider a core part of my interests were motivated by the interests of my students and postdocs. A student of mine, Nathan Veirling-Claassen (previously Dorea Vierling-Claassen), was very interested in neurological diseases. The disease whose connections to brain rhythms were most studied was schizophrenia (SZ). Peter Uhlhass and others had been emphasizing the importance of rhythms to brain diseases such as SZ, but there was very little modeling attempting to connect changes at a physiological level to changes in brain rhythms. Nathan’s project considered work of Kwon and colleagues (1999), who looked at responses of patients with SZ and controls to 40 Hz auditory inputs; controls had the standard 40 Hz steady-state response, but patients with SZ showed a preference for 20 Hz responses. In collaboration with Peter Seikmeier and Steve Stufflebeam, who did related experimental work, we created two computational models, one large/detailed and one small/more abstract to try to understand the origin of the difference in response (Vierling-Claassen et al. 2008). The models were based on postmortem studies indicating that cortical interneurons in subjects with SZ have decreased GAT-1 (a GABA transporter) and GAD 67 (one of two enzymes responsible for GABA synthesis); these alterations change the GABA kinetics. The models transition from control to schizophrenic frequency response when an extended inhibitory decay time is introduced, as thought to happen in SZ (Lewis et al. 2005). Working simultaneously with the two models was eye-opening. We expected that we would see much more with the more complex and detailed model, but it was so complex that we had trouble understanding the basic phenomena. The smaller model enabled us to more quickly understand what was important to getting the 20 Hz responses, and that understanding constrained the larger model enough to produce the results in the larger model as well. The larger model helped us to understand the importance of cellular heterogeneity, which was hard to model with small numbers of cells. Since Nathan was working for a math PhD, the results were also used to generate a model we could study analytically, and Nathan produced new mathematics about families of excitatory/inhibitory oscillators with periodic input (Vierling-Claassen and Kopell 2009). After that, Nathan went on to become an experimentalist, working with Chris Moore and now contributing to understanding neurological disease.

That was the last paper that I published on SZ until very recently. Gyury Buzsaki invited me to do a review for Biological Psychiatry on SZ and brain rhythms (Pittman-Polletta et al. 2015). By then, I had read enough more on SZ and rhythms (including the work of Kevin Spencer and much more from Peter Uhlhass) to realize that I had a story I wanted to tell about the subject, even if it was going to take a lot of work to dig up the evidence. Most of this literature search was done by first author, Ben Pittman-Polletta, with help from Bernat Kocsis, Sujith Vijayan, and Miles. We used the review to spell out the reasons why we thought that changes in rhythms were so important to neurological diseases. The basic picture that we sketched, using many papers for support, was this: Changes at the cellular and molecular level—especially those affecting the function of inhibitory interneurons—alter the rhythmic coordination of neuronal activity. These alterations interfere with local processing, which is mediated by rhythmic activity. Perturbations of the oscillatory structure of local processing upset large-scale coordination of neuronal activity across brain regions. Finally, distorted local processing and large-scale coordination produce altered cognition. The big (ten thousand foot) picture is very similar to the one that is guiding the work with Emery Brown and which is also (I believe) relevant to many other neurological diseases. The details are different, but in each case the framework provides ways to proceed to tease out those details.

More Neocortical Rhythms: From in Vitro Recordings to in Vivo Control of Behavior

It was always the hope that the deep understanding that can come from manipulation of slices would lead to hypotheses about cognition. Of course, everyone recognized the difficulty and perils of trying to make such a leap. In the earlier days of studying in vitro rhythms, most of the results were about single frequency bands in single regions of the brain. As the slice experiments got more sophisticated (based on earlier understanding), they were more able to reproduce the multiple rhythms found in vivo, as well as address interactions among regions. Although the rhythms in slices are cleaner and more powerful than those in vivo, they are believed (at least by some of us) to be similar in mechanism, enough for us to use these as clues to understand how rhythms might facilitate function in vivo.

Still More Betas. The beta oscillation that I had considered with Miles and Roger was the beat-skipping beta in hippocampus in vitro. Through my interest in PD and propofol, I had become aware of other mechanisms for producing beta rhythms in the brain. About this time, I started working with Miles on still more beta rhythms in vitro. With Anita Roopun and others, Miles was showing that different parts of the brain could produce rhythms of exactly the same frequency in completely different ways (Roopun et al. 2006; Roopun et al. 2010). In secondary somatosensory cortex (S2) a parietal, multimodal area, the intrinsic burster (IB) cells could produce such a 25 Hz (beta 2) rhythm in the presence of the glutamatergic agonist kainate and the absence of any chemical synapses, communicating through gap junctions. In primary auditory cortex (A1), there was another 25 Hz rhythm, this one requiring a cholinergic agonist (carbachol) as well as synaptic interactions between IB cells and interneurons that mediate GABAa inhibition significantly slower than that of the FS cells. These slow-inhibitory interneurons, likely LTS cells, are dendrite targeting, unlike the FS cells. A very peculiar finding was that each of these betas could live happily in their respective deep layers while the superficial layers produced a standard noise-driven gamma. Indeed, the slices could be cut along layer four, and the gamma and beta rhythms would continue to exist, even a little more happy (higher power).

The most unexpected result concerned the gamma/beta 2 in S2. When the kainate was partially antagonized (mimicking the reduction of excitatory input), after some time the gamma and beta 2 rhythms switched to beta 1 (15 Hz; Roopun et al. 2008). Now the rhythms in the superficial and deep layers were dependent on one another. How that could occur, and what it might be good for, were subjects that I explored with Mark Kramer, then a postdoc in our group. Mark created a model showing that the beta 1 is a concatenation of the gamma and beta 2: Each cycle of beta 1 contains one cycle of a gamma rhythm and one of a beta 2 rhythm. (Do the math: it works to get a 15 Hz rhythm!) Each gamma cycle triggers a beta 2 cycle by rebound from inhibition and similarly for beta 2 and gamma. The model could have been right out of a Rube Goldberg construction. But it made many specific predictions that we tested, and it passed all tests. So we are comfortable using it to think about what might be implications.

This beta 1 rhythm has properties that other rhythms have not yet been shown to have. An important one is that it continues even though the excitation that initially caused the gamma and beta 2 has diminished; this happens because the rhythm is sustained by rebound from inhibition. In addition, it has another property concerning cell assemblies: In models of gamma oscillations (Borgers and Kopell 2005), multiple assemblies of cells that get feedback inhibition from the same collection of FS inhibitory cells compete with one another. The most active assembly takes control of the inhibitory neurons, and uses them to suppress other cells. By contrast, multiple streams of input to different sets of pyramidal cells have a different effect when the target network is already displaying a beta rhythm (Kopell et al. 2011); they can coexist even though they share feedback inhibition. This allows for a kind of short-term memory that can permit the manipulation and coordination of cell assemblies. We think this is especially important since it occurs in a parietal cortex, a critical area for multimodal coordination and interactions of brain regions. The special properties of the beta 1 rhythm have been motivating current work with Miles and Anne-Lise Giraud about expectations and errors of expectations (more below).

Multiple Gammas in the Same Slice. Miles’ lab has produced many surprises. One surprise concerned two different gamma frequencies in the input and superficial layers of rodent A1 in vitro. These rhythms have totally different mechanisms and can be made to each appear by themselves (Ainsworth et al. 2011). At some levels of bath application of the glutamate agonist kainate, they are synchronous; at higher doses, they break apart with the superficial layers displaying a much higher gamma frequency. Though other groups had seen multiple gamma bands in vivo and in vitro, this was the first paper to show that the different “flavors” of gamma could manifest in different anatomical layers. Furthermore the deep layers of A1 respond to the superficial layer activity when the kainate dose is low (corresponding to input signals that are less salient) but to the input layers when the latter is producing a faster rhythm. It was not at all clear what were the underlying mechanisms for these observations and what were the functional implications. That led Shane Lee and me, working with Miles and Matt Ainsworth, to make a multilayer model of A1; I think that was my first multilayer model (Ainsworth et al. 2011). Via this model, we were able to understand in a mechanistic way what allowed the rhythms to synchronize or break apart. In conjunction with the experiments, it suggested an important functional implication: When signals are highly salient, they may not need to be processed further in the superficial layers in order to provoke a response via the output (deep) layers. When the input is not quite so salient, further interaction with other signals, taking place in the superficial layers, may be important to processing the signal for further action. Thus, the work suggested that layer-specific signals create dynamic regulation of coordination.

There was another important result about multiple gamma rhythms from the Whittington group, with modeling help from mine, this one concerning the entorhinal cortex (Middleton et al. 2008). The authors discovered what was probably a new kind of interneuron, which we named a “goblet cell” for the shape of the neuron. This cell was mostly in layer three, while the FS interneurons were more concentrated in layer two; these cells types are mutually inhibitory. The standard gamma in the usual artificial cerebral spinal fluid is formed by the interaction of FS cells and pyramidal cells, as in the rest of the neocortex. However, the FS cells of the EC require excitation mediated by NMDA currents, and in the presence of ketamine (an NMDAreceptor antagonist), the FS cells are inhibited and the goblet cells are disinhibited; this allows the formation of a gamma rhythm from the goblet cells and the pyramidal cells, a rhythm a little slower than the more standard gamma. The potential significance of this new gamma rhythm comes from the fact that the slower gamma rhythm matches that of CA3 and the faster one that of CA1. The CA3 and CA1 targets are parts of separate pathways. To the extent that the matching of frequencies facilitates communication (partially understood via modeling), the work suggested that modulation of NMDA receptors could change the routing of signals. This came out shortly before the in vivo work of L. L. Colgin and M. B. and E. I. Moser (Colgin et al. 2009), showing routing of two bands of “gamma” rhythms (one a much higher frequency) to different parts of the hippocampus.

Top-Down Gamma, Attention, and Beta Signaling. Although bottom-up signals are believed to be mostly associated with gamma rhythms, and topdown signals with beta rhythms (Bastos et al. 2015), this is not entirely true. Even in vitro, it is possible to get top-down gamma signals. Anita Roopun of Miles’ group examined a slice that contained A1, S2, and the connections between them (Roopun et al. 2010). She and colleagues showed that, without cholinergic modulation, there was top-down gamma from S2 to A1 between the superficial layers. Although S2 could produce a beta rhythm in its deep layers, A1 did not hear it; there was no Granger causality signal. When carbachol is added, the deep layers show both top-down and bottomup signals, and there is a very strong top-down beta signal to A1. Thus, cholinergic modulation changes the direction of signaling between A1 and S2, even in slice.

At this point, there had already been a number of studies pointing to the importance of top-down beta signaling in the context of attention (Fries et al. 2001; Buschman and Miller 2007). Attention is often accompanied by cholinergic modulation, so this study motivated me and postdoc Jung Lee (no relation to Shane Lee) to try to understand the role of top-down beta in attention. To do this, we decided to reproduce the results of Fries and colleagues (Fries et al. 2001; Fries et al. 2008), in which attentional effects led to increased gamma in the superficial layers. This was not an obvious place to start, since Pascal and colleagues were mainly concerned with the increased gamma, and we were concerned with the role of the top-down beta. Our modeling results (Lee et al. 2013) showed the connection between top-down beta and increased gamma in the superficial layers (the presumed target of Pascal’s recordings). Only in the presence of cholinergic modulation, the top-down beta caused the activation of a beta-frequency network in the deep layers, which included the activation of interneurons mediating slow GABAa inhibition; this inhibition, ascending to interneurons in L4 and the superficial layers and targeting inhibitory cells, changed the interaction of excitation and inhibition in those layers in such a way as to produce more activity and more gamma power in both the input and the superficial layers. So we showed how top-down activity in some frequencies to which the bottom layers are resonant could produce changes across all the layers. Since gamma is good for creating cell assemblies, it became clearer how the top-down signals could produce a gain increase that would be useful in passing signals along to the next region.

Recent work with Jung and Miles is suggesting an even more complex and interesting story; this has to do with the top-down superficial gamma that becomes top-down and bottom-up in the presence of cholinergic modulation. Jung’s modeling (Lee et al. 2015) has shown that, in the absence of cholinergic modulation, the top-down gamma, which goes primarily to the FS cells of the superficial target network, can at least partially prevent input from the thalamus from reaching the superficial layers. Adding cholinergic modulation changes the situation so bottom-up and top-down gamma can actually alternate in talking to one another. The simulations predict that top-down processes using both gamma and beta may work in concert to ensure appropriate cortical filtering during enhanced primary representation of input in attention-related tasks. The Roopun work (Roopun et al. 2010) and the subsequent modeling reveal a highly regulated system in which modulation affects interlayer and interregional interactions, and brain rhythms are critically involved in mediating these interactions. It is examples like this and the ones above that give me hope that a deep study of brain dynamics, pulling together in vivo, in vitro, and modeling work, can help to understand cognition at a more mechanistic level.

Meanwhile, slice physiology continues to throw more surprises at us. Miles’ group studied a “sleeping slice” of S2 that produced a delta rhythm with other faster rhythms nested in it, and Roger produced a traubian model of it (Carracedo et al. 2013). This work is inspiring thoughts about cortical delta and its role in active sensing (Lakatos et al. 2008). Fiona LeBeau, a continuing collaborator of Miles, has been studying rodent frontal cortices and finding dynamical patterns that are very different from those found in sensory and parietal cortices. They are also finding a huge heterogeneity of cellular properties, which is likely to be closely related to the ability of frontal cortex to be very broadly tuned and participate in multiple tasks. These physiological findings are motivating a lot of modeling work in our group, notably about the nature of decisions (more below).

Wading into Data Analysis

In almost all my career, I’ve been working with nonlinear differential equations, using them to explore how different processes affect one another. I had no training in statistics, except for a course in probability as an undergraduate. I knew statistics were important, but I treated them as facts I was given, to contemplate and figure out how processes interact. I now realize how naïve it was to treat analyzed data as pure facts. As I hang out more and more with experimentalists, and participate in the sometimes-frustrating discussions about how to analyze the data that was so effortfully acquired, I look at the methods section of papers with a new and more probing eye. My education started at the hands of two postdocs in my group, Adriano Tort and Mark Kramer. Adriano contacted me in 2005, to ask if he could come on a Brazilian Fellowship to work with me. He had undergrad training in physics, was getting a master’s degree in math and a PhD in biochemistry related to medicine (which may have been associated with still another degree). He had a letter of recommendation from Jacob Palis, my fellow Smale-advisee from Berkeley, though Jacob did not mention the connection. I remember asking myself what I could possibly do with such a person; I realized soon after he arrived what a gift he was to me. I don’t think Adriano knew that much math or statistics or computation when he arrived, but somehow he seemed able to inhale what he needed and breathe out a finished ability to work at a professional level. He wrote several papers with me I’m still very proud of, using dynamical systems modeling (mentioned above with theta oscillations). It was his idea to also start writing papers on data analysis. When Adriano left my group, it was to become a full professor in Brazil and start his own lab. (I’m not sure he had ever done any experimental work before.) I recall that the competition involved writing essays (closed book) on a very large number of subjects. He told me that he managed to write about twice as much as anyone else in the allotted time, and I wouldn’t be surprised if his essays had four times as much content. Although the competition was open to all levels, Adriano got the job.

Mark, who is/was very interested in epilepsy, had a previous background working in ECoG with Bob Knight, and had come to my group to get experience modeling at a more physiological level. He was already skilled in aspects of data analysis, and teamed up with Adriano. The issue of crossfrequency coupling had come up in our work on gamma and theta rhythms. It is easy to see rhythms and interactions of rhythms when they aren’t there, but appear as an artifact from filtering or other kinds of manipulation of the data. In a methods paper, Mark and Adriano described how artifacts may arise and suggested means to detect them (Kramer et al. 2008). We also worked with Ann Graybiel’s group to analyze cross-frequency coupling within and between hippocampal and striatal LFP signals as rats performed a task requiring active navigation and decision making (Tort et al. 2008). The amplitudes of the high-frequency oscillations and their phase within a co-occurring theta changed in different parts of the task. Furthermore, at different times in the task, the particular subbands of frequencies engaging in the cross-frequency coupling changed in a repeatable way. This experiment displayed remarkable temporal structure in the brain, closely related to function; I thought this was pretty convincing evidence of the importance of rhythms in cognition, but minds change slowly. Adriano and I also wrote data analysis papers with the group of Howard Eichenbaum. In one of these (Tort et al. 2010), Adriano used ideas from physics to construct a new algorithm for computing cross-frequency coupling, and this method has been picked up by many others. Ever since, I’ve had an undeserved reputation for being an expert in data analysis. However, Mark and Adriano have had a lasting effect on my group by teaching others, who teach others etc., and attracting data analysis experts to our group. So, in fact, our group continues to have these skills, and we have been involved in analysis of data from multiple labs.

While Mark was working with me, he was also continuing his work on epilepsy, and developing his own research program involving meso-scale network analysis (in the spirit of connectomics). Near the end of his postdoc, he applied for and got a career award from the BWF (this was before ShiNung), which paid a significant amount of his salary for the next few years. I made good use of that to get BU to hire Mark as an assistant professor. BU did not make it easy: As in many institutions, the higher administration was suspicious of someone coming from an internal group, even though there was tremendous support both within the math department and in neuroscience circles. The negotiations went up to within an hour or two of when Mark needed to reply to another offer, but eventually the administration came through. Mark has now become a mainstay of the computational part of the BU Program in Neuroscience, and it is hard to imagine that program without him. He and Uri Eden (a former student of Emery’s that I also helped bring to BU) have an ongoing weekly neural data analysis “happening” in which investigators can bring their statistical questions and problems and get advice. This has been a great boon to the Boston neuroscience community.

Scientist as Amoeba

As I’ve moved throughout my career, I keep picking up new things. But the new things haven’t been random. Almost every new interest builds on what I’ve done before, which determines where my head is at that point. The specifics of what I learned doing the pure, and then applied, math help to inform both the questions I ask and the methods that occur to me to start with. The image of an amoeba comes to mind: Wherever I am intellectually, I’m always extending a few pseudopods to sample the environment around me. Sometimes the latter is very tasty, and I move the bulk of my interests in that direction. In addition to the themes that I mentioned above, there were other directions I started on, and may go back to. For example, for a few years, I collaborated with Leslie Kay on rhythms in the olfaction system (Kay et al. 2009) as well as thinking about olfactory rhythms in insects (Sivan and Kopell 2004).

I’m continuing most of the major threads that I’ve begun in the past 15 or 20 years. I’m still interested in the physiological bases of brain rhythms, and the emerging data about this from the lab of Miles Whittington suggests a level of complexity we have yet to explore computationally. The work on PD and anesthesia continues to be very rich, and other neurological diseases are presenting important questions with significant computational components. Currently, three of my students are MD-PhDs. Our initial forays into normal cognition are showing that the insights from the study of the physiology of rhythms, and also the changes in them in pathological states, can be useful for understanding how dynamics contribute to normal brain function. And even mathematical efforts are productively continuing: Simulations about any of the other themes almost always throw off mathematical questions concerning why the simulations behave the ways they do. These are more specific, involving more mathematical and physiological structure, than the early foundations that I and others helped lay.

It seems to me that all those threads are now converging, and the area of convergence (not a point) is an intellectual framework I call “dynomics” (Kopell et al. 2014). An extension of “connectomics,” this framework goes beyond the construction of the connectome by emphasizing not only which brain regions are connected to which others, but what signals are sent along the connections and how such signals coordinate pairs of regions. It also goes beyond “functional connectomics,” which deals with slowly changing networks of connected regions associated with brain activity during a particular brain state (such as attention or rest; see Bullmore and Sporns 2009).

One of the main themes I associate with dynomics is the idea of routing via fast dynamics: Signals that are given to some local network create an output that depends heavily on context, which can manifest physiologically as modulation states or other inputs to the same structure. Some signals may be filtered out (Cannon et al. 2014), and others may be enhanced (Lee et al. 2013). Thus, how a signal is carried around the brain through a network of networks depends on all these task- and state-dependent contingencies and works via ms.-precise dynamics. It is impossible to study all tasks and all states. So the construction of an all-inclusive theory that would contain all there is to know about this subject, as suggested by the -omics ending, is a fantasy. But I think that is also true of all the other omics, starting from the ur-omics, genomics; as people learn more, inevitably there are complications and convolutions, and separations into other intellectual pathways (proteomics, metabolomics, and so on). I start out without the fantasy that I think was/is fairly widespread about the ability of genomics, connectomics, etc. to provide a complete explanation of anything. But even without unreasonable expectations, the partial understanding provided by the study of these subjects has been extraordinary useful. So the labeling of the study of dynamics in the brain as “dynomics” is an attempt to point out that this is a valid and important area for study, one that needs to go on in parallel with the study of large- and small-scale connectivity.

This label aptly summarizes the themes I’ve been attempting to pursue. On the mathematical level, it is both explicit and open-ended: All signals with temporal structure arrive at a set of neurons that have a state with its own instantaneous temporal structure. How does the latter affect the processing of the former? The interaction of any two pairs of regions, with input from other regions as well, poses a question of this form that can be translated into computational and even mathematical questions. Almost all the mathematics that I now do fits into this class of questions.

The dynome concept also provides a lens through which to view large issues of cognition. What is an expectation/prediction? How is active sensing carried out? What happens when we make a decision? Thinking in terms of dynamics makes one frame those questions differently than if one wants a kind of abstract answer. For example, though essentially all cognition involves previous history that leads to expectations, how such expectations are manifested in physiology and how they change reactions to stimuli is far from understood. The dynome concept leads me to think of predictions as dynamic “preparations” of network pathways: earlier experience sets up a network via plastic changes (and initial conditions) to have different dynamic reactions than if the earlier experience had not happened. “Prediction errors” are then anything that happens if other pathways are used and hence there are other outcomes. This kind of mechanistic thinking is very different from the well-known and much-cited theories of Karl Friston on predictive coding (Friston 2012), which often are expressed in an abstract form about changing probabilities. With Anne-Lise Giraud, I’ve begun to think about specific situations involving prediction errors (Arnal et al. 2011), using intuition gained from studying interactions of regions via rhythms, to work toward a more mechanistic and specific set of explanations.

Similarly, there is a large literature in modeling about decision making that has been highly successful in accounting for many results on experiments concerning decisions. For the most part, however, these theories address the phenomenology of decision making (such as accumulation of evidence) rather than the underlying biophysical mechanisms, with models that are fairly abstract, or they find biophysical mechanisms that could underlie the abstract ideas (for a review, see Wang 2012). I’ve started thinking about decisions (mostly rule-based decisions rather than accumulation of evidence) from a different point of view. Issues of decision making involve routing of signals in an essential way: Given the current and past stimuli in a given context (whether cued or learned from feedback), some motor activity is chosen. Thus, inputs are somehow mapped to motor outcomes. In general, this involves large fractions of the brain (especially if the task is at all complicated), and signals must be routed though all parts of the brain that take part in this mapping. Since I believe that signal routing is partially controlled through the expression of brain rhythms, the origin of a “decision” is a very attractive question for me. With some of my current group of students and postdocs, we are investigating interactions of prefrontal cortex and the basal ganglia, making use of our knowledge in rhythms in those areas to investigate such decisions.

I’ve started to work with Charlie Schroeder on issues of active sensing, which involves attention. The central set of questions is how the brain arranges that sensory signals manage to arrive at an optimal moment when the brain is prepared to work with them. Ongoing low-frequency rhythms in the brain in the waking state, such as delta oscillations (Lakatos et al. 2008), are likely to be major players, and it is likely to take computational modeling (and maybe even some math) to figure out how these rhythms facilitate sensory processing. Pascal Fries and Sabine Kastner are doing experiments on attention and dynamics that are very interesting to me, posing specific questions about mechanisms of various kinds of attention. I suspect that essentially every aspect of normal and pathological cognition can be recast in terms of neural dynamics (not necessarily rhythmic) and routing of signals. Whether that will turn out to be a fruitful—and tasty—thing to do I’m eager to explore.

Onward and sideways!

On Math, Numerical Simulations, and Modeling

Creating mathematical models and testing them with numerical simulations is a completely different intellectual endeavor than pure math, which involves stating hypotheses and finding out the consequences of those hypotheses, as backed up by proofs. The latter is as close as we can get to ground truth. However, the trade-off is generally that the hypotheses have to be very constraining in order that the problem be tractable to available techniques. To apply this to any phenomena outside of math generally involves moving away from the limiting circumstances of the hypotheses under which the desired conclusion can be derived. Letting go is a very slippery slope intellectually. Sometimes, one can prove results “somewhat” away from limits (e.g., a ratio of two different time scales is very large or very small), but it has been observed many times that the calculations that hold rigorously only in some limit actually work far from this limit. So when is numerical observation a real contribution to the literature? With the advent of high-speed computers, the sociology has changed with respect to this question: In some past decades, numerical observations not backed by proofs were considered suspect; now proofs not backed by numerics are suspect.

The issues surrounding numerics get much thornier when the models are so complicated that they are nowhere near anything that can be analyzed by mathematical techniques. Though some people dismiss models with the remark that a model can be tuned to do anything, I think the state of affairs is much more nuanced, and much more like experimental science. To me, the central issue in working with numerical models, one that I grapple with in every paper that I write, is what constitutes intellectual honesty. The naysayers are correct that it often is possible to tune a model to recreate some phenomena. This may or may not give insight. If the assumptions of the model (or the parameter ranges that are chosen for the model) are wildly unphysiological or extremely implausible, the answer is probably not. The model parameters don’t have to match numbers that were measured, because all such numbers are themselves fallible—for example, measured in particular circumstances in a particular way, and might change in different preparations in different ways. But a model should include a vigorous defense of how the chosen parameters were arrived at. Even if the parameters are reasonable and the model can account for a variety of phenomena, it can be thoroughly wrong: The phenomena may be consequences of entirely different mechanisms not considered in the model.

It’s a continuing puzzle, both intellectual and moral, how to operate in such an environment, and something that modelers need to be trained to face. On the one hand, the inability to create “truth” can be paralyzing for some people, and it is likely the reason that fewer mathematicians than physicists turn to neuroscience. (At least in the mathematical world, it is believed that physicists are less fastidious about dotting i’s and crossing t’s.) On the other hand, the knowledge that models are forced to be fallible tempts some people to grant themselves more leeway than they should honestly take, and at least some of the readers (if not the reviewers) can see this in the finished product. (I have heard some students—not mine!—say that they were told to “reproduce” some data, no matter how they get there.) I know of no method of dealing with this other than disciplined self-criticism, an open mind, and (in the end) a willingness to be wrong in print. There is also an unevenness in the quality of reviewing of computational papers for noncomputational journals (especially highprofile ones): Reviewers tend to pounce on details that are not central, or give the paper a pass on main issues regarding the correctness or relevance of a model. Since computational papers need to be read by experimentalists, this is an ongoing problem for the computational community and for any parts of the experimental community that are listening to the computational conversation. In some sense, these are problems of a growing and successful computational community; in the early days, when theoreticians talked among themselves, these problems were not relevant. But problems they are, and I hope the computational community will figure out how to address them. Of course, this is closely associated with the general pressures that all scientists are feeling now to produce results that will allow papers, grants, jobs, tenure, etc. It seems to me that the pressures, and the response to them, have gotten distinctly worse over the past decade, and I deeply hope that this will be reversed.

Though the conversation among experimentalists and theorists/modelers has gotten more extensive and deeper over the years, I sometimes wonder what we really understand about each other’s knowledge base and thought processes. An incident I keep coming back to occurred when I was quite junior and Gabe was giving a talk at a small workshop that had as participants mathematicians, physicists, philosophers, and biologists. A well-known and very distinguished neuroscientist gave a talk that, implausibly, centrally involved a highly technical area of mathematics known as tensor theory. As I looked around the audience, all the mathematicians and physicists seemed to be shaking their heads sideways in disagreement and/or disbelief. But the biologists apparently believed they had understood perfectly. I concluded that items that are fact based and subject to critique for one community are apt to be metaphorical for the other, a prime reason why interdisciplinary reviewing is so hard. Metaphors can be very useful, but not so much for understanding mechanisms.

As I near the end of my career, I’ve become drawn to more and more scientifically ambitious questions and more accepting of the limitations of my (and everyone else’s) work. I’m now addressing questions that likely cannot be fully answered with the experimental and modeling tools that we now have. However, I’m convinced of the inadequacy of experimental tools alone, including big data approaches. Big data can supply huge amounts of information that can be queried, but what determines which questions are asked of such databases? This requires ideas and hypotheses. From where do they come? A study of a variety of experimental work can lead to ideas about how phenomena are connected and open new intellectual pathways. However, as the phenomenology gets more and more complex, it becomes harder and harder to suggest implications—too many things can happen in too many contingent situations. This is the essential reason for modeling, and also the reason why modeling is so fraught. It would be easy to dismiss the whole activity of modeling (as some do), if only there were some better alternative. More data alone won’t save us.

Herding Cats

For most of my career, I’ve been collaborating with a variety of people. Indeed, as a theory person, I’ve been highly dependent on my experimental collaborators for data. For young theorists, it is often difficult to find experimental collaborators. I’ve also been struck by how much students and postdocs tend to stay within their labs, and not learn from the much larger scientific community. Finally, when I was “growing up” scientifically, there were no signposts or well-trodden paths for those of us interested in things interdisciplinary. All this has motivated me to form scientific networks and to be chief cheerleader within them. I discovered that I liked to do this and was good at it. One reason may have had to do with family: I married in 1978 and have two stepchildren (and by now five grandkids), but I was rarely a custodial parent. Mentoring lots of younger colleagues, students, and postdocs tapped into my underused maternal instincts. I have been known to be fierce in defense of my mentees and, when invited, sometimes formed close personal relationships, forming part of my extended family. (My husband and I have also “adopted” various nonmentee young adults over the years, helping them in various ways.)

One of my first attempts at community-building was an Army-sponsored group of people from various institutions working on CPGs to which I gave the unfortunate acronym CRP (Center for Rhythmic Processes). It had no home space and just a plaque outside my door; I noticed that people would dance a bit as they passed my office. That lasted through the length of an Army Research Office grant supporting it.

The second attempt (1997–2011) was called the Center for BioDynamics (CBD). It was headed up by me and Jim Collins, who had the idea to start this. Jim, who is now highly successful in the fields of synthetic biology and systems biology, was then a young professor of biomedical engineering who had worked on genetic oscillators and other topics for which dynamics were critical. The idea was to create a group of investigators within BU who were all interested in some aspects of dynamics within biology. Getting grants for groups has never been straightforward. We became aware that NSF Division of Mathematical Sciences (DMS) had a call for Group Infrastructure Grants (GIGs), and we persuaded them that human capital could indeed be infrastructure, which we were prepared to create. This grant supported eight of us from a variety of departments around BU, not for senior salary, but for the support of graduate students and postdocs. It was an NSF version of a training grant, but was sui generis, like all the other training-like grants that I’ve put together. Our hope was not only to support such students but to change the culture of BU so that interdepartmental interactions became easier and more widespread. In this, we were quite successful, and the later neuroscience and systems biology initiatives at BU date from our efforts. At the end of the five-year grant, we were deemed successful, but NSF no longer had GIGs. So we were invited to put in a smaller proposal for a smaller number of people under the standard program for standard grants, which we definitely weren’t. This continued the NSF tradition of being able to work in a flexible way, passing the hat among potential constituencies. This got us through another five years. After that, the NSF DMS had a more formal funding opportunity called Research Training Grants (RTGs). As usual, we didn’t quite fit the description of fundable RTGs, but this was overlooked. At the end of 15 years, we decided not to apply for a further grant as CBD. By then, the computational neuroscience and the systems biology parts of the CBD had both grown to be independent initiatives (the other parts of math biology were sustained but didn’t grow); this was the BU version of the growth and decline of the Gordon Conference in Math Biology: Progress called for further specialization. CBD was officially decommissioned in 2011, though its Web site is still up.

Early on in the history of the CBD, I was asked to serve on an advisory board for the Burroughs Wellcome Fund (BWF). The main job of the board was to advise on institutional grants associated with the interface between the physical sciences and the mathematical sciences. After serving on that board for a couple of years, it occurred to me that I might be very good at running the kind of group project that BWF was supporting. This was also a BU endeavor, which we called the Program in Mathematical and Computational Neuroscience (PMCN), again a kind of cross-department training grant with a mandate to do community building, but this time with a more focused scope. Howard Eichenbaum was the codirector. It was not really a program, but centers were proliferating at BU, and this was a compromise among various pressures on names. The P enabled us to have an unofficial logo of a pumpkin (try pronouncing PMCN). We nursed the five-year funding for seven years, and used it create a strong and vibrant computational community at BU.

At the end of the PMCN grant, I decided to expand the scientific community for this effort more broadly across the Boston area and still more focused as to theme. A new beginning required a new name, and I called it the Cognitive Rhythms Collaborative (CRC), a catchy name intended to suggest a rock group. The mission of the CRC was to build a scientific community around the set of questions concerned with the measurement, analysis and modeling of brain rhythms, aimed at a deeper understanding of brain function in normal and pathological situations. In other words, it was everything I was interested in, and a good excuse to get together the large number of groups in the Boston area with overlapping interests. The CRC started with informal dinner meetings open to all CRCers, sponsored by the McGovern Institute, with intense interactions rather than formal talks. (I have a reputation among collaborators for intense scientific interactions; Charlie Schroeder once referred to an informal small group meeting I had arranged as a “Vulcan mind meld.”)

A year of two into this experiment, the NSF DMS got a new director who was interested in helping to create “people networks,” to enhance collaborations, to mentor students and postdocs, and to move science forward at a faster pace. At the beginning of his job, he went on a listening tour to many math departments, and I was put on his schedule. I had no inkling of his new ideas, and he had none about my previous activities, but we soon realized that we had common interests: I had already created a people network. It was not what he had in mind (he was thinking more in terms of purely mathematical networks), but it was close enough. A year or so later, he invited me and one other group (headed by Chris Jones and dealing with atmospheric science) to apply for a five-year grant for the CRC. We got the grants, and our groups provided a loose template for a more general program that NSF started a year or two after.

The CRC is open to all comers, but I made sure that some of the key Boston players would be on board. Some were obvious: at MIT, Bob Desimone, Emery Brown, Earl Miller, Ann Graybiel, Chris Moore, Matt Wilson; from Martinos Imaging Center, we had Matti Hamalainen, Steph Jones, Steve Stufflebeam, Seppo Ahlfors, Sydney Cash, and Patrick Purdon; from BU, there was me and Mark Kramer, Uri Eden, Oded Ghitza, Xue Han, Howard Eichenbaum, Michael Hasselmo, Michelle McCarthy, Kamal Sen, Jason Ritt, Barbara Shinn-Cunningham, and Lucia Vaina; and there were other people interested in brain dynamics from other institutions, including Emad Eskandar, Donald Katz, Robert Sekuler, Christoph Borgers, Bernat Kocsis, Daniel Goldin, Kevin Spencer, Ritchie Brown, Robert Stickgold, and Daniel Polley, including some from outside of Boston (e.g., Miles). Some of the members were not obvious, for example Ed Boyden, who knew a lot about many, many things, but not so much brain dynamics. He and I had our first serious discussion when we sat next to each other a McGovern dinner—possibly at the 2007 Scolnick Prize dinner. That led us to start talking about applying optogenetics to rhythms and to collaborations with Miles. I was very happy to have him be a part of the CRC; he was always the first to respond whenever I sent out broadcasts asking for input or help.

Among us, the CRCers have a very broad variety of skills, including genetics, technology development, in vivo and in vitro physiology, using techniques for human measurements (EEG/MEG/Ecog), neurosurgery, statistics, and dynamical systems modeling. Though there were subsets of people who already talked to one another, the CRC created a framework in which these interactions were much more frequent and specific, especially among the younger colleagues associated with the senior members. With funds to support a significant number of postdocs, we were able to produce working groups on a variety of topics. We also had the data analysis group run by Mark Kramer and Uri Eden; this group helps all CRC members (and anyone can become a CRC member) with data issues, as well as creating cutting-edge new analyses. There has also been a yearly retreat and a minisymposium. We did one large meeting so far. Through these mechanisms, student, postdocs, and faculty have multiple options for intense or casual interactions throughout the year. It is the impression of many of us that the CRC has notably improved the collaborative atmosphere in this field, with happy reactions from students and postdocs, and I’m at least as pleased with this as anything I’ve done in science.

Having never acquired an ongoing sugar daddy for these organizational efforts (and with BU definitely not interested in finding such a donor), I had to keep reinventing my scientific networks to appeal to the next transient funder and my own evolving interests. This wasn’t necessarily a bad thing (though it took continual effort). Endings that were out of my control enabled me to reformulate what the network was supposed to do and reengage only those people who were active and relevant. I was very fortunate to be able to find new opportunities as old ones melted away and be able to build on the skills and communities I had helped to create. But I do hope that we can make the CRC outlive the ending of its funding.

Meanwhile, other things were happening involving BU and neuroscience. Starting from the time I was working on the CBD, Steve Grossberg was actively running a department (Cognitive and Neural Studies, CNS) and a center (Center for Adaptive Studies). Steve’s group was focused on issues of mathematical psychology and used techniques and approaches that were more engineering based. Those I worked with were more biophysically based, and the two groups were not highly interactive. About the time that the CBD ended, the CNS department was decommissioned, and Barb ShinnCunningham started a center with a long name, informally called CompNet by everyone. This group was to marry the remnants of CNS with the CBD group to take better advantage of the rich range of skills at BU; I helped a bit as codirector. CompNet served a very good transitional role, and now we have still another organizing umbrella, Center for Systems Neuroscience, with a new building and leadership of Mike Hasselmo. As I attempt to keep going my scientifically focused but geographically more spread network, I’m very happy to see this developing neuroscience community at BU. For more on BU history of neuroscience, see http://www.bu.edu/neuro/graduate/computational-neuroscience/cnhistory/.

Academic Travel

One of the great perks of working in academia is the ability to travel. I’ve done my share of colloquium talks, conferences, and panels, but there are a few trips that stick in my mind for the unexpected experiences. The first one of these was in graduate school. Some professors I knew were associated with a summer school in L’Aquila, Italy; not enough students had applied, and I was asked if I wanted to go (fully supported). It was not my field, but I was not about to turn down this opportunity. The school was in the foothills of the Apennine mountains, and I was eager to climb some accessible route. I kept hinting throughout the time of the school that someone should organize such an outing, but no one took me up on it. So near the end, I organized this trip. The plan was to climb up a fairly easy route and then take the funicular train back down. There were a lot of us, with a multitude of mother tongues, and English was more tolerated than embraced. This made it hard to move the crowd along at the pace required to make the last train down, and we did indeed, barely, miss the last train down. A highly fit group of young Frenchmen arrived at the top when we did, and then ran down the mountain in the small amount of time before darkness fell. But we were not so fit or skilled, and found ourselves in the dark, without flashlights, trying to pick our way downward. Luckily, the moon soon arose and helped, but it was not easy or fast. As we neared the bottom, we heard a lot of dogs barking: They were part of a search team that had been sent for us by the Frenchmen. I think I will not be soon forgotten at L’Aquila!

Another unforgettable trip occurred in 1981. Out of the blue, I got a call from a woman who was executive director of Committee of Concerned Scientists, a human rights organization. She was looking for a woman scientist to accompany her to Moscow and Leningrad to visit “refuseniks” (those who had been denied permission to leave, mostly Jews) and dissidents. I had been recommended to her by a colleague, and she gave me one hour to decide whether to go; we weren’t going to leave for some weeks, but preparations needed to be made. I used the hour to check the credentials of that group, which I had not previously heard of, and then accepted. I prepared for this in the spirit of cloak and dagger: I knew that I should not have material in Cyrillic, since it would be clear that I didn’t know any Russian. But we needed a list of names and addresses of those we planned to visit. So I transliterated the list into English letters and created a scientific bibliography. When we needed to hand an address to a cab driver, I transliterated it back to Cyrillic, not necessarily faithful to the original. One of those we visited claimed I had written his address with a Yiddish accent! We were aware of being trailed, though we were not stopped. I gave the last of the famous “Sunday seminars” (given on a Tuesday to evade the KGB) at the home of Irina Brailovsky, whose house was known to be bugged, and when she introduced me, she spoke right into the mike on the ceiling. So this was the only talk I’ve ever given that was piped straight to the KGB; I wonder what they made of the discourse on the BZ reaction. That talk was also notable to me because of the avidness with which the audience absorbed the material. Not all of them understood English, and after each sentence or two, the audience erupted in Russian, discussing the content among themselves; when they quieted down, I went back, briefly, to speaking. We also visited the wife of Andrei Sakharov and brought her some things from the states. I kept up with some of the people we visited, especially when they were later able to leave Russia. And I started being more involved in human rights work.

A later trip to the then–Soviet bloc occurred when I was invited to give a talk at an International Congress of Mathematicians, held every four years, and this time in Warsaw in 1983. It was a time when Solidarity was very active in Warsaw, and many people had been imprisoned for their political activities. I was unsure whether to go or boycott, and I called a well-known member of Solidarity who happened to be visiting at Harvard. His advice was to go and smuggle in anything I could for Solidarity. So I packed my suitcase with needed carbon paper and some embargoed books. The agents at the Warsaw airport were carefully checking, but somehow I managed to get on a line in which suitcases were not being opened, and so my contraband made its way safely inside. The Poles seem ecstatic at having so many foreigners around, with a loosened sense of political control. One said to me something like: “Everyone is here, and they are talking about everything!” There was a plan among a subgroup of speakers to dedicate their talks to some imprisoned person. I was assigned someone (whose name I could barely pronounce) and started my talk with a one-sentence dedication. The next speaker was Russian, and he was clearly very upset by this; he made movements suggesting he wanted to cut me off, but my dedication was too brief to allow this. He started his own talk by saying (with meaningful emphasis): “I’m going to be talking on a theme similar to that of the previous speaker, but I have a different interpretation.” I don’t know how much the audience understood the veiled political allusion, which was clear to me.

There were also many memorable trips that I took with groups of MacArthur Fellows, with one or more of the fellows organizing a trip to places where they worked. I got to dig for dinosaurs in Montana with Jack Horner, spend time on Indian reservations, explore the Amazon (including a butterfly farm) and the Galapagos Islands, and travel around Madagascar. It was an extraordinary privilege to travel with these experts and get access to places not easily reachable.

In Sickness and Health

As a child I was very athletic (good genes; my mother was women’s athletic director at a camp I went to). I was highly active through graduate school. A few years after that, shortly into my time at Northeastern when I was close to 30, I contracted mononucleosis (again I was a late-bloomer—people usually get this at an earlier age). Mono is believed to be viral, and for some unlucky people, it has after-effects that can linger. For me, the after-effects never went away. One of main symptoms of mono is intense fatigue, as well as swollen lymph glands, and those came back at irregular intervals for irregular periods of time. I kept working during those times, though there were moments in which I had to head for the nearest flat surface and collapse. (In my current office, there is a couch for that purpose). I recall teaching a class in which I had essentially no voice. The class was small and I gathered them around me at the blackboard (I was not contagious) and whispered my pearls of wisdom. The sequelae were especially bad for the first few years, and I kept canceling acceptances for conferences and speaking invitations. Since these were all about topics from my graduate work that I was trying hard to flee, those invitations were a mixed blessing. My husband guessed that I might be using the mono as an excuse not to go. I wasn’t sure; I thought that wasn’t so, but it was hard to tell.

Various versions of this have gone on through the years, with “flares” that ranged up to a few months. I continued to work, and be mostly productive, with times when reviews were months late, and classes or invitations were canceled. It was not for almost another 40 years that this illness was diagnosed: chronic fatigue immune dysfunction syndrome (CFIDS); it has a lot of other names, including systemic exertion intolerance disease, myalgic encephalomyelitis, and postviral fatigue syndrome. The mother of all flares occurred in 2009 at a SfN meeting. I had signed myself up to do too much: I was running a short course at which I was also giving a talk, I was actually standing in front of a poster (for a full four hours) and talking about it, though by that point my voice and my energy had long since parted ways with me. I was visiting the requisite number of other posters, seeing the friends I wanted to make contact with, having meals with new potential collaborators, going to socials and other meetings, and not giving myself enough time to rest in between. I knew I was stressing myself, but I convinced myself that there was good stress and bad stress and this was all the former. Bad mistake! At the end of the poster, I went to my room, slept for about 24 hours, and then took the first plane home. I did not start to recover for about a year.

As in other flares, I dutifully went to my doctor, without much hope. I had previously been sent to the usual array of specialists who did the usual array of tests, and I passed them all. Then the flare would pass before they could come up with a diagnosis. I was lucky that they did not say to my face that they thought I was malingering (a common experience of many people with CFIDS). This time, the flare lasted a year and my primary was a bulldog; she saw I was really sick and would not give up until she figured out why. (Being able to do something about it was another thing.) This was for better or worse: better that she really cared, which was the best thing she could do for me (including muscling her way into appointments for me with booked-up specialists), and worse because none of the specialists she sent me to seemed to have a clue. Since CFIDS is not understood (and I didn’t yet have a label), and it comes with a bewildering array of symptoms (neurological, muscular, cognitive (“brain fog”), immune-related, gastrointestinal etc., ad nauseum), I was thrown into the medical maw and saw at least one practitioner from essentially every department in the practice (well, maybe not dermatology). Most just expressed bafflement, as I meekly showed up for my appointments. One, a cardiologist to whom I had been sent after leaving a hospital to which I had been sent because I had trouble breathing, expressed annoyance when I went through the ritual of detailing the symptoms: Why did he have to listen to all that? What did it have to do with my heart? There was a clear implication in his manner to me that he hoped I would not darken his door again.

Eventually, after about six months of doctor-hopping, the second neurologist I saw had an idea. It seems that CFIDS is related to another mysterious illness called fibromyalgia, which is associated with pain originating at tender points. So he lay me down on the examining table, systematically poked a bunch of body parts, and counted how many times I screamed. I failed! (Use of terminology in which the patient actually gets a diagnosis from a test.) CFIDS is usually a diagnosis of exclusion, and my medical practice had done all that seemed to me possible in excluding everything else. It is commonly first triggered by mono, which was in my record. A look at my medical record now suggested to this neurologist that the previous string of undiagnosed illnesses had a common etiology. BINGO! I heard him dictating his report: “Patient accepts diagnosis.” I was indeed very glad to have a label that implicated my body. The bad news came next: He told me that nobody in the practice treated this illness, and I was on my own. Indeed, as far as I could later see, nobody in Boston treated this illness, partly because some of them didn’t believe in it and partly because everyone in the medical profession seemed to know that nothing they knew would be helpful. Getting a label was helpful partly because I could now stop going to doctor appointments and concentrate on getting better.

While I had continued to dutifully show up to my baffled interlocutors, I had earlier reached a similar conclusion to that of my second neurologist about the efficacy of standard medical treatment and started looking for alternative routes to health. This included yoga (done very, very gently), herbs, acupuncture, and a lot of sleep and rest. It was helping, but nothing got me even close to where I had been before this flare started (not to speak of before the mono). One day, a year or so after I became sick, when I could barely get out of bed, my friend Amy Wong showed up and dragged me (leaning on her arm for support) to see her qi gong sifu (teacher) in Chinatown. Sifu Donald Wong (no relation) taught a version of a Chinese standing meditation technique. Perhaps because I had previously done some baby yoga, I responded very quickly to his exercises and started coming regularly (once a week). For a while, each session made me feel temporarily worse and then better than before the session; this was “detoxing.” Over months, my health gradually returned, something surprising to my doctors, and not usual. I’ve continued the practice of dragging sick friends to Sifu Donald, with mixed results but some definite successes. Now that I’ve had more than five years of practice, with his encouragement, I’ve also begun to teach the basics of qi gong in an informal class at BU.

It occurred to me that meditation has a lot in common with doing mathematics or trying to solve a scientific puzzle by the Method of Pure Thought. Both require an intense but very relaxed concentration, to allow an awareness of many things while blocking out other things (such as shopping lists and deadlines). I recall a story that was told to me by the wife of my fellow math student Mike Shub. She said he did most of his mathematics lying down on a sofa with his eyes closed, and she couldn’t tell if he was working or sleeping.

A couple of years after starting qi gong, after watching others in my Chinatown gym work out with various martial art routines, I started showing up early for the qi gong class and doing tai chi with a martial arts teacher, Sifu Larry Wong (no relation to Sifu Donald or friend Amy). This time, it was not my gender that earned me the privilege of hanging out, but my age; Sifu Larry was amused at the idea of teaching someone who was starting at age 70. And, of course, I was pleased by the opportunity to begin something entirely new and very physical at age 70. The tai chi he is training me on is a martial art, not “tai chi for grannies.” Although he shows me the uses of all the moves (blocking, punching, kicking) for fighting, he is discouraging me from actually doing the latter; bones don’t heal as fast at this age. But I hope to talk him into letting me at least spar.

On Recognition and Gender

Though I’ve experienced a fair number of incidents in which my gender was a disadvantage, I’m guessing that these have been balanced by others in which my gender was helpful. Certainly after more consciousness got raised, and perhaps even before then, being female made me stand out, and got the work I did some extra attention. How that might have played into recognition I’m not sure. I do know that I have been the beneficiary of some major privileges: fellowships (Sloan and Guggenheim) that allowed me to reduce teaching; a chair (and then a more padded chair) from Boston University, that gave me extraordinary freedom and some “play” money; and the opportunities that come with being a MacArthur Fellow and a member of the National Academy of Sciences.

About recognition itself, I’m very grateful but also ambivalent about the whole idea of prizes. Recognition has been extremely helpful in my career. Yet recognition sometimes seems to be bestowed in random (as well as political) ways. I’m very aware of many people doing excellent work with less external emotional support and recognition, and (in my opinion) many people doing not so good work who are extremely successful. I’ve learned to be zen about other peoples’ opinions (even before doing meditation, though that helps): I enjoy (but not too much) the ones that agree with me and listen hard to other points of view (but mostly to the reasoning, not necessarily the conclusions). Mainly, I’ve been very grateful to be a player in an ever-changing game, with the opportunities to work with and learn from wonderful people.

Acknowledgments

I have many people to thank:

My husband, who encouraged me at times when no-one else did.

Lou Howard (1929–2015), who showed me how to be a scientist.

My collaborators, who taught me more than I could ever learn in classes or from books, and who made it fun to do science.

My students and postdocs, who did the work, inspired me, led me to new places, and enabled me to give back at least a little of what I’ve been given.

All the scientists whose work influenced mine, and who I don’t have space to cite.

My colleagues at Boston University, who have helped create a warm scientific nest from which I could make forays into unexpected directions.

The funders, who provided the money to allow my scientific adventures.

Thanks!

Selected References

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Borgers, C., S. Epstein, and N. J. Kopell (2008). “Gamma oscillations mediate stimulus competition and attentional selection in a cortical network model.” Proc Natl Acad Sci USA 105(46): 18023–18028.

Borgers, C., and N. Kopell (2003). “Synchronization in networks of excitatory and inhibitory neurons with sparse, random connectivity.” Neural Comput 15(3): 509–538.

Borgers, C., and N. Kopell (2005). “Effects of noisy drive on rhythms in networks of excitatory and inhibitory neurons.” Neural Comput 17(3): 557–608.

Borgers, C., and N. J. Kopell (2008). “Gamma oscillations and stimulus selection.” Neural Comput 20(2): 383–414.

Borgers, C., G. Talei Franzesi, F. E. Lebeau, E. S. Boyden, and N. J. Kopell (2012). “Minimal size of cell assemblies coordinated by gamma oscillations.” PLoS Comput Biol 8(2): e1002362.

Bose, A., N. Kopell, and D. Terman (2000). “Almost-synchronous solutions for mutually coupled excitatory neurons.” Physica D 140(1–2): 69–94.

Bosman, C. A., J. M. Schoffelen, N. Brunet, R. Oostenveld, A. M. Bastos, T. Womelsdorf, B. Rubehn, T. Stieglitz, P. De Weerd, and P. Fries (2012). “Attentional stimulus selection through selective synchronization between monkey visual areas.” Neuron 75(5): 875–888.

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Cannon, J., M. M. McCarthy, S. Lee, J. Lee, C. Borgers, M. A. Whittington, and N. Kopell (2014). “Neurosystems: brain rhythms and cognitive processing.” Eur J Neurosci 39(5): 705–719.

Carracedo, L. M., H. Kjeldsen, L. Cunnington, A. Jenkins, I. Schofield, M. O. Cunningham, C. H. Davies, R. D. Traub, and M. A. Whittington (2013). “A neocortical delta rhythm facilitates reciprocal interlaminar interactions via nested theta rhythms.” J Neurosci 33(26): 10750–10761.

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Ching, S., A. Cimenser, P. L. Purdon, E. N. Brown, and N. J. Kopell (2010). “Thalamocortical model for a propofol-induced alpha-rhythm associated with loss of consciousness.” Proc Natl Acad Sci USA 107(52): 22665–22670.

Ching, S., M. Y. Liberman, J. J. Chemali, M. B. Westover, J. D. Kenny, K. Solt, P. L. Purdon, and E. N. Brown (2013). “Real-time closed-loop control in a rodent model of medically induced coma using burst suppression.” Anesthesiology 119(4): 848–860.

Ching, S., P. L. Purdon, S. Vijayan, N. J. Kopell, and E. N. Brown (2012). “A neurophysiological-metabolic model for burst suppression.” Proc Natl Acad Sci USA 109(8): 3095–3100.

Chow, C. C., and N. Kopell (2000). “Dynamics of spiking neurons with electrical coupling.” Neural Comput 12(7): 1643–1678.

Chow, C. C., J. A. White, J. Ritt, and N. Kopell (1998). “Frequency control in synchronized networks of inhibitory neurons.” J Comput Neurosci 5(4): 407–420.

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Ermentrout, B., M. Pascal, and B. Gutkin (2001). “The effects of spike frequency adaptation and negative feedback on the synchronization of neural oscillators.” Neural Comput 13(6): 1285–1310.

Ermentrout, G. B., R. F. Galan, and N. N. Urban (2008). “Reliability, synchrony and noise.” Trends Neurosci 31(8): 428–434.

Ermentrout, G. B., and N. Kopell (1984). “Frequency Plateaus in a Chain of Weakly Coupled Oscillators, I.” SIAM J Math Anal 15(2): 215–237.

Ermentrout, G. B., and N. Kopell (1986). “Parabolic bursting in an excitable system coupled with a slow oscillation.” SIAM J Appl Math 46: 233–255.

Ermentrout, G. B., and N. Kopell (1990). “Oscillator death in systems of coupled neural oscillators.” SIAM J Appl Math 50: 125–146.

Ermentrout, G. B., and N. Kopell (1998). “Fine structure of neural spiking and synchronization in the presence of conduction delays.” Proc Natl Acad Sci USA 95(3): 1259–1264.

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Fuchs, E. C., H. Doheny, H. Faulkner, A. Caputi, R. D. Traub, A. Bibbig, N. Kopell, M. A. Whittington, and H. Monyer (2001). “Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation.” Proc Natl Acad Sci USA 98(6): 3571–3576.

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Gillies, M. J., R. D. Traub, F. E. LeBeau, C. H. Davies, T. Gloveli, E. H. Buhl, and M. A. Whittington (2002). “A model of atropine-resistant theta oscillations in rat hippocampal area CA1.” J Physiol 543(Pt 3): 779–793.

Gloveli, T., T. Dugladze, H. G. Rotstein, R. D. Traub, H. Monyer, U. Heinemann, M. A. Whittington, and N. J. Kopell (2005). “Orthogonal arrangement of rhythm-generating microcircuits in the hippocampus.” Proc Natl Acad Sci USA 102(37): 13295–13300.

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Howard, L. N., and N. Kopell (1977). “Slowly varying waves and shocks in reactiondiffusion equations.” Studies in Applied Math 56: 95–145.

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Izhikevich, E. (2007). Dynamical Systems in Neuroscience. Cambridge, MA: MIT Press.

Jones, C., and N. Kopell (1994). “Tracking invariant manifolds with differential forms in singularly perturbed equations.” J Diff Equa 108: 64–88.

Kay, L. M., J. Beshel, J. Brea, C. Martin, D. Rojas-Libano, and N. Kopell (2009). “Olfactory oscillations: the what, how and what for.” Trends Neurosci 32(4): 207–214.

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Kopell, N., and G. B. Ermentrout (2002). Mechanisms of phase-locking and frequency control in pairs of coupled neural oscillators. In Handbook of Dynamical Systems, Vol. 2, B. Hasselblatt and A. B. Katok, Eds., 3–54. New York: Elsevier.

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Kopell, N., and M. Landman (1995). “Spatial structure of the focusing singularity of the nonlinear Schrodinger equation: a geometric analysis.” SIAM J Appl Math 55: 1297–1323.

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Kopell, N., M. A. Whittington, and M. A. Kramer (2011). “Neuronal assembly dynamics in the beta1 frequency range permits short-term memory.” Proc Natl Acad Sci USA 108(9): 3779–3784.

Kopell, N. J., H. J. Gritton, M. A. Whittington, and M. A. Kramer (2014). “Beyond the Connectome: The Dynome.” Neuron 83(6): 1319–1328.

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Kramer, M. A., R. D. Traub, and N. J. Kopell (2008). “New dynamics in cerebellar Purkinje cells: torus canards.” Phys Rev Lett 101(6): 068103.

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Kwon, J. S., B. F. O’Donnell, G. V. Wallenstein, R. W. Greene, Y. Hirayasu, P. G. Nestor, M. E. Hasselmo, G. F. Potts, M. E. Shenton, and R. W. McCarley (1999). “Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.” Arch Gen Psychiatry 56(11): 1001–1005.

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Lee, J. H., M. A. Whittington, and N. J. Kopell (2013). “Top-down beta rhythms support selective attention via interlaminar interaction: a model.” PLoS Comput Biol 9(8): e1003164.

Lee, J. H., M. A. Whittington, and N. J. Kopell (2015). “Potential Mechanisms Underlying Intercortical Signal Regulation via Cholinergic Neuromodulators.” J Neurosci 35(45): 15000–15014.

Lewis, D. A., T. Hashimoto, and D. W. Volk (2005). “Cortical inhibitory neurons and schizophrenia.” Nat Rev Neurosci 6(4): 312–324.

LoFaro, T., N. Kopell, E. Marder, and S. Hooper (1994). “Subharmonic coordination in networks of neurons with slow conductances.” Neural Comput 6: 69–84.

Lorincz, M. L., V. Crunelli, and S. W. Hughes (2008). “Cellular dynamics of cholinergically induced alpha (8–13 Hz) rhythms in sensory thalamic nuclei in vitro.” J Neurosci 28(3): 660–671.

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Marder, E., N. Kopell, and K. A. Sigvardt (1998). How computation aids in understanding biological networks. In Neurons, Networks and Motor Behavior, P. S. G. Stein, S. Grillner, A. I. Selverston, and D. G. Stuart, Eds., 139–150. Cambridge MA: MIT Press.

McCarthy, M., and N. Kopell (2012). “The effect of propofol anesthesia on rebound spiking.” SIAM J Appl Dyn Syst 11(4): 1674–1697.

McCarthy, M., N. Kopell, and E. Brown (2006). A computational analysis of anesthesia-induced paradoxical excitation. Society for Neurosciences Abstracts.

McCarthy, M. M., E. N. Brown, and N. Kopell (2008). “Potential network mechanisms mediating electroencephalographic beta rhythm changes during propofolinduced paradoxical excitation.” J Neurosci 28(50): 13488–13504.

McCarthy, M. M., C. Moore-Kochlacs, X. Gu, E. S. Boyden, X. Han, and N. Kopell (2011). “Striatal origin of the pathologic beta oscillations in Parkinson’s disease.” Proc Natl Acad Sci USA 108(28): 11620–11625.

Middleton, S., J. Jalics, T. Kispersky, F. E. Lebeau, A. K. Roopun, N. J. Kopell, M. A. Whittington, and M. O. Cunningham (2008). “NMDA receptor-dependent switching between different gamma rhythm-generating microcircuits in entorhinal cortex.” Proc Natl Acad Sci USA 105(47): 18572–18577.

Nadim, F., Y. Manor, N. Kopell, and E. Marder (1999). “Synaptic depression creates a switch that controls the frequency of an oscillatory circuit.” Proc Natl Acad Sci USA 96(14): 8206–8211.

Netoff, T. I., M. I. Banks, A. D. Dorval, C. D. Acker, J. S. Haas, N. Kopell, and J. A. White (2005). “Synchronization in hybrid neuronal networks of the hippocampal formation.” J Neurophysiol 93(3): 1197–1208.

Olufsen, M. S., M. A. Whittington, M. Camperi, and N. Kopell (2003). “New roles for the gamma rhythm: population tuning and preprocessing for the Beta rhythm.” J Comput Neurosci 14(1): 33–54.

Pervouchine, D. D., T. I. Netoff, H. G. Rotstein, J. A. White, M. O. Cunningham, M. A. Whittington, and N. J. Kopell (2006). “Low-dimensional maps encoding dynamics in entorhinal cortex and hippocampus.” Neural Comput 18(11): 2617–2650.

Pittman-Polletta, B. R., B. Kocsis, S. Vijayan, M. A. Whittington, and N. J. Kopell (2015). “Brain rhythms connect impaired inhibition to altered cognition in schizophrenia.” Biol Psychiatry 77(12): 1020–1030.

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Roopun, A. K., M. A. Kramer, L. M. Carracedo, M. Kaiser, C. H. Davies, R. D. Traub, N. J. Kopell, and M. A. Whittington (2008). “Period concatenation underlies interactions between gamma and beta rhythms in neocortex.” Front Cell Neurosci 2: 1.

Roopun, A. K., F. E. Lebeau, J. Ramell, M. O. Cunningham, R. D. Traub, and M. A. Whittington (2010). “Cholinergic neuromodulation controls directed temporal communication in neocortex in vitro.” Front Neural Circuits 4: 8.

Roopun, A. K., S. J. Middleton, M. O. Cunningham, F. E. Lebeau, A. Bibbig, M. A. Whittington, and R. D. Traub (2006). “A beta2-frequency (20-30 Hz) oscillation in nonsynaptic networks of somatosensory cortex.” Proc Natl Acad Sci USA 103(42): 15646–15650.

Rotstein, H., M. Wechselberger, and N. Kopell (2008). “Canard-induced mixed-mode oscillations in a medial entorhinal cortex layer II stellate cell model.” SIAM J Appl Dyn Syst 7(4): 1582–1611.

Rotstein, H. G., D. D. Pervouchine, C. D. Acker, M. J. Gillies, J. A. White, E. H. Buhl, M. A. Whittington, and N. Kopell (2005). “Slow and fast inhibition and an H-current interact to create a theta rhythm in a model of CA1 interneuron network.” J Neurophysiol 94(2): 1509–1518.

Santaniello, S., M. M. McCarthy, E. B. Montgomery, Jr., J. T. Gale, N. Kopell, and S. V. Sarma (2015). “Therapeutic mechanisms of high-frequency stimulation in Parkinson’s disease and neural restoration via loop-based reinforcement.” Proc Natl Acad Sci USA 112(6): E586–595.

Saraga, F., C. P. Wu, L. Zhang, and F. K. Skinner (2003). “Active dendrites and spike propagation in multi-compartment models of oriens-lacunosum/moleculare hippocampal interneurons.” J Physiol 552(Pt 3): 673–689.

Serenevy, A., and N. Kopell (2013). “Effects of heterogeneous forcing on inhibitory networks.” SIAM J Appl Dyn Syst 12(3): 1649–1684.

Sharp, A. A., M. B. O’Neil, L. F. Abbott, and E. Marder (1993). “The dynamic clamp: artificial conductances in biological neurons.” Trends Neurosci 16(10): 389–394.

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Sivan, E., and N. Kopell (2004). “Mechanism and circuitry for clustering and fine discrimination of odors in insects.” Proc Natl Acad Sci USA 101(51): 17861–17866.

Skinner, F. K., N. Kopell, and E. Marder (1994). “Mechanisms for oscillation and frequency control in reciprocally inhibitory model neural networks.” J Comput Neurosci 1(1–2): 69–87.

Somers, D., and N. Kopell (1993). “Rapid synchronization through fast threshold modulation.” Biol Cybern 68(5): 393–407.

Terman, D., A. Bose, and N. Kopell (1996). “Functional reorganization in thalamocortical networks: transition between spindling and delta sleep rhythms.” Proc Natl Acad Sci USA 93(26): 15417–15422.

Terman, D., J. E. Rubin, A. C. Yew, and C. J. Wilson (2002). “Activity patterns in a model for the subthalamopallidal network of the basal ganglia.” J Neurosci 22(7): 2963–2976.

Tort, A. B., R. Komorowski, H. Eichenbaum, and N. Kopell (2010). “Measuring phase-amplitude coupling between neuronal oscillations of different frequencies.” J Neurophysiol 104(2): 1195–1210.

Tort, A. B., M. A. Kramer, C. Thorn, D. J. Gibson, Y. Kubota, A. M. Graybiel, and N. J. Kopell (2008). “Dynamic cross-frequency couplings of local field potential oscillations in rat striatum and hippocampus during performance of a T-maze task.” Proc Natl Acad Sci USA 105(51): 20517–20522.

Tort, A. B., H. G. Rotstein, T. Dugladze, T. Gloveli, and N. J. Kopell (2007). “On the formation of gamma-coherent cell assemblies by oriens lacunosummoleculare interneurons in the hippocampus.” Proc Natl Acad Sci USA 104(33): 13490–13495.

Traub, R. D., A. Bibbig, F. E. LeBeau, M. O. Cunningham, and M. A. Whittington (2005). “Persistent gamma oscillations in superficial layers of rat auditory neocortex: experiment and model.” J Physiol 562(Pt 1): 3–8.

Traub, R. D., D. Contreras, M. O. Cunningham, H. Murray, F. E. LeBeau, A. Roopun, A. Bibbig, W. B. Wilent, M. J. Higley, and M. A. Whittington (2005). “Singlecolumn thalamocortical network model exhibiting gamma oscillations, sleep spindles, and epileptogenic bursts.” J Neurophysiol 93(4): 2194–2232.

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Traub, R. D., N. Kopell, A. Bibbig, E. H. Buhl, F. E. LeBeau, and M. A. Whittington (2001). “Gap junctions between interneuron dendrites can enhance synchrony of gamma oscillations in distributed networks.” J Neurosci 21(23): 9478–9486.

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Margaret Stratford Livingstone

BORN:

Danville, Virginia

April 3, 1950

EDUCATION:

Massachusetts Institute of Technology, Cambridge, MA, Biology, BS (1972)

Harvard University, Cambridge, MA, Neurobiology, PhD (1981)

APPOINTMENTS:

Visiting Fellow, Princeton University (1981–1983)

Research Fellow in Neurobiology, Harvard Medical School (1982–1983)

Instructor, Harvard Medical School (1983)

Assistant Professor of Neurobiology, Harvard Medical School (1983–1986)

Associate Professor of Neurobiology, Harvard Medical School (1986–1988)

Professor of Neurobiology, Harvard Medical School (1988–2014)

Takeda Professor of Neurobiology, Harvard Medical School (2014–present)

HONORS AND AWARDS:

Phi Beta Kappa

Presidential Young Investigator Award, 1984

NIH Research Career Development Award, 1985

Office of Naval Research Young Investigator Award, 1986

Mika Salpeter Lifetime Achievement Award, 2011

The Caroline P. and Charles W. Ireland Distinguished Visiting Scholar Prize, 2012

The Grossman Award from the Society of Neurological Surgeons, 2013

Roberts’ Prize for Best Paper in Physics in Medicine and Biology, 2013

Margaret Livingstone has studied the role of monoamines in lobster behavior and in learning in fruit flies, but for most of her career, she studied visual processing. In collaboration with David Hubel, she revealed the interdigitating parallel nature of the visual system. In 1984 they described a new subdivision in primate primary visual cortex involved in processing color, and described the anatomy and physiology of this previously unknown system. Her laboratory showed that macaques, like humans, have specialized regions of the temporal lobe that are selectively involved in face processing. She has explored the ways in which vision science can understand and complement the world of visual art.

Margaret Stratford Livingstone

Early Years

I feel silly writing my ‘biography’ because I don’t feel done yet, and I can’t imagine why anyone would want to read it anyway, so I am going to imagine I am writing to a young person, I hope a woman, who is thinking about a career in neuroscience. My route to becoming a neuroscientist has been haphazard, and if a young person has the sense to be reading the biographies of established neuroscientists, they already know more than I did until I was halfway through medical school. I have included some personal history that I was inclined not to, because I know that the question of what kind of personal life you can have as a scientist looms large for many women, and I am proud of being a single mother and doing good science. I have also revealed how uncertain I have felt at times, to help dispel the notion that you have to be a genius to succeed in science. I have always felt, and still do, like an amateur amongst experts, but I think knowing that you don’t understand something that you find fascinating is a good place to start if you want to do good science; I wish I had been more comfortable when I was younger with feeling mystified. If you finish this essay and think “I could do that, but I wouldn’t have been so naive, or disorganized, or I wouldn’t have put up with that,” then this exercise will have been worth it.

I was born in Virginia in 1950, but my family moved almost yearly. My father rose through the ranks of an insurance company, and every time he got promoted, we moved, because it was thought bad policy to promote someone to a position above a previous colleague. Relocating employees of large companies was common practice in the 1950s because wives and families were considered subordinate to a man’s career. So I was always a new kid, and usually had the wrong accent. When I try to understand how I came to do science, I suspect that my not fitting in socially was a factor. Before I went to college we lived in Danville, VA; Leaksville, NC; Draper, NC; someplace in South Carolina; Charlotte, VA; Atlanta, GA; Norwalk, CT; Arlington Heights, IL; Roanoke, VA; and St. Petersburg, FL. When we moved to Connecticut I was in the first grade, and had to go to special speech classes, because they thought my southern accent was a speech defect. It took my parents months to realize that I didn’t actually have a speech defect because my father was in a new job and my mother had to deal with moving and a new baby. We moved when I was a freshman in high school and halfway through my senior year in high school. I was insecure and socially inept.

Our present culture and mind-set are so different from what I grew up with that I want to try to describe what it was like in the 1950s in the Southern United States. It was not a great place to be a smart girl, and I know it was an even worse place to be a minority, though I was largely unaware of those issues. I never felt like being smart was socially acceptable, but I studied hard. I was not popular though I deeply wished I were; I do not know if I studied to compensate, or whether I was unpopular because I studied. Science was not interesting in the schools I attended; it consisted mostly of memorizing lists of phyla and species. I liked math, but none of the high schools I attended offered anything beyond basic algebra. I did collect skulls that I found and made skeletons from road kill by soaking the carcasses in lye, but it never occurred to me that I should aspire to do anything except become a wife and mother. My original impetus for studying science, and eventually engineering, was that I worried I wouldn’t get married—I didn’t seem to be particularly attractive to boys, so I figured I would need a job to support myself.

I wished I could be a cheerleader, but the unwritten rule was that only popular girls could do that, so I didn’t even try. I took three years of home economics because it was required (of girls; boys took shop), and learned, in school (!), to cook, sew, and keep house. I remember a lesson in which we were taught not to keep our nails too long because they would snag on our stockings and not to have a windblown hairdo because it looked messy. I also learned, in those home-ec classes, to let boys do the talking, and how to ask questions that would “bring him out.” Jim Crow laws were in effect, and I had been told that as white girl I was supposed to use the bathroom labeled “ladies” not “women.” Water fountains were labeled explicitly “white” and “colored.” It is amazing to me now that I accepted all these customs as reasonable, but all the people around me, especially adults, certainly did. Billy Graham, the evangelical preacher, was a local celebrity who visited our high school and gave sermons in the auditorium. We pledged allegiance and said the Lord’s Prayer every morning in class. Church was socially very important, but I had trouble reconciling logic with religion, and refused to go, even though it made me still less popular. Big hair was in; I slept nightly on two-inch rollers with bristles! My junior year I finally had a boyfriend, but he broke up with me after he found out my PSAT scores were higher than his. My second boyfriend was socially above me and was regularly an escort at Debutante balls, to which I was not invited, not being FFV (first families of Virginia). Dates were invariably to drive-in movies, or to drive endlessly, in circles, around the Shoney’s (a local hamburger place). I can’t imagine why we did this, but I was thrilled to be included.

Young people today would be horrified by the blatant sexism and racism that were the norm in the culture I grew up in, yet the main reason I thought so much outside the box was because I didn’t fit in. I feel very lucky to have ended up in science despite the social pressure not to. I had read widely enough to realize (contrary to the pervading local culture) that people of color should be equal to whites, but I assumed the practice of “separate but equal” was fair, until I read a Life magazine story that showed the reality of that policy. Similarly, reading Betty Friedan’s The Feminine Mystique in my late teens made me realize that I had more choices than I had thought. My mother had a college degree, and loved math and science, but she worked for only a few months after college before becoming a housewife, because that’s what everyone she knew did. She often told me she regretted not working, though she said being a wife and mother was completely fulfilling; she said she didn’t mind playing a supporting role because she thought my father was the most brilliant and wonderful man in the world. My father always called me his “first born,” but my younger brother his “son and heir.” He encouraged me to aspire to go to a good college, but we both assumed I would get married and be a housewife.

I started high school in North Caroline, moved to Virginia, and then, in the middle of my senior year, to Florida. In all three schools, obligatory pep rallies were a regular event, in which the entire student body crowded into a hot auditorium the day of some sporting event to cheer and chant and pray in unison. I abhorred pep rallies, and I still cannot abide spectator sports. By moving so much, I managed to hit 3 consecutive years of state history classes, in three different Southern states, so I know more about the War of Northern Aggression than you can imagine. When I moved to Florida in my senior year, I had to take two semesters of “Americanism vs. Communism” in a single semester because an entire year of that subject was a state requirement for graduation; the textbook was J. Edgar Hoover’s Masters of Deceit. That last move was particularly devastating because I had finally settled in socially in Virginia, and even had a boyfriend. I tried to convince my father to let me stay in Virginia to finish my senior year, but my mother was dying of a glioblastoma, and my father needed me to run the household.

College Years

Florida was horrible. Only a few students in my class planned to go to college, and those who did planned to go to the local community college, except two or three of the smartest kids who wanted to go to Florida State. To go to an out-of-state college was unheard of. I had applied to and was accepted by three colleges before we moved to Florida: MIT, Cornell, and Duke. My Florida guidance counselor did not know what the initials M.I.T. stood for. I was so shook up by moving, and by my mother’s illness, that I chose to go to Duke rather than MIT because MIT terrified me, and Duke was where my mother had had her brain surgery. I acquired a new boyfriend who worked in a gas station and, in retrospect, was not very nice to me. It was a relief to leave home to go off to college, even though there was a need for me to stay home and take care of my three younger siblings and my very sick mother.

At Duke, I enrolled in the Engineering School because I thought as an engineer I could support myself and would not need a husband (I was still insecure about the possibility that I could attract a husband), and because it seemed like a good major for someone who liked math and science. This was 1968. Drugs and protest hit the Duke campus like a tidal wave. Classes were boycotted to protest the Vietnam War (I am still unsure about the logic of this since most of our parents were paying a lot of money for us to attend Duke). It seemed like everyone was marching, protesting, drinking, doing drugs, and having sex. Nobody much cared about classes, except to a small extent at the Engineering School. I had to take mechanical drawing and materials science. I learned a lot about cement and metal fatigue, but I found it boring. I got a job as an engineer with the Army in Washington, DC (the only summer job I could get as a student engineer) and was supposed to help design bullets (shells?) that would “long time out.” That is, if they failed, they would blow up at the end of their timer, not the beginning. I don’t think I did anything useful engineering-wise that summer, and I didn’t like working as an engineer. My two male supervisors took me and some visiting dignitaries to a strip bar one evening, and I didn’t like that either, but it never occurred to me to object.

I decided that I had made a mistake by not going to MIT, so I applied to transfer for my junior year. I am now pretty sure that in the late 1960s Cambridge was just as crazy as Durham, but I didn’t know that. I was just as crazy as everybody else, but I had had enough of beer and drugs and sex and thought maybe there was something else I might get out of college. The whole country was nuts then. I think that the craziness of the country during the 1960s was more a phenomenon of demographics than politics. The largest cohort of people in the country, the baby boomers, hit their teenage years then and got overwhelmed by hormones, so I think our whole culture became dominated by us and our adolescent behavior. It really was an astonishing time.

When I arrived at MIT, I was depressed at first because it was cold, dark, and wet, and the classes were really, really hard. It was the first time in my life I had assignments that required thinking, rather than memorization and practicing what I had been shown how to do, but it was absolutely exhilarating. I took introductory biology from Salvador Luria. His lectures consisted of telling us how he and his friends had worked out the principles of microbiology. Our tests challenged us to design experiments to figure out something unknown. Boris Magasanik taught the next semester. I was hooked. Then I took biochemistry from Gene Brown who told us how he and his colleagues had deduced each step in the Krebs cycle. I loved MIT. All the women lived in one dorm, McCormick, so the number of women at MIT was limited by the number of rooms there—35 women (in all of MIT) when there was only one McCormick tower, and 70 when they built the second. The women at MIT were astonishing. Although reading Friedan had made me realize that I could work instead of getting married,¹ at MIT I found brilliant women who thought they could do anything. They thought they could do what they enjoyed and found interesting. My favorite classes were biology and biochemistry, probably because the teachers were so enthusiastic and interesting, so I decided to go to medical school, largely because I somehow got the idea that medicine involved research. I am not sure why I thought this, but I did. I was accepted at Stanford and Harvard Medical Schools, but because Stanford sent me a letter saying that they were accepting a disproportionate number of women in order to address the dearth of women in medicine, I went to Harvard. Stanford really could have put it better.

I loved the first two years of medical school, except biochemistry, in which we had to memorize the Krebs cycle, which was much less interesting than it had been learning from Gene Brown how they had figured each step out. I understand that premeds have to memorize all of intermediary metabolism in order to even get admitted to med school these days. I think that is unfortunate. I loved physiology, anatomy, and histology. I took neuroanatomy from the great Walle Nauta, who, using the Nauta method, had worked out most of the tracts in the spinal cord and brainstem. After a whole semester, though, of neuroanatomy from 8 a.m. to noon on Tuesdays, Thursdays, and Saturdays, we only made it as far north as the midbrain. Years later, I met Walle at a conference, and he remembered me as the girl with narcolepsy.

We didn’t get sent to the clinic until after two years of “basic sciences,” and there I was not so happy. I felt too much the distress of the patients and their families, as they were undergoing one of the worst times of their lives. The emotional stress made it hard for me to think logically. I felt frantic. I did rotations in medicine and obstetrics, and then neurology. I took neurology at Boston City, the last year that Norman Geschwind was chair. I loved that: we spent most of our time talking about how to diagnose what was wrong with someone by doing clever neurological tests. I remember one epilepsy patient whose locus the house staff could not diagnose (this was before MRI), though they suspected the temporal lobe. The patient did not show any of the classic signs of temporal lobe involvement (aura, interictal hypergraphia, or hyperreligiosity), but NG carefully questioned the patient and discovered a suitcase full of drawings under his hospital bed, so the locus was in the temporal lobe, not that it made any difference to the patient. Then I did a rotation in psychiatry at Mass Mental. Again, we talked endlessly about how to deduce what was wrong with someone’s brain by talking to them and asking them to do simple things. I was mesmerized by a talk Joseph Schildkraut gave about the (then-novel) idea that dopamine might be involved in schizophrenia: the efficacy of drugs that block amines in ameliorating psychosis, the complementarity of schizophrenia and Parkinson’s disease, the Parkinsonian symptoms of antipsychotics, and the psychotic symptoms that could be a side effect of Parkinsonian drugs. He provided all kinds of indirect yet converging evidence. It was like a detective novel. I decided I wanted to get a PhD and discover how to make drugs that modified aminergic circuitry. I asked the pharmacology department at Harvard if I could do a thesis on synthesizing monoamine-oxidase inhibitors, and I spent a year messing around and not accomplishing anything. Then I asked Ed Kravitz in the Neurobiology Department if I could study what monoamines actually did in his lab.

The Department of Neurobiology

The department was fantastic. There were two elderly Hungarian men: one was the chairman, Steve Kuffler, and the other was the guy who delivered the mail. For the first few weeks, I had the two of them mixed up. We had lunch seminars where the “young Turks,” David Van Essen, Jim Hudspeth, Darwin Berg, and Eric Frank, used to pepper every speaker with so many questions that they never finished what they came to say. My first course in the department was some kind of neurophysiology class, and I was so overwhelmed by how much the other students knew that I went to one of the teachers, Ann Stuart, and asked her if she thought I should drop out of science. She wisely said no, that some students are just better than others at sounding smart, but it doesn’t make them better scientists. (I am afraid it is a talent that I still lack, and one that is useful for getting grants.)

Ed put me on a project looking for serotonergic neurons in lobsters. I incubated bits of lobster tissue in radioactive serotonin precursor, then used paper electrophoresis to migrate small charged molecules, like amines, along the paper. I had marked where serotonin would end up by staining for nonradioactive serotonin in the “hot zap.” I cut out the spots from the different tissues where the serotonin should be and counted them in the scintillation counter. Several were quite radioactive, but I had not yet got the concept of a baseline so I had to go back and repeat the experiment, cutting up the entire strip of migrating radioactive stuff from each tissue, and this time comparing the spots to the rest of the strip. I did find out where serotonin was made in the lobster, but that didn’t excite me. I wanted to know what it was doing in the overall behavior of the animal. I asked Ed if I could just inject amines into some lobsters to see what would happen. Ed had been studying himself for some time what serotonin and octopamine (the lobster equivalent of epinephrine) did at the lobster neuromuscular junction, and, since both amines made the thumb muscle of the lobster tonically contract, Ed said no, I couldn’t do that experiment because the lobster would just contract all its muscles.

Ed used to take his entire lab to Woods Hole every summer, so that summer I helped pack everything up and schlepped it all down to the Cape. Because so many labs there study lobsters, there were a lot around, and a member of another lab let me have six lobsters to try out my experiment of just injecting amines, which I had been yearning to do for months. I put yellow bands on three lobsters and red bands on the other three. I injected the yellow-banded lobsters with some octopamine (about a pinch as I recollect, dissolved in seawater), and the red-banded lobsters with some serotonin. In a few seconds the red-banded lobsters all rose up on their hind legs and spread their claws high and wide; the yellow-banded lobsters all raised their tails, lowered their heads to the ground, and spread their claws forward, as if they were bowing. You didn’t need to know anything about lobster behavior to realize that the red lobsters were in an aggressive pose, and the yellow ones submissive, though I did happen to know those were typical postures for aggressive and submissive lobsters. The lobsters were not acting aggressively and submissively, though; they were just frozen in those stereotyped postures. So I went and found Ed, and brought him back. The six lobsters were still frozen in those opposing postures. Ed was impressed and admitted that he had been wrong not to let me do the experiment. He then said that he would get a postdoc in the lab, Ron Harris-Warrick, to do the physiological studies to find out why the two amines would have such interesting opposite effects. I asked if I could do the physiological experiments, and Ed said, no, Ron knew how to do physiology, and I was a chemist (after only a year I was a neurochemist!), and I needed to finish the project I had started, proving that the cluster of cells I had found really were serotonergic. I didn’t like that boring project, and I wanted to do physiology, which seemed a lot more fun than neurochemistry. But I did what Ed told me to, resentfully, and Ron began intracellular recording from various neurons in various ganglia in the presence and absence of octopamine and serotonin. Ron observed that some neurons fired more, some less, and some didn’t change.

Meanwhile, I read a lot of papers about invertebrate command circuits that were responsible for complex but stereotyped behaviors, like escape. I read about sustained responses in these command circuits, and learned that, although the neurons were mixed together in the ganglia, flexor and extensor axons exited out of different nerve roots. I realized I could use this anatomical quirk to find out whether serotonin and octopamine induced these postures by activating command circuits, but Ed wouldn’t let me do physiology, so one day I asked a professor from the physiology department if he had any recording equipment I could borrow. Elwood Henneman kindly lent me a polygraph, the kind that is used for electroencephalography (EEG). It wasn’t a fancy intracellular physiology rig, but it would record, with ink pens on a long piece of paper, squiggles that varied with the extracellular signals from the nerve roots. I bathed a lobster nerve cord in serotonin, and the squiggle from the nerve root that supposedly carried flexor activity got thicker; then when I bathed the cord in octopamine, I saw more activity from the extensor root. That meant that serotonin probably activated an entire flexor circuit, and octopamine the inverse. I showed Ed. Ed finally told me I could work with Ron on this project and that we could use a real physiology rig to measure activity in flexor and extensor circuits. We did not work well together. Once we were shoving each other aside trying to solder something together, and a blob of solder sank into my finger. I still have the scar. Ron said it served me right for being so pushy.

We did eventually get a nice paper out of this (Livingstone et al. 1980), showing that an entire flexor circuit was activated by serotonin, and an entire extensor circuit by octopamine, in both lobsters and crayfish, and this result suggested that monoamines could differentially modulate behaviors via differences in the distribution of amine receptors on functionally distinct neuronal circuits. Just today I heard Ed give a lovely talk on monoaminergic modulation of stereotyped aggressive patterns of behavior in fruit flies.

I got interested in the role of monoamines in learning. I had been following Eric Kandel and Jimmy Schwarz’s work on Aplysia, showing that serotonin provided the reinforcement signal for fear conditioning. And there was a lot of stuff being published about monoamines acting through second messengers, like cyclic AMP. So I got the idea that monoamines could trigger second messengers, and that this would somehow lead to changes in synaptic strength. Chip Quinn from Princeton gave a lunch talk in our department about the learning mutants he had isolated in Drosophila. He gave convincing evidence that flies could show associative learning, and that there were mutants who either couldn’t learn or forgot rapidly. I asked if any of these learning mutations affected monoamine synthesis or second messenger pathways. He didn’t know, but he was happy to have me come be a postdoc in his lab and test his learning mutants for defects in monoamine/second-messenger pathways (I was, after all, a neurochemist).

I wanted to finish the few months I had left of medical school, and then I planned to go to Princeton to work in Chip’s lab. The minimum clinical requirement for graduating with an MD from Harvard Medical School at the time was medicine (three months), surgery (two months), and three onemonth rotations. I had done medicine, neurology, obstetrics, and psychiatry, so I assumed I only had to finish two months of surgery and then I would get my MD/PhD. I went to the dean of students, Dan Federman, to schedule my last rotation. His office was full of boxes of books. He said the books were a textbook of medicine he had just written and asked if I wanted to buy one. They cost hundreds of dollars. I said no, thank you, I did not plan to practice since I wanted to do research. He asked, why, then did I want an MD? I said I wanted to do biomedical research and that an MD might be useful. When I asked about finishing my MD with a rotation in surgery, he said I had been away from the clinic so long (four years) that I really needed to do two more years of clinical rotations in order to qualify for an MD. I argued with him, but the best I could get him to concede to was another full year of clinical rotations before I could graduate. I am still astonished that a single person could have so much say over a student’s career, but this was before committees, and before the formation of an MD/PhD program with set requirements. I was devastated and decided reluctantly to forgo the MD in order to start my postdoc, because I was so excited about the experiments I wanted to do. My father, who had paid in full for two and a half years of Harvard Medical School, was furious that I wasn’t going to finish my MD and that Harvard had changed the requirements on me. He wanted to sue Harvard. He came up for my PhD defense, fuming. At some point Steve Kuffler took my father out into the hallway to talk, and after that, my father didn’t complain ever again about my decision.

Postdoc I: Princeton

I went to Princeton, and set up a mini neurochemistry lab. As usual, I borrowed, confiscated, rescued, or constructed most of what I needed. By then Duncan Byers had discovered that the learning mutant Dunce had a defective cyclic AMP degrading enzyme (Byers et al. 1981), which was entirely in line with my ideas of monoamines and second messengers being involved in associative learning. I figured out how to assay cyclic AMP and determined that another learning mutant, Rutabaga², had a defective calcium-dependent cyclic-AMP-generating enzyme (Livingstone et al. 1984). It seemed that an enzyme that could link neuronal activity via calcium with monoamine reward responses ought to be a key player in reinforcement learning. We also found that a mutant that couldn’t make dopamine also was defective in learning (Livingstone and Tempel 1983). Thus, three Drosophila mutants that couldn’t learn had defects in the monoamine/second messenger pathway. I was thrilled.

Postdoc II: Back to Harvard

I wanted to study the effects of monoamines in mammals. When I was still at Harvard, I had gotten to talking with David Hubel about the visual system, and I decided to do a second postdoc with David to see if monoamines would modulate activity in the visual cortex. The most sensible way to do this would have been to iontophorese monoamines onto the visual cortex while recording from neurons and mapping their response properties. We didn’t know how to iontophorese, but David did know how to put stimulating electrodes in different locations stereotaxically, so we decided instead to stimulate monoaminergic loci in the brainstem. We chose the locus coeruleus (LC) because it is a major noradrenergic nucleus, and we thought that stimulating the LC ought to flood the cortex with norepinephrine. We certainly observed changes in the visual cortex when we stimulated the LC, but we also noticed that every time we stimulated the LC the EEG went flat. We monitor EEG to make sure the animal is anesthetized. Normally a flat EEG means the animal is awake, whereas in sleep or under anesthesia the EEG is wavy. So we decided that maybe the differences in visual responses were due to differences in sensory processing between waking and sleeping. Since there was emerging evidence that monoamines were probably important, maybe essential, in controlling waking and sleeping, this seemed like a great thing to pursue.

We decided to study the differences in visual cortex physiology between waking and sleeping. To do this we set up cats for chronic recording (i.e., we implanted headholders beforehand under anesthesia) and recorded from them subsequently as they cycled between waking and sleeping. We saw much stronger visual responsiveness during waking compared with sleeping, not because responses were reduced during sleep, but because the neurons became very noisy during sleep. In particular, we saw large variations in firing that corresponded with the waves in the EEG, suggesting that the waves in the EEG are made up from synchronized firing in a lot of neurons (Livingstone and Hubel 1981). One of our cats did not fall asleep, after many hours, even though cats usually sleep a lot. So, thinking we knew what we were doing, we gave the cat a dose of diazepam (Valium) to make it drowsy. It had the opposite effect, which we later discovered had been previously observed—that diazepam has a paradoxically alerting effect in cats. So there we were for 12 more hours with that wide-awake cat. During that endless experiment, I read a book I found on David’s bookshelf to pass the time: Sociobiology by E. O. Wilson. The experiment was a failure, but the book was fantastic.

One of my postdocs makes fun of me because I spend a lot of time making things for experiments. I just spent half an hour using zip ties to mount a drilled-out sawed-off Tupperware container inside a standard monkey chair to adapt the chair for baby monkeys. (It works great.) I would feel silly about this, except I remember that the first time I really impressed David Hubel was when I made a cat-sleep-deprivation apparatus from a 4-foot diameter cardboard drum I had found at the demolition site of one of the Harvard Medical School buildings. I also remember that after we had used this huge drum to sleep deprive a cat, we took it into the men’s room to empty it into a toilet. It was bigger than the stall, and it was so awkward to aim at the toilet that I started laughing and couldn’t warn David, who was on the far side of the drum, that our aim was off. We both ended up with soggy cat excrement all over our feet. David used to spend hours in the lab making stuff too, using whatever he could find. He was more skilled than I am, though, and he actually machined things. My lab still thinks it is peculiar that I spend so much time building things and doing experiments myself, but it’s so much fun I can’t imagine not working this way. I also analyze my own data now, but I am not nearly as good as my postdocs since I didn’t even begin learning MATLAB® until I was 50. I am just now, at 65, trying to master UNIX. Learning to program late in life is challenging.

The Blobs

David and I decided to try a new technique, using radioactive 2-deoxyglucose (2-DG), which is taken up by active neurons but isn’t metabolized, so you can use autoradiography to identify active regions of cortex. The problem with 2-DG is that you can label only one kind of activity, because you have to kill the animal to do the autoradiography. You therefore can’t contrast one kind of activation with another. So David and I tried using tritiated 2-DG for one stimulus condition and 14carbon labeled 2-DG for a second condition, so that we could contrast two patterns. We could then cover the sections with Saran Wrap, and use X-ray film to visualize the 14C pattern (3H does not penetrate Saran Wrap), then once we had the 14C pattern, we could dip the same slides in emulsion and visualize the 3H pattern. This worked pretty well, but the exposures took months, and you had to titrate the two radioisotopes carefully or one would dominate the other.

While I was a graduate student, Charlie Gilbert, David Ferster, Mary Kennedy, and I shared a house in Brookline. Later on Josh Sanes moved in. It was great fun, and we had endless fascinating scientific discussions and wonderful dinners, since both David and Charlie are superb cooks. Mary and I generally chopped things and cleaned up, though she had mastered an excellent spaghetti carbonara. One day David Ferster and I were waiting on Charlie, in Torsten’s lab, to go home with us, and I noticed a tray of histology slides on a bench with very clear dark and light stripes in V1. I asked Charlie why there were stripes, and he said he didn’t know, because the slides had been stained for horseradish peroxidase (HRP), which Charlie and Torsten used to visualize the anatomy of single cells they had recorded from. Charlie guessed that the monkey must have had damage to one eye, but didn’t know why that should turn up in this stain for HRP. I mentioned this to David Hubel, because I thought it might be a good way to visualize ocular dominance columns. David remembered that Margaret Wong-Riley had sent him a letter with a slide showing that another similar histological stain for the enzyme cytochrome oxidase also showed ocular dominance columns, in animals in which one eye had been damaged or shut, but also showed a regular pattern in normal animals, with regular puffs of cytochrome-dark staining in the upper layers of V1. David had never learned to do histology himself, so he asked his grad student, Jonathan Horton, to see if he could get Margaret Wong-Riley’s (1979) stain to work. Jonathan did, and saw a dramatic pattern in tangentially cut sections. David wanted to use our double-label 2-DG technique to see whether the dark blobs represented one orientation or another, or all orientations, so we started dipping and staining and getting very confused because the blobs seemed to light up no matter which orientation we used. We decided that this question would be best answered the slow, hard way, by recording from cells in long tangential electrode penetrations, and later reconstructing the histology. I can remember laying out huge (4-foot wide) photographic prints of cytochrome-oxidase stained sections and trying to determine where we had recorded which cells. Jonathan thought that he ought to be doing these physiological experiments, and I can certainly sympathize with his point of view, but in the end, he did a lovely study that was completely independent (Horton 1984).

David and I discovered that the cytochrome-dark regions were full of color-selective cells, but the surrounding lighter regions were orientation selective. We discovered this because David always said, “If it won’t respond to a white bar, try black. If black doesn’t work, try red.” The color selectivity of the cells in the dark regions (we called them “blobs” because they were roundish) was striking and always fun to play with. It is very satisfying to deduce that a cell that at first is just barely responsive to a bar of light is selectively excited by blue and inhibited by yellow, or the reverse. I guess we all do science because we like figuring out mysteries, and each neuron’s selectivity is a little puzzle that you can solve, usually in just a few minutes. And you do it by waving a spot of light on a screen that you can see, and you listen to the firing of the cell by putting the electrical signals that the neuron generates through a loudspeaker. There is this real-time exploration of what the cell “wants.” The fact that these color cells were clustered into anatomically distinct regions was actually a rediscovery of something Charlie Michael had previously reported in 1981, namely that color cells in V1 tend to be organized in columns, but he didn’t have cytochrome-oxidase staining to anchor his physiology.

We found that cells in the blobs generally responded to color and didn’t care about orientation, but cells outside the blobs were the reverse. David was somewhat chagrined that he and Torsten had not noticed the existence of these blobs, and we discussed the various reasons. So, when writing up this study, I, tongue-in-cheek, wrote a paragraph to speculate on why no one might have stumbled on this before:

The historically minded reader may have wondered how so prominent a group of cells could have been missed by so prominent pair of investigators (H&W, 1968, 1974). We, of course, wondered the same thing and can think of several possible reasons. (1) Injured cells become sensitive to almost any visual stimulus… .(2) With no anatomical indication of nonhomogeneity in the upper cortical layers, it would have been easy to dismiss occasional, apparently sporadic groups of unoriented cells. (3) A sudden series of monocular unoriented cells could be interpreted as entering layer 4C, which occasionally might have seemed remarkably superficial. (Livingstone and Hubel 1984a, p. 315)

Then I passed the (by then enormous) typed manuscript back to David who worked on it for a while, then gave me his corrected version. I still remember falling off my chair laughing when I read what David had added: “(4) The prominence was ill-begotten.”

Using Equiluminance to Dissect Where and What

After recording from a lot of visual cortex, we came to realize that color and motion were not usually coded by the same cells: individual cells either cared about color, or about motion, but hardly ever both. Color and orientation tuning (shape selectivity) were also separated, though not as extremely as color and motion. Then we saw a demo that Patrick Cavanagh had made at a meeting for Vision Scientists. This was the dawn of personal computers, when a computer demo was novel, and this one really wowed me: Patrick had made a moving wheel with spokes that he could modulate from luminance-contrast to color-contrast-without-any-luminance-contrast (equiluminance) (Cavanagh et al. 1984). The motion of the wheel seemed to almost stop at equiluminance. I was so impressed by this demo, because it said to me that our perception of motion is basically colorblind, which was completely consistent with what David and I were seeing physiologically. I extrapolated to the idea that maybe the entire dorsal stream might be colorblind (not colorblind like red/green colorblindness, but colorblind in the sense of not seeing equiluminant contours, when the two colors defining the contour are equally light). This started a more than year-long argument with David Hubel. His first reaction to my suggesting that the entire dorsal stream might be colorblind was that stereopsis ought to be colorblind, and he thought it wasn’t supposed to be (there is, indeed, quite a bit of literature reporting that it is not). So we did the first of dozens of psychophysical experiments designed to test each of David’s objections to the idea that dorsal-stream functions are impaired (or disproportionately impaired) at equiluminance. Stereopsis was a difficult test for us because David’s equiluminance point was different from mine, so when I thought a stereogram looked flat, he ridiculed me and said that the stereogram had remarkably clear depth, and that maybe I just had defective stereopsis. But then we found a setting where he thought the stereogram went flat, which really surprised him, but was very convincing. So then he said that maybe stereo and motion might be diminished at equiluminance, but what about illusions of size? What about Vernier acuity? What about the differences in acuity between the dorsal and ventral streams? This went on for a year. I can remember crying when I got home once because I was so frustrated at his stubbornness in refusing to accept this hypothesis, but in the end, we did more than 50 different perceptual experiments, and he ran out of objections, so we published it (Livingstone and Hubel 1987a). Later he claimed that he always thought we had overstated our hypothesis. I regret that he was never completely convinced, but I still think we were right.

Color Constancy

In all this recording from blobs, we rediscovered something else that Charlie Michael had previously reported, namely that these color-selective cells in V1 were strongly surround suppressed, and this surround suppression was color-opponent (Michael 1978). We found that “red” cells respond poorly to a red spot on a red background, but strongly to a red spot on a blue-green background. That is, the color selectivity was dependent on the surrounding wavelengths. Around this time, in the early 1980s, Edwin Land invited us over to his Institute in Cambridge to talk about color. Land was also particularly impressed by how independent one’s perception of color can be from wavelength. We usually think of color as being a function of wavelength, but Land had a number of demonstrations that he showed us that revealed how much one’s perception of color depends on the surrounding wavelengths, again consistent with what we were seeing physiologically. How dramatic this can be was recently illustrated by a viral photo of a dress that appears to be blue and black to some people and gold and white to others, depending on whether the viewer interprets the dress as being in the shade or in the sun (the cues to this are ambiguous); it is just one of many examples of how strong surround effects can be on color perception. Land had demonstrated that a single wavelength can appear as one color in one context and a completely different color in another. We did an experiment together with Land to test whether this calculation happens in the retina or the cortex. We rigged up a particularly strong surround effect in one visual field that, for normal observers, spreads to influence the color of a spot in the other visual field, across the vertical midline, and tested the effect on a split-brain subject. We did this experiment (and repeated it several times, in this single split-brain individual in one afternoon), and it was quite clear that his color constancy did not cross the vertical midline, indicating that the calculation must depend largely on the cortex, not the retina (since the entire visual field is represented in each retina, but is split down the vertical midline in the two cortical hemispheres). That evening, Land took us to his club (very fancy) where I wrote out a draft of this result (Land et al. 1983) in a lounge, while a woman in a strapless gown played the piano. I remember this quite distinctly because from where I was sitting, she appeared naked.

Interconnected Modular Organization

We had noticed that there was a distinct cytochrome-oxidase pattern in V1 (small round blobs) and a coarser pattern of stripes in V2, and we did years of recording in V1, and later in V2, to try to understand what the pattern meant. Roger Tootell also had been looking at the cytochrome-oxidase patterns, and did gorgeous 2-DG experiments to try to figure it out (most of these papers were written by Roger when he was supposed to be a postdoc in our lab (Tootell, Hamilton, et al. 1988; Tootell, Hamilton, and Switkes 1988; Tootell, Silverman, et al. 1988; Tootell, Switkes, et al. 1988); nevertheless, I hope he agrees that our results have turned out to be marvelously complementary. After recording for a couple of years in V1, we got a windfall when Roger Spealman told us about a large group of about 50 squirrel monkeys out at the primate center who had been bought for a malaria study but hadn’t been used (or had been controls for a vaccination). We got them for free, and this allowed us to do a study that otherwise would have been prohibitively expensive: we made a series of HRP injections in V2 to see what the anatomical connections were between the two cytochrome-oxidase patterns in V1 and V2. I still have the slides from those experiments: you can see the results just holding up the slide. Figure 1 is an unmagnified picture of one of the slides lit from the side with an automobile headlight (our crude dark-field). They were so clear, and so astonishing! When we injected one kind of stripe in V2, we saw patchy labeling in V1 only in the cytochromeoxidase blobs; when we injected cytochrome-pale stripes in V2, the labeling in V1 was also patchy, but now only in the interblobs. Thus, blobs in V1 projected to dark stripes in V2, and interblobs in V1 projected to pale stripes in V2; and the feedback connections were also compartment specific (Livingstone and Hubel 1983, 1984a, 1987b). This specificity of interconnectivity was completely unexpected. We also found compartment-selective interconnectivity within V1 and within V2 (Livingstone and Hubel 1984b, 1987b). All this led us to conclude that there were functionally and anatomically distinct pathways carrying different kinds of visual information.

Fig. 1.  A section of macaque V1 showing the gorgeous patchy pattern of connections between V1 and V2. This section was a couple of centimeters across, so you could see the patches just by eye; here the patches are made bright by holding the section transversely in the beam of an automobile headlight.

Work/Family

By then I loved science; it never seemed like work. I had a sparse social life, always with other hard-working scientists, and one of those relationships led to my getting pregnant. I decided to have the baby, even though I wasn’t married and was up for tenure. No one had gotten tenure in our department since Ed Kravitz, 20 years previously, so I figured I had little chance, especially as my pregnancy became apparent. But the dean, Dan Tosteson, had recently decided that Harvard should abandon the policy of giving professorships only to world-class scientists recruited from outside Harvard, and should start giving tenure to deserving junior faculty who were already at Harvard. Much to my amazement, no one seemed to care that I was pregnant, and they gave me tenure. I juggled the baby, child care, and running a lab. I have no idea now how I did it; I can’t even remember much of that time, and I think Steve Macknik mostly ran my lab for a while. I do remember trying very hard not to seem to be abandoning science, so I brought my son, 1 or 2 weeks old, to a faculty meeting. I nursed him there, and mostly the older faculty smiled, and the younger faculty looked anywhere but at me. All the faculty were male. I thought nobody had minded and we were all being very progressive. Years later, when I was talking to a young woman postdoc about how she could handle breastfeeding and working, I told her about breastfeeding at a faculty meeting, and she said “I heard about that.” Having a baby was wonderful, fascinating, and satisfying, but doing it with a partner who wasn’t ready for it was not so great. I decided to have a second baby alone, and that worked out fine. It was important that I had enough money to have a live-in nanny, though I think at least a third, maybe half, of my salary went to child care or school tuition for many years. It was worth every penny.

Recording all night from anesthetized monkeys was getting exhausting, and my student Steve Macknik convinced me that the future was in recording from alert monkeys. Steve got Richard Andersen, who was then at MIT, to generously show us how to handle and record from alert monkeys. Steve started right off using alert macaques, but David and I decided to try squirrel monkeys first. There is a good reason why hardly anyone does physiology in squirrel monkeys, given that they are neurotic and skittish. We eventually also switched to alert macaques, and I have never gone back. Visual responses in alert monkeys are much more vigorous and clear than in anesthetized monkeys; all you have to do is convince the monkey to keep fixating on a tiny spot. Training monkeys is fascinating. They will do whatever they need to do to get a juice reward, and sometimes what they do is not exactly what you thought you were training them to do. It’s like raising children—you need to be aware of what it is you are reinforcing.

There was at the time a debate about whether physiological responses during normal viewing were qualitatively similar to what people had described for decades in anesthetized (paralyzed) animals whose gaze direction was fixed. Jack Gallant (1996) had reported that responses in freely viewing animals were completely different from the kinds of responses that had been described in anesthetized animals (e.g., orientation selectivity). David couldn’t believe this was true, so I worked out a way to map receptive fields in freely viewing monkeys using rapidly flashed stimuli and correcting for the monkeys’ gaze direction in mapping responses. David and I recorded together from alert monkeys for a while and came to the conclusion that responses in freely viewing animals were indeed qualitatively similar to what had been described previously (Livingstone et al. 1996).

Pushed to Independence

Sadly, I began to realize that even though David and I did science together as equal partners, of course the scientific community didn’t see it that way, and David got invitations to talk about our work all over the world, whereas nobody ever invited me anywhere. I realized I would have to branch out on my own, or be his sidekick forever, so I started recording by myself from direction-selective cells. David was never convinced anyway that you could figure out anything about a direction-selective cell using flashed bars. He thought you had to use actual movement. Given that movement on a CRT screen is a series of flashed bars, I don’t know why he insisted on this, but he did.

I found that I could map beautifully clear subunits in direction-selective cells using flashed bars, and together with Chris Pack (a postdoc in Rick Born’s lab who was much more mathematically competent than I am), we mapped these subunits in two spatial dimensions, plus time (Livingstone et al. 2001). This collaboration was fascinating, and fun, and we could see clearly how direction selectivity, especially in MT, derives from small, simple units, presumably the V1 inputs, that respond to a particular sequence of two spots of light (or dark). I still suspect that even in V1, direction selectivity will turn out to derive from a spatially offset combination of excitatory and inhibitory inputs. It has been a problem throughout my career that I started college behind in mathematics and never caught up. I wish I had taken statistics at some point.

In the late 1990s two new graduate students started working in my lab: Doris Tsao and Bevil Conway. Doris started studying stereopsis (Tsao et al. 2003), and Bevil followed up David’s and my observations on surround opponency in color (Conway 2001), both using my new approach of using rapidly presented stimuli in alert animals and accounting for gaze direction. The monkeys got so good at fixating that the gaze correction wasn’t necessary, but it helped early on. Just when Bevil and Doris got well settled in the lab, I was diagnosed with breast cancer. Because Steve, Doris, and Bevil were so independent, I don’t think the lab slowed down a bit during my crisis, but my world certainly narrowed down: my two sons and science; nothing else mattered. Happily, surgery was sufficient, and I am an almost 20-year survivor now, but my world never quite widened out again, which is fine by me.

Art

When I gave talks on the differences between the dorsal and ventral visual stream functions, I used images of Op art to illustrate the fact that our motion perception is colorblind, and I discovered that people remembered that part of the talk even if they didn’t remember anything else I said. So I started putting more and more works of art in my talk to illustrate various principles of vision. I had come to realize that artists have figured out such things empirically and often create much stronger effects than I could generate from just knowing the underlying science. People liked this so much that after a while I had hardly any science left in my talks. I decided to put all the art stuff I had collected by then into a book, and sent a draft to Abrams Press. The editor Eric Himmel told me he liked the book, but although it was obvious I knew a lot about vision, it was also obvious that I knew nothing about art. He asked me to read an art history book. I got Gombrich’s The Story of Art and enjoyed it tremendously. But when I got to the Renaissance I was struck by the image of the Mona Lisa. Gombrich urges the reader to look at her and notice: “the amazing degree to which Lisa looks alive…. Like a living being she seems to change before our eyes” (Gombrich 1995). He attributes this mysterious effect to Leonardo’s technique of sfumato, the blurriness of the contours, and thus to the indistinctness, which leaves her emotional state to our imagination. But I noticed that when I looked at her eyes, she seemed to be smiling more than when I looked at her mouth. Her expression wasn’t just a function of my mood, but quite clearly a function of my direction of gaze. I realized that this must be due to the differences in acuity between central (high-acuity) and peripheral (low-acuity) vision, so I immediately filtered an image of her face for low- and high-spatial frequencies, and saw that indeed her smile was more prominent in the low-pass version than in the high. That is, her smile is more apparent to peripheral vision simply because her smile is blurry. And as you move your eyes around the painting her smile systematically enhances and diminishes, depending on where you’re looking. I was thrilled by this discovery, and submitted it to half a dozen journals before getting it published as a “Correspondence” in Science (Livingstone 2001).

I took my sons to Europe several times when they were young,³ and toured art museums looking for works of art that showed things that artists had discovered that I could relate to vision science (and training my sons to recognize various artists by their style). In one tiny room in the Louvre, there were four Rembrandt self-portraits, nothing else. In all four of them Rembrandt portrayed himself as having one eye deviating outward. I had been toying with the idea that being stereoblind and having poor depth perception might be an asset for an artist whose goal was to flatten the world onto paper, so when I got back to Boston I collected reproductions of a lot of Rembrandt self-portraits. My student Bevil asked me whether it was always the same eye that deviated outward, and I said, no, if it were I could publish this. Bevil, himself a stereoblind artist, then pointed out that I needed to separate the etchings from the paintings, and when we did, it was clear that it was the eye on the left side of the paintings that always deviated outward, and in the etchings, it was the reverse. I hadn’t thought about the fact that when you make an etching, the image is reversed when printed. So Bevil and I quantified the effect, wrote it up, submitted it to a dozen journals, and finally got it published in the New England Journal of Medicine (Livingstone and Conway 2004; my only NEJM publication).

Faces

One day Roger Tootell asked me whether I had any trainee who might be interested in doing fMRI (a new and, at the time, somewhat-sketchy technique) in monkeys to try to correlate fMRI with single unit recording. I knew Doris wanted to map stereopsis on a larger scale than the single-unit recording she had been doing, so I asked if she would be interested. She was, and started spending most of her time with Wim Vanduffel and Roger Tootell over at the Martinos Center for Biomedical Imaging, which was at the forefront of fMRI innovation. She succeeded in mapping stereopsis in monkeys using fMRI (Tsao et al. 2003a), and then decided, along with Winrich Freiwald, to see if she could map responses to faces. They revealed a system of face-selective domains in monkey inferotemporal cortex (Tsao et al. 2003b), a place where face cells had been frequently found using single-unit physiology, though no large-scale organization had been seen, or even expected, before. Doris and Winrich then wanted to record from these face-selective domains, so they moved back to my lab to work out ways to target their electrode recordings to the fMRI-identified face patches. This was profoundly difficult to do, with roadblocks all along the way (e.g., to move the fMRI-scanned monkeys from the Martinos center to Harvard Medical School took six months of intensive bureaucracy). Doris persisted and, in the end, was rewarded by finding that the fMRI-identified domains were packed full of single units that were spectacularly face selective (Tsao et al. 2006). She and Winrich did a series of brilliant studies on this system of face patches. Doris and Winrich did most of this work on their own; I merely contributed monkeys and lab space, though I did take a large series of photographs of faces of my son’s dormitory residents when he was moving in as a high school freshman⁴: each kid, as well as the dorm parents and the custodian, from eight different viewpoints which Doris and Winrich used to study view invariance (Freiwald and Tsao 2010). I enjoy seeing my son’s photos in their papers.⁵

When Doris and Winrich found this organization of face patches in monkey inferotemporal cortex, I did a lot of reading about face processing and was surprised to learn how many people in the field of human face perception and human fMRI think that face processing is innate. That is, they assume, with some evidence admittedly, that we evolved specialized domains, with specialized circuitry, for processing this biologically important category of objects. I was surprised by this idea, given the impressive degree of experience (activity) dependence in the development of early sensory areas. I couldn’t understand how the wiring of V1 could be completely changed by visual activity, and yet temporal cortex, many synapses further along the hierarchy, could have a genetically predetermined template for something as complex as a face. It seemed more plausible to me that we wire up face selectivity by experiencing faces, especially given that we also have domains selective for text in a nearby part of inferotemporal cortex, and it is unlikely we evolved a domain for text, given how recently in human history literacy has become prevalent.

So a new postdoc, Krishna Srihasam, and I trained a group of monkeys to recognize human symbols, in order to find out if monkeys, like humans, could develop a symbol-selective domain as a consequence of intensive early experience. I used my extensive experience with my sons to design what was essentially a video game for teenage boy monkeys. These monkeys did indeed develop symbol-selective domains, but only if they were trained as juveniles, not as adults (Srihasam et al. 2012). This was surprising, but may be similar to human language learning, in that we learn languages easily and fluently as children but not as adults. Along with another postdoc, Justin Vincent, we are now exploring what kind of proto-architecture drives this organization (Srihasam et al. 2014), and I am finally getting to ask the question that has been bugging me ever since Doris and Winrich discovered the face patches: will a baby monkey who has been reared without ever seeing any kind of faces have a normal face-patch system? I spend a lot of time now taking care of baby monkeys while wearing a mask so they never see any faces, and I can’t imagine having more fun doing anything else.

On Looking Back

I have succeeded in science beyond my wildest dreams. Ever since I first realized what real science was, as an undergraduate at MIT, I have loved figuring things out about the brain. I have followed my interests, and I feel very lucky to have been able to do so. I do not understand why I could do this and so few other women do. I wish more women would go into science so it would be less lonely, and I think it would improve the culture of science. Although the tenure system does discriminate against women, you don’t have to be exceptional to do science; the pervading culture of science is that you do, but I know it’s not true.⁶ I have gone into a lot of detail so that the meandering, accidental trajectory of my career and the naïve enthusiasm with which I pursued it should be apparent. I hope this will encourage young women to realize that you don’t have to know where you’re going to make discoveries, though I do think you have to really enjoy it or you won’t concentrate and persist, which is critical. I was clueless for a very long time. I still seldom do hypothesis-based research. It usually seems that I am wrestling with questions to which I have no idea what the answer will be. Often, when I do an experiment for which I think I know what the result will be, it comes out completely different. Those are the best.

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¹Doing both was not an option as far as I knew.

²Chip’s learning mutants were named for vegetables. He wanted to name them for famous stupid people, like Lennie (in Of Mice and Men), but Seymour Benzer wouldn’t let him.

³I think it’s okay to do things with your kids that also benefit your science. It’s certainly efficient.

⁴Both my sons went to boarding school starting in the ninth grade. Where I grew up, only kids with serious behavior problems went to boarding school, but in New England, smart kids often go to boarding school. It is expensive, but it’s great because high school is when hormones first kick in and that is a very good time to have someone else set limits.

⁵Somewhere along here, in my late 50s, I married a very nice engineer. I recommend marrying engineers rather than fellow scientists because they are easily movable (they solve rather than contribute to the two-body problem) and are extremely useful. I think programmers and health-care providers might be similarly ideal.

⁶See Sarah-Jane Leslie et al.’s (2015) interesting article about the inverse correlation between number of women in a field and the perception that you have to be talented or a genius to succeed in the field (think music, math, philosophy): Expectations of brilliance underlie gender distributions across academic disciplines, Science 347, 262–265.

Giacomo Rizzolatti

BORN:

Kiev, Soviet Union

April 28, 1937

EDUCATION:

Facoltà di Medicina, Università di Padova (1955–1961)

Scuola di specializzazione in Neurologia, Università di Padova (1961–1964)

APPOINTMENTS:

Assistente in Fisiologia, Università di Pisa (1964–1967)

Assistente in Fisiologia, Università di Parma (1967–1969)

Professore Incaricato in Fisiologia Umana, Università di Parma (1969–1975)

Visiting Scientist, Dept. of Psychology, McMaster University, Hamilton, Canada (1970–1971)

Professore di Fisiologia Umana, Università di Parma (1975–2009)

Visiting Professor, Dept. of Anatomy, University of Pennsylvania, Philadelphia (1980–1981)

Professore Emerito, Dipartimento di Neuroscienze, Università di Parma (2009–)

Director of the Brain Center for Social and Motor Cognition, IIT Parma (2009–)

HONORS AND AWARDS (SELECTED):

Golgi Award for Studies in Neurophysiology, Academia Nazionale dei Lincei, 1982

President Italian Neuropsychological Society, 1982–1984

President European Brain and Behaviour Society, 1984–1986

Member of Academia Europaea, 1989

President Italian Neuroscience Association, 1997–1999

Laurea Honoris Causa, University Claude Bernard Lyon, France, 1999

Prize “Feltrinelli” for Medicine, Accademia Nazionale dei Lincei, 2000

Member of the American Academy of Arts and Sciences, 2002

Member of Accademia Nazionale dei Lincei, 2002

Foreign member of the Académie Francaise des Sciences, 2005,

Herlitzka Prize for Physiology, Accademia delle Scienze, Torino, 2005

Laurea Honoris Causa, University St. Petersburg, Russia, 2006

Grawemeyer Prize for Psychology, University of Louisville, United States, 2007

Prix IPSEN, Neuroplasticity, Fondation IPSEN, Paris, 2007

Laurea Honoris Causa, Katholieke Universiteit Leuven, 2009

Prix Signoret, Neuropsychology, Fondation IPSEN, 2010

Prince de Asturias Prize for Science and Technology, Spain, 2011

Foreign Member National Academy of Sciences, United States, 2012

Brain Prize Lundbeck Foundation, 2014

Laurea Honoris Causa, Università di Sassari, 2015

Giacomo Rizzolatti initially conducted studies on the physiology of sleep and vision.
Subsequently, his research concerned mostly the motor cortex. Among his main contributions is the description of goal-encoding motor neurons and of canonical neurons in area F5, of neurons encoding peripersonal space in area F4, and of the functional properties of presupplementary motor cortex. He discovered mirror neurons. Rizzolatti demonstrated the existence of the mirror mechanism for goal-directed actions in human parieto-frontal circuits and for emotions in human rostral insula. He also studied autism and neglect. He is famous for his motor theory of selective attention.

Giacomo Rizzolatti

Kiev and Soviet Union

I was born in Kiev (Soviet Union) in 1937. My father was Italian and my mother Russian. I know very little about my mother’s family, except that it came to Kiev from Odessa. The history of my father’s family is complicated. My great-grandfather, Pietro, emigrated from Friuli, a north-eastern region of Italy in the second half of the 19th century. At that time Friuli was a poor region and many “Friulani” were compelled to emigrate. Pietro Rizzolatti emigrated as well. He was, however, a skillful artisan, so he went to Kiev, rather than going to the Far East to construct the Trans-Siberian railway, as many emigrants from Friuli did. He started a small firm specialized in marble decorations. After a few years his firm grew and he became a respected and considerably rich citizen of Kiev.

Pietro Rizzolatti died a few years before the Soviet revolution. My grandfather Giacomo was born in Kiev. He had a bachelor degree in engineering. After the revolution most of his properties were nationalized, but, being an Italian citizen, he kept part of his house and a small land property in Korostichev, at the time a village, west of Kiev. He decided, therefore, to remain in Kiev in spite of the new regime. He continued to work (as an employee) in his firm.

My grandfather married Maria Galubowska, a lady from a small line of Russian nobility. It was a very fortunate marriage. My grandparents had four children. Three of them decided to become medical doctors. Among these was their eldest son, my father, Pietro. After high school, Pietro applied to the medical school of Kiev, but he was not admitted. He was dubbed (rightly) to be a “bourgeois” and only people of proletarian origin were allowed to go to medical school. Then my father went to the Urals where, for about two years, he worked in a mine. Being now recognized as a proletarian, he started his medical studies.

At the university, Pietro met my mother, Valentina Fedorkova, who also studied medicine. They survived the terrible years of Stalin terror, including the periodical “chistkas,” the collective processes used to identify possible traitors among professors and students. Just before graduating they got married.

Among many defects of the Soviet regime, there was a very positive aspect. At the end of the university the students were ranked according to their marks. The highest ranking students were given the opportunity to choose the jobs they preferred. My father remained at the university as an assistant in anatomy. In that period, on April 28, 1937, I was born.

This happy period for my parents finished very soon. At the end of 1937 all Italian citizens were ordered to go back to Italy. The order came abruptly and had to be executed immediately. Thus, in almost two weeks, my family was sent back to Clauzetto, a village of Friuli of about 1,000 people. Clauzetto was the place my great-grandfather had emigrated from seventy years before.

Early Life in Udine

If the Soviet regime was ferocious, the fascism was, in general, stupid. In our case, the return to Clauzetto was due to a law that forbade citizens to move out of their place of origin. Internal emigration was forbidden. This determined a kind of Catch 22 situation: to change residence some of the family had to find a job, but to have a job one must be resident in the job place. My family was stuck in Clauzetto.

Fortunately, Italians are much more clever than their politicians. Thus, a solution was found by the director of the hospital in Udine. He accepted my father as “Assistente volontario,” that is an assistant without salary. This was a pseudo-job, but sufficient to have the permission to move to Udine.

Udine was at that time a town of about 60,000 inhabitants. A bit provincial, but very civilized and proud of its culture, its own language (Friulano), and an ancient cultural heritage. Order, an almost compulsive love for work, and the sense of being a community rendered Udine more similar to a mittleleuropean town than to a typical southern-type Italian city.

The brief period of quiet life in Udine soon finished for my father. He was recruited into the army, but, being a doctor, he was enrolled in the Military Medical School in Florence and exited with the degree of “Sottotenente medico” (lieutenant doctor). A few months later World War II broke out and my father was sent to the Yugoslavian front. Fortunately in 1943, when the Italian army surrendered to Germans, he was in Udine and was not taken as prisoner to Germany.

The first things I remember of my life concern the war period. Following German occupation, Udine was bombed and, even if I also remember some pleasant episodes, those most vivid concern the bombing and the fear experienced during hours spent in the shelters. The last years of the war were particularly difficult for all of us. My father joined the Garibaldi brigade, a leftist partisan group. He continued to practice medicine in his private office and traveled, during the weekends, to the mountain where the Garibaldi brigade had their shelters, to cure wounded and sick partisans.

I was rather a precocious kid. My father, my grandmother, and especially my mother spent a lot of time with me. I learned to play chess when I was five. One of my greatest successes and happiest memories of these dark years was a chess match with a friend of my father, a respected member of Udine chess club. With my great joy and his disappointment, the match terminated with a tie.

I also learned to read very early. So I started school at five. My school years were very pleasant. The post–war era was a great period for most Italians. The economy was growing fast, and in 20 years, Italy changed form a poor agricultural country to one of the richest countries in the word. My family enjoyed this new well-being. My father was a general practitioner with many patients and a good income. Soon after the war Tania, my sister, was born and a few years later my mother decided to stop working to devote all her time to my sister, my father, and myself.

A New Life: The Years in the Lyceum

I often think that my “conscious” life, a life with a “self,” started when I began my studies in the Ginnasio-Liceo Iacopo Stellini of Udine. The five years spent in this learning institution were my Lehrjahre, the years that formed my adult personality.

The Ginnasio-Liceo Stellini is more that 150 years old. The studies were difficult. The teachers were important personalities in the city, respected by the students and by their parents. A fundamental lesson we learned was that in order to succeed one has to work very hard. We were also taught that we were destined to be the future “ruling class” of the country with privileges and duties. This teaching may sound strange today, but our “Liceo” was very successful in training many students that became very distinguished in their fields. Three of us, students in the same period, are now members of the Accademia dei Lincei, the Italian very selective National Academy. Considering the size of Udine, this has been undoubtedly a great achievement of our school.

I was very lucky because besides good professors, I also had an exceptionally nice and friendly group of classmates. Besides studying, we had parties, went on bicycle rides, and went to motion pictures together. Our friendships still continue.

I was particularly fond of a girl, during those long years at the Ginnasio-Liceo, always sitting in the first desk near the door. Her name was Leni Bronzin and, in addition to being pretty, she was different from the other girls, because she was broadly interested in reading, music, and culture. With her and a couple of other students, we discussed the books we read and many other issues. At the end of “Liceo,” my link with Leni became very tenuous. I had my life in Padua, where I started Medical School, and Leni was in Venice where she studied foreign languages. At the end of university years, we met again and enjoyed very much being together. We married in 1964, and after more than 50 years, we are still very happy together.

Another strong influence on my cultural development was my cousin Vitale Petrus and his (and my) great friend Tito Maria Maniacco. They were both older than me and, unlike me, very poor students, but both had talents for painting and Tito also for writing. Together they added other cultural aspects to my Lehrjahre, including a nonconformist attitude toward the conservative politics of those years.

The Medical Studies in Padua

In 1955 I enrolled in the Medical Faculty of Padua, one of the oldest medical schools and universities in the world. The standard of my professors as teachers was high. They believed in their work or, if you want, in their “mission.” Thus, the studies were very hard.

I liked the new topics that, considering my classical background, were almost completely new for me. Yet, these years have been by far the least exciting of my life. It was passive learning, with little discussion with other students and even less with the professors. I passed hours and hours studying in my room in Antonianum, the residential college where I stayed the whole six years of my medical studies. Attending to lectures was not compulsory and, except for some lessons, I eventually discovered that it was more productive to study at home. As far as the practical medical experience, it was difficult to achieve it at the university hospital because the number of students was relatively high and that of assistants relatively low. I learned much more during the summertime, when I attended the hospital in Udine, where the doctors were very pleased to teach to a university student.

The social life of the students was dominated by the old “goliardic” tradition. Goliardia was historically a free behavior that the students enjoyed during the rigid middle-age society. In modern times, goliardia was reduced to making practical jokes on freshmen. One of the most popular was that of compelling the first-year students to climb the statue of Cavour, a monument located close to the old central building of the university and to take a mock exam from him based on sexual jokes and innuendos. It might seem an amusing event, but, as most other “goliardic ceremonies,” it was repetitive and rather boring.

Things changed radically in my fifth year, when I entered the Neurological Clinic as an “allievo interno.” The director of the clinic was Professor G. B. Belloni, an excellent clinician and a good pathologist of the nervous system. The intellectually dominant figure was, however, Hrayr Terzian. Terzian was Armenian, educated in Venice and in Padua. Terzian divided students and colleagues into two categories: “bravo” and “mona.” This last is a rather vulgar but common word of Venetian dialect meaning “definitely stupid.”

This classification was shocking for a student like me convinced that his professors were great men. Terzian was unfair as far as the medical and teaching capacities of his colleagues were concerned, but right in relation to their scientific merits. During fascism and during war, Italian science remained isolated from the rest of the world and became inferior to that of the other major European countries and the United States. Terzian was an exception because, at the beginning of his career, he spent time in Pisa in the lab of Professor Moruzzi, one of the few Italian centers of international reputation, and later in Marseilles working with Henry Gastaut.

In 1961, I graduated in medicine with the maximum of marks cum laude. The graduation ceremony, following a tradition going back to the medieval times, took place at night. After the official part of it, started the “goliardic part.” The friends of the newly graduated fellow waited for him in the oldest courtyard of the university and kicked him in the ass, meaning to expel him both practically and symbolically from the free student life.

Studying Neurology

Since the beginning of my medical studies, I thought that neurology was the most fascinating branch of medicine. So after getting my MD degree I entered neurology. In the clinic, besides duties in the ward, I was working in the electroencephalography (EEG) laboratory, which was overseen by Terzian. It is curious, considering my subsequent discoveries of mirror neurons, that Terzian was the first to describe with Henry and Yvette Gastaut (Gastaut, Terzian, and Gastaut 1952) the “mu rhythm,” the EEG rhythm that desynchronizes during motor activity and that (we know now) is correlated with mirror neuron activity (see Altschuler et al. 1997).

I liked clinical work. At that time semiology was the basis for neurological diagnosis. This implied deep knowledge of neurological diseases and a great capacity of reasoning in order to make differential diagnosis. I liked also to talk with patients and to help them within the rather narrow possibilities of neurology of that time.

My fellow medical interns were motivated people. Most them studied neurology with the aim of getting a job in a hospital or starting a private practice. A few had the ambition to remain at the university. Among them was Nicola Rizzuto. We graduated in the same year and worked together during our internship in neurology. We became good friends and tried to do some research together. The difficulty of conducting serious research in the clinic was the most disappointing part of our internship. I managed, however, almost by chance, to publish a paper describing two rare cases of self-induced light-sensitive epilepsy, but, this type of anecdotal research was highly unsatisfactory (Ravenna and Rizzolatti 1964).

The limits of this form of clinical research were also clear to Terzian. One day he called me in his office and told me that if I really wanted to be a “true” university professor, I should learn a basic technique that could be applied to neurology. He offered me two opportunities: one was to go to Marseilles to work on epilepsy, the other to learn neurophysiology. I chose neurophysiology.

In 1963, Professor Arnaldo Arduini, the oldest pupil of Professor Giuseppe Moruzzi, obtained a chair in physiology in the University of Ferrara. Arduini needed somebody to help him and was happy to accept me in his lab. So I moved for six months to Ferrara and began my training in neurophysiology. Arduini would later play an important part in my life when he accepted me as his assistant in Parma.

My first approach to physiology was interesting, but not exciting. Arduini and I recorded mass activity from the pyramid tract and measured it during slow-wave sleep and wakefulness. The results showed a clear pyramidal activity increase correlated with EEG desynchronization (Arduini and Rizzolatti 1964).

The major weakness of Ferrara was that Arduini was the only physiologist. I spent most of my free time with a nice and friendly group of biochemists, or studying neurology and psychiatry in my room. However, I became sufficiently interested in physiology to go back to Arduini the following year to finish the work we started. In the meantime, Arduini moved to Parma, where he had a much larger, but virtually empty institute. I finished with him my work on pyramidal tract and the results were accepted by Professor Belloni as my neurology thesis.

The year 1964 was a crucial year for me. In that year I obtained my degree in neurology. Terzian strongly advised me to continue an academic career, but not in Padua. According to him, I had first to complete my training in neurophysiology in Pisa, which was the best center of neurophysiology in Italy. Professor Moruzzi, the director of the Institute of Physiology of Pisa, accepted me and found for me a tiny fellowship. This, together with the salary of Leni, who taught English in the middle school, allowed us to marry. We married in March 1964. In September we started our new life in Pisa.

Physiology in Pisa: Sleep Studies

The Institute of Physiology of Pisa is a large, imposing building located close to the city’s medieval walls. There is a small garden in front of the building and a very large one, almost a small park, behind it. Professor Moruzzi, as it was tradition in those days, lived in the institute. His office, a large room full of books, was located on the second floor. It was there that he received me at my arrival. Professor Moruzzi had an impressive personality that commanded respect. The institute was undoubtedly his institute and everybody working there accepted his ethical values. He had an almost religious idea of science and a scientist, a real scientist, had to devote all of his time and energy to science.

When I arrived to Pisa, Moruzzi was at the apex of success. When still young he realized that the isolation of Italy from the world scientific community imposed by fascism was a strong handicap for becoming a good scientist. So he moved from Italy to Bruxelles where he worked with Frédéric Bremer and subsequently to Cambridge where he collaborated with Lord Adrian. After Word War II, Moruzzi moved for about one year to Chicago where he discovered, with Magoun, the arousing effect of the electrical stimulation of brain stem reticular formation. This finding changed radically the way of conceiving sleep and more general brain functions. Back to Italy, Moruzzi created in Pisa a unique center for studying the nervous system.

My interview with Moruzzi went very well. I told him about my limited experience in physiology. He replied not to worry. He decided I was to work with Lamberto Maffei, who could teach me all technical aspects of physiology. The work of the team formed by Maffei and myself will be supervised directly by him. The decision of Moruzzi to put me in Lamberto’s lab was very successful. Lamberto was only one year my senior, but he had been working in physiology since the beginning of his studies in medicine, and, as Moruzzi told me, he was already an accomplished physiologist. I learned a lot from him. Lamberto was a very practical person, so he organized the lab in such a way that my little expertise in physiology could be useful for our team.

We carried out the experiment on midpontine pretrigeminal cats, a “preparation” in which, following a section of the brain stem, the animal is paralyzed except for vertical eye movements. Pretrigeminal cats do not feel pain and show a predominantly desynchronized EEG. This EEG pattern is frequently interrupted by short episodes of synchronized sleep. The surgery was typically done by Maffo (as we called Lamberto in those times). Once the preparation was ready it was my turn to work. I took care of the animal and, using a micromanipulator, isolated single neurons from the dorsal part of the lateral geniculate body (LGB) and from the optic tract. As soon as a neuron was isolated, Maffo turned on a lamp that generated a sine-wave stimulus, and by using a tiny computer named “CAT,” established the time relation between the stimulus and the responses of the recorded neuron.

We addressed two main issues. The first was the transfer properties of LGB neurons to sinusoidal light stimuli presented at different frequencies. Maffo was very interested in this problem that was a continuation of his previous work on the retina. The second issue was to see how sleep-wakefulness cycles modulated the transfer of visual information.

We worked very hard. The experiments lasted the whole day from 8:30 in the morning till the evening and we ran them every day except on Saturday morning (devoted to reading in the splendid Pisa library) and Sunday (mostly for the family). Occasionally, we were helped by a gentle and quiet medical student, Luigi Cervetto. Our efforts were rewarded. At the end of the year we had seven publications, including a paper in Science (Maffei, Moruzzi, and Rizzolatti 1965) and one in the Journal of Neurophysiology (Maffei and Rizzolatti 1967), at that time a top journal in neuroscience. The most exciting result was the change in information transfer during slowwave sleep relative to wakefulness. While during wakefulness the modulation of the LGB spikes by sinusoidal light gave as an output a sinusoid, this information was completely lost during sleep.

Our work was greatly appreciated by Moruzzi who was constantly informed about the progress of our experiments and helped us in writing the papers. Lamberto and I worked very well together and became very good friends. I liked his quiet leadership and his way to train me giving me progressively more to do in the experiment. Although our careers later diverged, our friendship is still very strong. I was very happy when some years ago Maffo became the Presidente of Accademia dei Lincei, the most prestigious Italian scientific institution.

My first year in Pisa was also very successfully from a social point of view. In front of our lab was that of Franco Magni, just back from the lab of John Eccles, and of Piergiorgio Strata. Strata is a very brilliant scientist, whose discussion abilities are as unique as his knowledge of physiology. We immediately became friends and our friendship increased with years. He become later interested in the organization of the university and more generally in those aspects of politics that concerns research. Even now, if I need some advice or desire to discuss an issue concerning research politics, I call Piergiorgio in Turin where he is professor of physiology.

In July 1965, Pietro, our first son, was born in Udine where Leni’s and my family lived. Leni did the birth preparation exercises in Pisa together with Dolly Strata, Piergiorgio’s wife, and Benedetta Cervetto, our student Luigi’s wife, and this made our friendship stronger.

Physiology in Pisa: Corpus Callosum and Superior Colliculus

After my successful collaboration with Maffei, I was sure to continue my collaboration with him. Instead, in July, a few days before Pietro’s birth, Moruzzi called me and told me that it would be more appropriate for my education to enlarge my experience and to change lab and topic. His suggestion was the lab of Professor Ottavio Pompeiano.

Pompeiano had a good reputation as vestibular system physiologist, which was acquired mostly for his studies done at the Karolinska Institute. I never read his work, but in Pisa he was more famous, among postdocs, for his almost compulsive desire to publish papers and use the coworkers as manpower, than for his research on the vestibular system. Diplomatically, I did not mention these considerations to Moruzzi, but told him that I preferred to work on sleep. In those days, Giovanni Berlucchi was back to Pisa from a sabbatical he spent with Roger Sperry at Caltech. Moruzzi thought to create a new group led by Giovanni. He offered me to join this group and I was happy to accept. Thus in September 1965, I started my work with Giovanni.

Giovanni has been a central person in my scientific and personal life. His love for science, an almost religious sense of duty, and a rich culture outside science rendered his personality unique even among the highly intelligent and motivated young people around Moruzzi. My encounter with him helped me in my scientific maturation. In addition, Leni and Luisa, Giovanni’s wife, become good friends and, thus, a mere scientific collaboration became an enduring family friendship.

The first studies we did together concerned the auditory system and the modulation of the transfer of auditory information to cerebral cortex and cerebellum (Berlucchi, Munson, and Rizzolatti 1966a). These studies, which we carried out with John Munson, a student of Robert Doty, were well accepted by the scientific community. A nice reward was an invitation to Siena where, in addition to a scientific meeting on evoked potentials, there was also a rich social program. This program included the possibility to see the Palio, an exciting rough horse race that goes back to middle age.

Giovanni and I frequently discussed the data of Sperry on the split brain as well as his ideas (which I never fully understood) on consciousness as an emergent property. In the same years, reading the famous paper by Lettvin, Maturana, McCulloch, and Pitts (1968) on the frog eyes and the great papers of Hubel and Wiesel (1959, 1962), I became more and more interested in the visual system. This and the discussions with Giovanni on the role of the corpus callosum in vision led us to record from this structure. This decision was boosted by the arrival in Pisa of Mike Gazzaniga, a coworker of Roger Sperry in the famous split brain experiments, and a good friend of Giovanni.

Mike was a pleasant and witty teammate. Giovanni, Mike, and I worked very well together, and my friendship with Mike became stronger with the years. The first issue we addressed was to study what type of information was transmitted in the posterior third of the corpus callosum. Not surprisingly, we found the various types of receptive fields previously described in cortical areas 17, 18, and 19. However, the callosal receptive fields were all located along the vertical meridian of the visual field. We interpreted these data as evidence that the representation of the visual field on the cerebral cortex is on a continuum, the neurons associated with the vertical meridian being the “trait d’union” necessary for bringing together the two half visual fields (Gazzaniga, Berlucchi, and Rizzolatti 1967).

Recording from the fibers of the corpus callosum was not easy and we did many experiments before obtaining good results. In one of his books, Mike Gazzaniga describes one of these initial experiments. He writes that, during a particular experiment, instead of the typical “cracking” sound of action potentials, the loudspeaker started abruptly to transmit the notes of “Yellow submarine.” At this point I would have said: “Finally we are able to record high order information from the corpus callosum.” The first part of the story is true, while the second is a nice embellishment by Mike.

Mike left us very soon. He was offered a position at University of California in Santa Barbara and he accepted it. We were a bit disappointed, but it turned out that a team of two, Giovanni and myself, was sufficient to continue our work on corpus callosum. Our next project was to assess how the information coming via corpus callosum and that arriving from LGB was integrated in area 17. To study this integration, we split the chiasm and presented the stimuli to each eye of the ipsilateral hemisphere. We found that there were neurons that were driven not only by the ipsilateral eye, through direct geniculo-cortical pathway, but also by the contralateral eye through the corpus callosum. The two monocular receptive fields of a given cell lie in close contact with the vertical meridian. We suggested that this convergence provides the continuity of the cortical visual map across the interhemispheric gap. We sent this paper to Science, where it was accepted after minor revisions (Berlucchi and Rizzolatti 1968). This was my second Science paper emerging from about two years of work in Pisa.

A visual structure that had been neglected for many years in mammal visual physiology was the superior colliculus (SC). An experiment that played a fundamental role in putting the SC in the foreground in vision physiology was a study by Jim Sprague (1966). In this study, he described an enduring hemianopia following a large unilateral visual cortical lesion recovered after a lesion of SC on the intact side.

Jim Sprague was an old friend of Professor Moruzzi. In 1966 he came to Pisa for a sabbatical. Jim belonged to the generation between Moruzzi’s and mine. He was professor at Penn and famous for his contributions on the cerebellum, spinal cord, and brainstem reticular formation. Jim was a great gentleman. Rarely in my life have I found a person so kind and full of consideration for others. In spite of the age gap, we became good friends. Thirteen years later, when I spent a sabbatical at Penn, I appreciated him even more both as a scientist and as a person.

When Jim arrived to Pisa, Pier Lorenzo Marchiafava and I were discussing the possibility of recording single neurons from SC. Actually Pier Lorenzo had already performed a pilot experiment. Pier Lorenzo was a highly motivated, witty, intelligent researcher, but somehow, he was (or pretended to be) different from the other pupils of Moruzzi. He liked fast cars and girls, and there were rumors that, once, he made the provocative proposal to Moruzzi to build a swimming pool in the institute. “Just to enjoy ourselves between experiments.” After my departure from Pisa, he published several interesting papers on the retina.

Jim was enthusiastic to join Marchiafava and myself in recording single neurons from SC. We discussed two projects. One was to study the responses of SC neurons to stationary and moving stimuli. We carried out the experiments in midpontine pretrigeminal cats (see above). The second project was to inactivate the visual cortex and to see whether cortical inactivation affected neuronal receptive field properties in the SC. While the inactivation project gave rather ambiguous results, the characterization of the SC receptive field properties was very successful. An important observation was that the habituation of neurons’ responses to repeated visual stimuli and that of vertical eye movements (the only motor responses of midpontine pretrigeminal cat) to identical stimuli had the same time course, as also did the recovery from habituation (dishabituation). In other words there was a clear link between visual attention and SC activity (Marchiafava, Rizzolatti, and Sprague 1968).

At the end of the academic year 1966–1967 my contract with the Institute of Physiology expired. If I could, I would have stayed in Pisa. In addition to the exceptional scientific atmosphere, there was also a lively social life. I already mentioned some of my closest friends, but there were many other interesting and friendly people: Norman Kahn from Columbia; Dick Poppele from Minneapolis; Adrian Morrison from Penn; Giancarlo Carli, who, after a period at Johns Hopkins, became professor of physiology in Siena; and Carlo Marzi, now professor of psychology in Verona.

In the meantime Terzian, my mentor in Padua, has been appointed director of the Clinical Neurology in Cagliari. Thus, in the spring of 1967, Leni and I went to Cagliari to see our future new city and, possibly, to look for a house. Nicola Rizzuto was already there. We were greeted by Terzian with enthusiasm and were guests of Nicola in his apartment. However, when I started to talk with Terzian on the possibility to build a lab for physiological experiments, he became very vague, saying that this was something for the future. First, he needed to organize the clinical work. Talking (for hours) with Nicola, I learned that indeed the situation of the clinic was like that of a provincial hospital and no serious research could be carried out there. My visit to the clinic confirmed his view.

Leni and I returned to Pisa very sad. On the one side, I was reluctant to abandon clinical neurology, and on the other, after the years spent in Pisa in touch with “real” research, I did not want to go back to routine clinical work, with only very vague hopes to continue my research in the future. There was also a financial problem. If I was going to refuse Cagliari, I had to find a job. Where? Back to Udine? My links with Padua were severed. The old director Professor Belloni was on the verge of retirement and my mentor Terzian had left for Cagliari.

I decided to talk with Moruzzi, with the hope that maybe he could help me. Moruzzi listened to me very carefully and then said that he could help me because there was an opening in Parma, where an assistant had decided to leave the job, and Arduini, the director of the institute, was looking for a replacement. It was a tenure track position and in a few years, if my work was satisfactory, I could become “assistente di ruolo” (assistant professor with tenure). Moruzzi spoke with Arduini, who accepted me with enthusiasm.

Parma: Sleep Again

In autumn of 1967 I was in Parma. Leni and Pietro remained in Pisa. They joined me the following year. The Institute of Physiology of Parma consisted mostly of walls. The predecessor of Professor Arduini, Professor Pinotti, was a respiration physiologist who moved to Turin and took away with him all of his instrumentation. So when Arduini became the institute director he found the institute virtually empty.

Arduini was the first pupil of Moruzzi and helped him very much in creating the Pisa Institute. The discovery for which he was most famous was that of the theta rhythm in the hippocampus, a slow rhythm that surprisingly appears in the hippocampus during wakefulness. This discovery was done with John D. Green, when Arduini was on sabbatical at the University of California, Los Angeles (UCLA).

Arduini was happy of my return to Parma and helped me very much in my career. First of all, although I was a young assistant, he gave me complete scientific independence, and, very generously, allowed me also to use the best among the few instruments of the institute. Later on, when I started teaching, he gave me the Course in Neuroscience, which was much easier for me to teach than other parts of physiology. Arduini was a good organizer and because of his scientific stature and great personal honesty he had a strong influence on faculty. During the years in which I was with him in Parma, his interest for experimental physiology progressively vanished. He was more interested in theoretical problems such as, for example, how to quantify neural activity, and later mostly in philosophical problems.

Besides myself, in the institute, there were nominally two assistants: Ruggero Corazza and Andrea Cavaggioni. However, when I arrived, Corazza was in Boston and Andrea was in Baltimore. An important presence in the institute was Maria Grazia Arduini, Arduini’s wife, who worked as a histologist. She was a superb technician and yet she worked without salary because Arduini thought it was not fair to give a paid position to his wife.

Before coming to Parma I thought that an interesting project in sleep physiology was to extend the study of activity of LGB from slow sleep and wakefulness to the sleep phase characterized by rapid eye movements (REM sleep). In order to do this, I had to learn how to record from behaving cats. I did all the preparatory work in Pisa. So, after a few months in Parma I was able to implant my first cat. Working alone was very hard. The institute’s janitor (Renzo Tebaldi), a very kind man and a good amateur cyclist, was the only person that helped me, when free from his duties. He sometimes even stayed with me some time after his working hours.

The results were coming very slowly. Here Moruzzi helped me again. A young Russian physiologist, Lev Mukhametov, had the permission from his government to come to Italy. He was interested in sleep physiology and to work in one of the groups directed by Moruzzi. Moruzzi told him that in Parma there was Rizzolatti, one of his former pupils, who also spoke Russian and suggested that Lev join me in Parma. Lev accepted and we started a very productive collaboration.

Lev was (and is) an easy-going, practical, and very talented scientist. He already had experience in sleep physiology and was very happy to study the neuronal activity in behaving animals and to learn this technique. He was a very hard-working person determined to go back home with scientific results obtained abroad. Both of us had no family in Parma. So, except for occasional movies seen after dinner, we spent all our time in the lab recording from morning to night, and the results started coming.

In the first study we recorded the spontaneous activity of LGB neurons. As expected, we found a clear difference between spontaneous activity during slow sleep and wakefulness. The new finding was the activity during REM sleep. As soon as EEG, electromyography (EMG), and eye movements indicated the occurrence of REM sleep, the neuronal spontaneous activity abruptly changed and was characterized by a well-spaced, unclustered discharge, similar to that of wakefulness. Activity in optic tract fibers was not modulated by the behavioral states (Mukhametov, Rizzolatti, and Seitun 1970).

The presence of these different patterns in LGB raised the question of how these patterns may influence the transmission of visual stimuli to the visual cortex. The main obstacle to address this issue was the difficulty of maintaining stable visual stimulation in behaving cats. We solved this problem by paralyzing the intrinsic and extrinsic ocular muscles by cutting cranial nerves III, IV, and VI and the cervical sympathetic trunk. This technique had been devised a couple of years before by Berlucchi, Munson, and myself (Berlucchi et al. 1966b). The visual stimuli were delivered by a lamp cemented to a contact lens inserted on the eye.

The responses were quantified as “absolute response,” that is, the number of spikes during the second starting with stimulus onset, and “relative response,” the same responses referred to background activity. The absolute responses were very large in wakefulness, decreased in the synchronized sleep, and increased again, reaching its maximum, during REM periods of desynchronized sleep. The relative responses, however, were highest during wakefulness. We concluded that, accepting the signalto-noise ratio as the biologically fundamental measure, the transmission through LGB was impaired during sleep relative to wakefulness by two different mechanisms: (a) a postsynaptic inhibition (pause-burst pattern) during synchronized sleep and (b) a marked increase of spontaneous activity during desynchronized sleep (Mukhametov and Rizzolatti 1969).

These data were published in Archives Italiennes de Biologie, one of the top journals for sleep physiology of that time. Before sending them to the editor, we asked Emilio Bizzi to read them. Emilio is another of Moruzzi’s students. When I was in Pisa, he had already left for the States. He visited Pisa, however, from time to time and during these visits we became friends. Bizzi is especially known for his contributions to motor physiology. However, he also studied sleep and is the discoverer with Brooks of the “pontogeniculate-cortical waves,” one of the characteristics of the REM sleep (Bizzi and Brooks 1963). At the time of my collaboration with Mukhametov, Emilio was in Milan. We took advantage of this fact and discussed our findings with him. He was also so kind to correct our English.

The Soviet bureaucracy was unpredictable. Thus, although both Mukhametov and I thought that the possibility for him to come to Italy again was almost zero, he actually got the permission to work in Italy for another period. This allowed us to record from some additional animals and to analyze a series of neurophysiological data, which, according to the histological analysis, were obtained from “nucleus reticularis thalami,” a nucleus that sends its output top-down to other thalamic nuclei. The data revealed that the neuronal discharge pattern in the different phases of sleep-wakefulness cycle was similar to that of the LGB but with some differences. A notable difference was that during REM sleep the activity of nucleus reticularis was more regular than that in the LGB and almost indistinguishable from that observed in nucleus reticularis during wakefulness. We interpreted these findings as support for theories (e.g., Berger 1969) that maintain that REM sleep represents an endogenous stimulation of the nervous system necessary for the setting up of connections between neurons. Only a pattern similar to that present in wakefulness can fulfill this function (Mukhametov, Rizzolatti, and Tradardi 1970).

My collaboration with Lev ended with this paper. These were two years full of scientific rewards and pleasant camaraderie. Also for Lev the years spent in Parma studying sleep in behaving animals were very useful for his career and for his subsequent fundamental studies on the sleep of dolphins and other aquatic mammals (e.g., Mukhametov, Lyamin, and Polyakova 1985).

The work I did in Pisa and in Parma was appreciated by both Moruzzi and Arduini, who suggested that I apply for “Libera docenza.” This title, which corresponds to the German “Privat docent,” gave the title of professor and was a fundamental step for becoming full professor for Italian scholars in an academic career. The discussion of my findings with the Members of the Libera Docenza Committee and the subsequent lecture on a topic of human physiology (respiratory mechanics!) went very well. Thus, in May of 1969, I received the title of “Libero Docente in Fisiologia Umana.”

Neuropsychology with Berlucchi and Umiltà

When I was still in Pisa, Giovanni Berlucchi and I discussed the possibility to apply our findings concerning the organization of the corpus callosum to humans. There was an old study by Poffenberger (1912) that reported that crossed reaction times to visual stimuli are significantly longer than uncrossed reaction times. We decided to verify these findings, which were not confirmed by other studies (see Smith 1938), and to test, by presenting the stimuli at different distances from the visual field midline, whether the interhemispheric transfer was performed by visual callosal fibers.

We carried out the experiments in Bologna with Carlo Umiltà. Carlo was a young psychologist from Bologna who had been trained in physiology by Arduini. From time to time he was in Parma to work with Arduini on analysis of their data. In one of his visits I proposed to Carlo to carry out in his lab the reaction time experiment that I had discussed with Giovanni. Carlo accepted.

At that time in Bologna there was as a visiting professor Ray Hyman, a psychologist from Eugene, Oregon, famous for his studies on choice reaction times and who, after returning to the United States became even more famous for having exposed the paranormal capacities of Uri Geller, a very popular illusionist. He accepted to supervise our work. Finally, some help was given to us also by Woodburn (Woody) Heron, a student of Donald Hebb, who was a visiting professor in Pisa.

Our first experiment confirmed the data of Poffenberger. Visual stimuli presented on one side of the fixation point elicited faster reaction from the ipsilateral than from the contralateral hand. The delay between crossed and uncrossed responses remained constant regardless of the distance of the stimuli from the fixation point (Berlucchi et al. 1971). Thus, the interhemispheric transfer was not mediated by the visual part of the corpus callosum.

Our previous neurophysiological findings that only the stimuli near the vertical meridian are encoded by both hemispheres raised the possibility of studying the functions of the two hemispheres independently, by presenting visual stimuli distant from the vertical meridian. We decided therefore to measure choice reaction times to letters and faces presented to the two hemispheres. The results showed that the reaction times to letters were systematically faster when presented to the right visual field, while the reaction times to faces were faster when presented to the left visual field. This effect was independent of the hand used for responding. Our interpretation was that the material presented to the nondominant hemisphere for that material had to be transferred to the dominant effect for recognition. This interhemispheric transfer took more time than that related to the Poffenberger effect (Rizzolatti, Umiltà, and Berlucchi 1971).

These two papers on interhemispheric transfer were both published in Brain. They were among the first papers that demonstrate the possibility of studying functional hemispheric asymmetries in normal human subjects using a simple inexpensive method. They were received with great interest. A demonstration of this interest was the election of Giovanni and, a couple of years later, of myself into the International Neuropsychological Symposium group. This group is essentially a private club that has a fixed number of members, has rigid rules, and meets once a year in Europe, typically on the Mediterranean shore. There were formal presentations and discussions, but the beauty of the club consisted in the hours free from programmed session where people could meet and discuss in a very informal and free way. The leaders of the group, when I became a member, were Hans Lucas Teuber and Brenda Milner. Other outstanding members were Norman Geschwind, Ennio De Renzi, Henry Hecaen, Amedeo Vignolo, Jacques Paillard, Mortimer Mishkin, Charlie Gross, and Edoardo Bisiach, in other words the most prominent clinical and experimental neuropsychologists of that time. For a young man, it seemed almost incredible to have the possibility to meet and discuss with the greatest figures of neuropsychology in a completely informal way.

Hamilton, Ontario

After I had moved to Parma, Woody Heron arrived to Pisa from McMaster University where he was professor of psychology. Woody came to Pisa to work with Moruzzi and Berlucchi. Giovanni involved him in one of our reaction time experiments. Thus we met and became friends. Woody was an extremely gentle person. His shyness was legendary. However, when his shyness could be overcome, his great culture and intelligence became immediately apparent.

Before coming to Italy, Woody received a considerable grant and invited me to spend one year at McMaster. At the beginning, Leni and I were uncertain about what to do. In fact in March 1970, Beatrice, our second child, was born. However, after many hesitations we accepted Woody’s invitation.

We arrived at Toronto after a long flight and an unexpected stop in Amsterdam. Fortunately, Pietro found a small girl sitting close to him on the plane, with whom he played most of the time, and Beatrice slept quietly in a hammock that a steward placed above our heads. Woody was at the airport waiting for us and drove us to our house located in Dundas, a beautiful village near Hamilton, not far from McMaster University.

The atmosphere at the Department of Psychology was very friendly, and Woody and some other colleagues helped us in solving the practical difficulties related to our arrival. Unfortunately, Woody’s scientific programs were very vague and, after some time, he suggested that, while he was organizing his experiments, I could do some neurophysiology with a postdoc, Barry Jones, an intelligent young medical doctor who later became a clinical neurologist. Professor R. Pritchard kindly allowed us to use his lab. We studied the functional properties of SC in anesthetized cats, but without success. Although no publication came out from my time at McMaster, the years spent there were very useful to enlarge my vision of science, to learn how research was done in America, and, especially, to learn psychology.

At the time behaviorism was the dominant psychology at McMaster. I attended some lectures on it and read many papers on this topic. I found the ideas of Skinner on behavior, including human behavior, very appealing. Abe Black, who was one of the major figures at McMaster, advised me how to condition a dog. Thus, I experienced personally the power of operant conditioning.

Thanks to the generosity of Woody, I also had the opportunity of making several trips. First, I visited Montreal and had conversations with Peter and Brenda Milner. Another trip was to Philadelphia, where I visited the lab of Jim Sprague, and to Baltimore, where I met Gian Luigi Poggio and Vernon Mountcastle. I had a long conversation with Poggio who tried to convince me that there was no point in studying the properties of visual areas beyond primary visual cortex (“it is premature”) and a short one with Mountcastle, who showed very little interest in my research. More rewarding was my visit to Eugene, where Carlo Umiltà was on sabbatical. There I met two extraordinary persons, Michael Posner and Steve Keele. I had a lot of interactions with them in the following years and, with Michael, also many debates on the mechanisms of attention.

Back to Parma: Superior Colliculus

In September 1971, I returned to Parma, where I started my experiments with new coworkers: Marcello Camarda, Larry Grupp, and Michele Pisa. Marcello was a neurologist from Palermo, whose mentor wanted him to learn some basic science. Larry was a Canadian from Toronto. He liked the seminars I gave on SC at McMaster and decided to change his field from psychology to neurophysiology. The third member of the team was Michele Pisa, a Sicilian who already had some training in physiology in Pisa.

My three coworkers were hard-working people, but each of them wanted (when I was not in the lab) to be the leader of the group. Discussion among them was a constant feature of the first year of our collaboration. However, the success of the experiments and my diplomatic skills made the work of the team progressively more pleasant and, at the end, Larry and Marcello even became friends.

The idea behind our experiment was that the SC has a fundamental role in selective attention. Imagine that two visual stimuli requiring incompatible responses arrive simultaneously to the animal. It is very plausible that some interactions between them could occur before the command to act is issued. Our hypothesis was that these interactions occur already in the SC. To test this hypothesis we presented a stimulus (S2; typically a black spot) outside the receptive field of the recorded neurons in the moment in which the stimulus (S1) entered its receptive field, triggering a neuronal response. We found that in more than 80 percent of the tested units, presentation of S2 produced a strong inhibition of the neuronal discharge (Rizzolatti, Camarda, Grupp, and Pisa 1974).

I liked this experiment very much. Our paper reporting it was accepted by the Journal of Neurophysiology, without any major criticism, but its success among the visual physiologists has been very limited.

Subsequently, we described the same effect in an extrastriate visual area located in the cat lateral suprasylvian gyrus known as “Clare-Bishop area.” In contrast, a control experiment showed that the effect of S2 on neurons of area 17 was minimal, or completely absent. This finding supported the view that the control of attention was determined by the centers that control eye movements, rather than by those processing visual information for object recognition (Rizzolatti and Camarda 1975).

In addition to these neurophysiological experiments, I continued my neuropsychological research. In both areas I received great help from the presence in the lab of Gus Buchtel. Gus was a very precise and meticulous researcher with an excellent preparation in both physiology and clinical neuropsychology. He gave a more methodological solidity to our experiments. He stayed with me a couple of years, then moved to Montreal to work with Brenda Milner and eventually became professor at the University of Michigan in Ann Arbor.

At the beginning of 1975, I presented my curriculum vitae (CV) for becoming full professor of physiology. In September of the same year, the National Committee approved my titles, and in November, the Faculty of Medicine appointed me as professor of human physiology, a position that I have held for more than 35 years.

Monkeys in Parma

The appointment as full professor, and the many accompanying invitations to present my data in Italy and abroad, was very rewarding. I remember, for example, with particular pleasure the week I spent in Berlin (actually in Dahlem) with Professor Grusser, or the invitation by Professors Baumgartner and Akert to give a seminar in Zurich, where I was also offered a position.

Yet, I felt that there were other researchers who were more in the forefront of physiological research than me. I was greatly impressed by the paper by Mountcastle on the organization of the parietal lobe (Mountcastle et al. 1975) as well as by the work of Hyvärinen (1982). I found also very exciting the papers of Bob Wurtz and Mickey Goldberg (1971) on the monkey SC. Their results were similar to mine. Their impact, however, was undoubtedly much greater. The major difference was that they worked on monkeys, while I ran experiments on cats.

I decided therefore that an advanced research program needed monkeys. Professor Arduini gave me his support. It is almost unbelievable today to see how easy it was to do research on animals in those years. Arduini called the chief veterinarian of Parma and asked him for permission to run experiments on monkeys. The chief veterinarian did not see any problems. In response to our inquiry regarding who should be responsible for the welfare of animals, he said: “You! I know everything about cows and pigs, but you, as medical doctor, are more expert than me on what concerns primates.” Thus, we bought the first monkey, a Macaca fascicularis, in a pet shop and learned how to treat it well. This monkey remained with us for several years as our mascot. Then we imported other monkeys from Germany. A new era began.

The first experiment that we conducted on monkey was carried out with the help of Ivan Pigarev. Ivan arrived in Parma from Moscow. He was (and is still) working in one of the institutes of the Russian Academy of Sciences. Ivan looked like a character from a novel of Dostoyevsky. He is tall, with a long beard, and with a hieratic aspect. Ivan is one of the most creative and original scientists I have ever met. In spite of the difficulties that all Russian scientists faced after the collapse of the Soviet regime, Ivan managed to continue his work, mostly abroad. His finding that the visual cortical areas process signals from visceral organs during sleep is of great interest and, in my opinion, has not received, the attention it deserves.

Our initial experiments on monkeys were carried out using awake curarized, to induce paralysis, animals. We explored the caudal part of the frontal lobe with the aim to localize the frontal eye fields (FEFs). In this exploration, we found, rostral to the arcuate sulcus, neurons with properties similar to the face neurons previously described by Charlie Gross (Gross, Rocha-Miranda, and Bender 1972) in the temporal lobe (Pigarev, Rizzolatti, and Scandolara 1979). The most interesting results came out, however, when we started to record from the cortex immediately posterior to the arcuate sulcus. Neurons in this premotor region responded to tactile and/or joint stimulation. Hands and mouth were the body parts most abundantly represented. Some neurons exhibited tactile responses that were conditional on the arm location. For example they responded to tactile stimulation of the hand, but only when the hand was close to the mouth. We interpreted these data as evidence that this part of the postarcuate cortex encoded hand, mouth, and especially hand-to-mouth movements (Rizzolatti, Scandolara, Matelli, and Gentilucci 1981a).

The great surprise was, however, the presence of a large number of visual neurons. Unlike neurons in the FEF, which responded to far stimuli, postarcuate neurons responded exclusively to stimuli located close to the skin or within the monkey’s reaching distance. Most of these neurons were bimodal with the visual receptive field spatially related to the tactile field. This was the first description of what we later described as the peripersonal space (Rizzolatti, Scandolara, Matelli, and Gentilucci 1981b).

Philadelphia

At the end of September 1980, Leni, Pietro, Beatrice, and I left Parma for Philadelphia. Jim Sprague invited me to spend a sabbatical year as visiting professor in the Department of Anatomy of the University of Pennsylvania. Leni and children arrived to Heathrow from Milan and I reached them from Brighton. In Brighton there had been a meeting of the European Brain Behaviour Society, where I presented my new data on premotor cortex with great success.

Jim organized our stay in Philadelphia in the best possible way. We had a beautiful house in Bala Cynwyd, a rich community in Lower Merion Township. The house was nicely furnished and had everything we could need, including a piano and many classic records. The children attended excellent public schools completely free.

We had already met Dolores Sprague, Jim’s wife, in Pisa, but it was in Philadelphia that Dolores and Leni became close friends. Dolores and Jim also tried to render our life as pleasant as possible. They introduced us to their friends and also gave us opportunities to appreciate life in Philadelphia.

As in my previous stage abroad, the scientific part of my visit was not successful in terms of publications. I was supposed to work with Larry Palmer and to learn from him to program computers. Unfortunately, I found it rather difficult to communicate with Larry and thus our collaboration slightly vanished. Another person I was supposed to work with was Alan Rosenquist. Alan was friendly and very communicative, but constantly busy with administrative duties. Thus, the first months of my stay, the only person I worked with was Jim.

Of course Jim was also extremely busy, yet he found some time for me. He reconstructed for me the cortical lesions and the corresponding thalamic degenerations of an experiment I performed in Parma (see below). To see Jim drawing the thalamus and to establish which nuclei were degenerated and which were normal was an aesthetic pleasure. I learned a lot from him.

Later, thanks to Adrian Morrison, an old friend from Pisa, who was professor in the Veterinary School at Penn, I made a connection with people working with the 2-deoxy-glucose technique for measuring neuronal activity. Together with Antonella Antonini, a previous student of Berlucchi working with Jim, we also tried this technique. Furthermore, in the little time he was able to devote to me, Alan Rosenquist showed me an early PET machine and made me acquainted with new possibilities that this technique opened for study of the brain.

I also made several travels, visiting labs and friends both in the United States and in Canada. One of the most interesting was a visit to Duke, where I was a guest of Irv Diamond. I liked his idea that the primary motor and visual areas were a later evolutionary acquisition derived form primitive “association” areas. We planned to do some comparative work together using Galago crassicaudatus but, with the exception of a paper on this topic published some years later (Fogassi et al. 1987), I returned to Italy completely absorbed by the monkey motor system.

Parma: Anatomy and Physiology of the Premotor Cortex

The decade (1980–1991) that extends from my return to Parma to the discovery of mirror neurons was very productive, in physiology, anatomy, and psychology.

After moving from curarized cats to curarized monkeys, I decided that working on behaving monkeys was the only appropriate way to investigate motor and cognitive functions. Thus, with the help of Ivan Pigarev, who was back to Italy, I shifted from curarized to behaving monkeys. This change was immediately fruitful.

We started studying the response properties of postarcuate neurons. We found that a large percentage of them were bimodal (tactile and visual) and that their visual receptive fields were independent of eye position, remaining always in register with the tactile receptive field. This was the first description of neurons that encode visual stimuli in body-part coordinates (Gentilucci, Scandolara, Pigarev, and Rizzolatti 1983).

Prompted by these findings, we decided to see what would be the effect of destruction of the area housing these neurons. With Massimo Matelli and Giuseppe Pavesi, a medical student, we ablated the postarcuate cortex of the macaque monkey. We found motor deficits, such as reluctance to use the contralateral hand, but the most interesting result was the presence of a severe hemi-neglect in both the somatosensory and visual modalities. The visual neglect was limited to the peripersonal space. Control experiments in which FEFs were unilaterally ablated showed a decrease of eye movements contralateral to the lesion and neglect for the far visual space (Rizzolatti, Matelli, and Pavesi 1983).

These data were published without difficulties in Brain. At one point, however, the editor did not like the term “peripersonal.” He wrote to me: “A word formed by a Greek (peri) and a Latin word (personal) is unacceptable.” He complied, nonetheless, when I responded that many other words in English have Latin and Greek roots (e.g., television).

I was very excited by these new neuropsychological data and started to study the old literature on anatomy of this region. I soon found that the distinction between motor, premotor, and supplementary motor cortices was a tremendous oversimplification and that earlier authors, as for example the Vogts, described several cytoarchitectonic areas in the agranular frontal cortex.

With Matelli and Luppino, a postdoc working with me (now professor of physiology in Parma), we decided therefore to reinvestigate the organization of motor cortex by examining the patterns of cytochrome activity in the monkey frontal agranular cortex. We found five distinct areas that we called frontal areas (F) and gave them a number (1 to 5). F1 corresponds to primary motor cortex (M1); ventral premotor cortex is formed by two areas (F4 and F5). In addition, there was an area in the dorsal premotor cortex (F2) and one on the cortical medial surface (F3). The rostralmost part of the agranular cortex was difficult to characterize. Our later studies, where we used the Nissl method and some histochemical techniques, confirmed our subdivision and showed the existence of two additional areas: F6, rostral to F3, and F7, rostral to F2 (Matelli, Luppino, and Rizzolatti 1985).

Our interest in anatomy was boosted by the arrival in 1983 of Mitchell (Mitch) Glickstein from Oxford for a sabbatical. Mitch is one of those rare persons that you immediately like and our friendship is today as strong as then. Mitch introduced anatomical connectivity in Parma, teaching the horseradish peroxidase (HRP) technique for neuronal labeling and tract tracing to Matelli. Connectivity studies are still present in Parma after 30 years.

Mitch was also interested in the history of science. Francesco Gennari (1750–1795), the famous anatomist, had studied in Parma. He was the first to identify the nonhomogenous structure of the human cortex. His finding, the presence of a strip (stria) in the visual cortex, is still used to define the primary visual area (striate cortex). Mitch was interested in finding the history of the life of this extremely talented student. He managed to find some interesting data, including the record of Gennari’s birth in the archives of a small village in the mountains near Parma. We published together the results of this research in Trends in Neurosciences (Glickstein and Rizzolatti 1984).

Our mastery of the HRP technique allowed us to trace the connections of the different sectors of the agranular frontal cortex (Matelli, Camarda, Glickstein, and Rizzolatti 1986). By this means, we demonstrated that while there are no connections between the mouth and hand field in the primary motor cortex, such connections are very rich in area F5. We suggested that this finding indicates that F5 does not encode movements but something more complex, which later I called motor acts (Matelli, Camarda, Glickstein, and Rizzolatti 1984).

In the same period, I became interested in the functional properties of areas F4 and F5. On this issue I published twin papers. The first of these (Gentilucci et al. 1988) concerned the general organization of the ventral premotor cortex. By combining single neuron recordings and intracortical microstimulation, we found that the inferior portion of Brodmann’s area 6 is somatotopically organized. The proximal movements are mostly located in area F4, whereas the distal movements are in area F5. The second paper became very important for my future research (Rizzolatti et al. 1988). Here I rejected the concept that the premotor cortex encodes individual movements. I showed instead that the firing of F5 neurons correlates with specific goal-related motor acts rather than with single movements made by the monkey. Using the motor acts as the classification criterion, we subdivided F5 neurons into four main classes: “grasping-with-the-hand-and-the-mouth neurons,” “grasping-with-the-hand neurons,” “holding neurons,” and “tearing neurons.” Another very interesting finding was the discovery that many neurons in F5 responded to visual stimuli. They lacked receptive field, but discharged when there was correspondence between the type of grip encoded by the neuron and the size of the stimulus effective in triggering it. For example, neurons discharging during precision grip became active during the observation of a small object such as a peanut, whereas neurons encoding power grip became active during the observation of a large object like an apple. These types of visuomotor neurons are now known as canonical neurons.

My main coworkers in these studies of F4 and F5 were Massimo Matelli and Maurizio Gentilucci. Additional help was given by Cristiana Scandolara and Marcello Camarda.

Massimo Matelli was, among my students, probably the one to whom I have been able to transmit the religious feeling for science that was my heritage from Moruzzi. Massimo had his own happy personal life, but he considered life in the institute and research as something sacred. His was a very good surgeon, and a very great observer, but his real talent was anatomy. His work has been appreciated very much by anatomists and especially by Karl Zilles, with whom Massimo was a good friend. He was also an excellent teacher and a real leader. He died in 2003 from a tumor.

Maurizio Gentilucci is an engineer. He arrived from Pisa to give us technical help. After an initial period in which he was just doing his job, he became interested in research and greatly helped in transforming our lab from a merely visual lab to a motor lab. He became particularly expert in movements kinematics and in the relationships between language and movement. He is now professor of physiology in Parma.

The Mirror Neurons

As described above, our approach to the motor system was different from that of most researchers of the motor system. We were not interested in studying movement productions, but in correlating the discharge of premotor neurons to the monkey motor behavior (reaching, grasping, holding, etc.). Following our initial studies (see above), we adopted a more quantitative approach. For this purpose, we trained monkeys to retrieve objects of different sizes and shapes from a testing box, with a variable delay after their presentation. I carried out this work with a new team formed by four brilliant students: Luciano Fadiga, Leonardo Fogassi, Vittorio Gallese, and Giuseppe Di Pellegrino.

After a few experiments, we observed, to our great surprise, that a relatively large proportion of F5 neurons discharged when the monkey observed the experimenter performing specific motor acts, such as grasping food for placing it inside the testing box. Most interestingly, some of these neurons were activated only when the motor act of the experimenter coincided with the monkey motor act encoded by the recorded neuron.

In the winter of 1991, we sent a report on this surprising set of neurons to Nature. Nature rejected it for its “lack of general interest.” Then I sent the paper to Professor Otto Creutzfeldt, who was then editor of Experimental Brain Research. After a few days he called me back saying that, according to him, the paper was of extraordinary interest. Thus the paper “lacking general interest” appeared in 1992 (Di Pellegrino et al. 1992) and, in spite its lack of interest, has been cited (to date) around 2,500 times.

After this first note, we published two papers on the same topic (Gallese, Fadiga, Fogassi, and Rizzolatti 1996; Rizzolatti, Fadiga, Gallese, and Fogassi 1996). In these papers, we described in more details the properties of neurons responding to others’ actions and used for the first time the term mirror neurons. With this term we dubbed those neurons that discharge both when the monkey performs a given motor act and when it observes a similar motor act performed by the experimenter. The viewing of an object even very interesting, such as a piece of food, was not effective in activating these neurons. The mirror actions most represented were grasping, manipulating, and placing.

We proposed that mirror neurons represent internally, in the observer, the actions done by others. We also proposed that the fundamental, but by no means only functions of this representation, is to “understand actions done by others.” By the term “understanding others’ actions,” we meant the capacity of an individual to recognize the goal of an observed action, to differentiate it from other actions, and to use this information to act appropriately. We did not imply a role of mirror neurons in self-consciousness.

Fadiga, Fogassi, and Gallese worked with me many years and each of them, according to their personality, has been very important in developing the concept of the mirror mechanism as a fundamental mechanism in neuroscience as well as in psychology, sociology, and philosophy. They are all now professors of physiology. Giuseppe Di Pellegrino was with us only in the first year of the mirror neuron research. After the publication of the first note on mirror neurons, Giuseppe obtained a job offer from the United States and left us.

The Wonderful Years of Human Frontiers

The last decade of twentieth century was characterized by my friendship and collaboration with three scientists: Marc Jeannerod, Michael Arbib, and Hideo Sakata.

The story of our collaborations started in 1989, in Helsinki, where I presented my data on visual responses in area F5. Immediately following my presentation, Hideo Sakata gave a talk on the functional organization of the parietal area, which is now known as area AIP. After describing the functional properties of neurons of this area, he concluded that the functional role of AIP was visuomotor transformation for hand action. There was a close similarity with my view on the functional role of area F5.

After the symposium we met and found that our ideas on the functional organization of the cortex were very similar. We therefore considered the possibility of starting a collaboration. One means to make this feasible was to obtain a grant from the Human Frontiers Science Program (HFSP). A condition for this grant was the creation of an international interdisciplinary research team. We thought of Marc Jeannerod, as a neuropsychologist, and Michel Arbib, as a computer scientist. We contacted them, and they both accepted. The new-formed team won the HFSP grants three times. This allowed us to work together for nine years.

Our group was very well matched. Hideo was a well-established neuroscientist, professor at Nihon University, and author of several important publications on the functional properties of parietal cortex. He was also coauthor with Mountcastle of the fundamental paper on motor properties of the parietal lobe (Mountcastle et al. 1975).

Marc Jeannerod started his career as a sleep physiologist with Michel Jouvet. Our friendship began in those old times. Marc was one of the first scientists to understand the importance of the motor system in cognition and was also the deepest theorist in this field. A few years before the beginning of our collaboration he elaborated the theory of independent channels for reaching and grasping, which was the basis for our first grant request. He was professor of physiology at Claude Bernard University in Lyon.

Michael Arbib started his career at MIT with Norbert Wiener, the founder of cybernetics, and Warren McCulloch. He became famous at a young age for his papers and books, among which was the very successful Brains, Machines, and Mathematics (1964), which was written when he was only 24 years old. Michael was a good friend of Marc and elaborated Marc’s theory of independent channels for visuomotor transformation in mathematical terms. He was (and still is) professor at the University of Southern California (USC) in Los Angeles.

We published all together only one paper where we summarized our views on the cortical mechanism underlying grasping movements. This paper appeared in Trends in Neurosciences in 1995 (Jeannerod, Arbib, Rizzolatti, and Sakata 1995) and still represents a fundamental perspective for understanding the cortical basis of hand grasping.

The major importance, however, of our collaboration consisted in discussions and in new ideas, which each group used in their research. We had meetings in France, Japan, California, and Italy. Our students took part in them. From these discussions started many collaborations. For example, Luppino and Gallese went to Tokyo to work on AIP. Akira Murata, from Sakata’s lab, came to Italy and did splendid work on canonical neurons (Murata et al. 1997). Marc and I met frequently and Marc also spent a minisabbatical in Parma. The discussions with him helped me a lot in the theorization of the function of mirror neurons. I will describe later the important collaboration I had with Arbib. Last, but not least, our meetings were characterized by a unique friendly atmosphere. Frequently, our wives, Jacqueline, Prue, Harumi, and Leni were also with us and helped in creating the warm friendship that was broken only by the recent disappearance of Marc and Hideo.

The Mirror Mechanism in Humans

As soon as we found that the observation of an action done by others activates the premotor cortex of the monkey, we wondered whether the same mechanism could be present in humans. One way to demonstrate it was to use brain-imaging techniques. At the time Ferruccio Fazio, whom I met years before as a student in Moruzzi’s lab, had just established a PET center in the San Raffaele Hospital in Milan. He was happy to collaborate with us and I started there the experiment with him and Daniela Perani, a neurologist working in the center, plus Matelli and Fadiga from my group.

The experiments were carried out in the following way. Students were lying in the scanner and observed one of the experimenters (typically Matelli) grasping objects. In spite of weak sensitivity of the PET technique, we found a clear activation of the caudal part of the inferior frontal gyrus (Rizzolatti et al. 1996). I replicated this experiment a few months later at USC with Scott Grafton, a neurologist and expert in brain imaging, and Michael Arbib (Grafton, Arbib, Fadiga, and Rizzolatti 1996). To see activations of the motor cortex during action observation, using this indirect technique, was a really thrilling experience.

A more complete localization of the action observation circuit was obtained later in an fMRI study I carried out at Jülich, a world-famous German research center (the Forschungszentrum Jülich), with a group of scientists working with Hans-Joachim Freund and Karl Zilles (Buccino et al. 2001). Object-related actions made with different effectors (mouth, hand, and foot) were shown to normal subjects. The observation of these actions determined activation in both the premotor cortex and in the parietal lobe. In the premotor cortex, the activation showed a somatotopic organization similar to the classical motor cortex homunculus. We concluded that when individuals observe an action, an internal replica of that action is generated in both their parietal and premotor cortex.

In 2010, a meta-analysis of 139 fMRI and PET experiments was carried out by Svenja Caspers et al. (Caspers, Zilles, Laird, and Eickhoff 2010). They confirmed our findings, revealing a bilateral network for both hand action observation and imitation. The involved areas were the superior temporal sulcus (STS) region; the inferior parietal lobe plus the adjacent cortex within the intraparietal sulcus; and the premotor cortex and areas 44 and 45.

While we were carrying out our initial brain imaging experiment, Luciano Fadiga suggested that another possible way to assess the presence of mirror neurons in humans was by transcranial magnetic stimulation (TMS). The logic was the following. If the observation of a goal-directed motor act activates the premotor cortex, it should also activate the primary motor cortex, because of rich connections between premotor and primary motor cortex. Thus, a shock, applied to the motor cortex, which at rest would be insufficient to elicit motor-evoked potentials (MEPs), should elicit a motor response when the subjects observed a motor act performed by the experimenter.

To test this hypothesis we recorded MEPs from hand muscles of subjects while they (a) observed an experimenter grasping three-dimensional (3D) objects; (b) observed an experimenter tracing geometrical figures in the air with his arm; and (c) were instructed to detect the dimming of a small light. This last condition was done as a control of the observer’s attention. The results showed that MEPs significantly increased in the two experimental conditions. Furthermore, the MEP pattern closely reflected the pattern of muscle activity recorded when the subjects executed the observed actions (Fadiga, Fogassi, Pavesi, and Rizzolatti 1995). A large number of TMS studies later confirmed these findings (see Rizzolatti, Cattaneo, Fabbri-Destro, and Rozzi 2014).

A third possible way to demonstrate the existence of mirror neurons in humans is by using EEG or magnetoencephalography (MEG). The activity of human sensorimotor cortex is characterized by a specific cortical rhythm called “mu rhythm,” the characterizing property of which is its reactivity to active movements (Gastaut, Terzian, and Gastaut 1952). Ramachandran and his colleagues reasoned that if the observation of an action would desynchronize the mu rhythm, this effect could be used to study the mirror mechanism in humans. Their results obtained using EEG recordings showed that this was the case (Altschuler et al. 1997).

I discussed these findings with Riitta Hari, one of the greatest experts in MEG, and we decided to test the “mu” reactivity using this technique. We recorded neuromagnetic activity of the human precentral cortex from volunteers while they were manipulating a small object and when they were observing another individual performing the same task. The median nerves were stimulated and the post-stimulus rebound of the precentral cortex activity was quantified. Object manipulation suppressed this rebound. Most interestingly, action observation also significantly decreased the rebound. These findings clearly indicated that MEG (and EEG) was a useful tool for understanding the machinery underlying action recognition in humans (Hari et al. 1998).

Space Coding (Area F4) and the Discovery of the Presupplementary Motor Cortex (Area F6)

Our investigations of the organization of the premotor areas were not limited to area F5. In the years in which we discovered mirror neurons, we also studied the functional organization of area F4. Among the new findings, of particular interest was the discovery that the extent in depth of visual receptive fields of F4 neurons was not fixed, but increased with the velocity of stimuli that were moved toward the monkey. We concluded that the velocityrelated expansion is due to the necessity to program an effective arm reaching movement toward the approaching stimulus (Fogassi et al. 1996).

Another sector of agranular frontal cortex that we were interested in was the mesial aspect. This part was considered traditionally as a single functional region and called the supplementary motor area (SMA). Our histological investigations of this region indicated that this view was wrong and that this sector was formed by two cytoarchitectonic areas: F3 and F6.

We studied areas F3 and F6 using intracortical microstimulation and single neuron recordings. The data showed that area F3 (the caudal area) contains a complete representation of body movements, with hindlimb located caudally, forelimb centrally, and orofacial movements rostrally. Movements were difficult to elicit from area F6 (the rostral area). However, by using longer durations of microstimulation, body-part movements could be elicited. Most of the evoked movements concerned the forelimb. Many of them mimicked the natural reaching and grasping movements of a monkey (Luppino et al. 1991).

Single neuron recordings showed that neurons in F6 were not influenced by how objects were grasped nor by where they were located. The most striking feature of F6 neurons was that their activity increased largely prior to the arm movement. This premovement modulation could start with stimulus presentation, with the saccade triggered by the stimulus, or simply after the monkey fixated a stimulus. We concluded that the onset of activity of F6 neurons signals when the monkey decides to perform the reaching-grasping arm movements (Rizzolatti et al. 1990).

At the end of 1991 I was in Japan for an HFSP meeting and, in this occasion, I visited Jun Tanji in Sendai. He showed me his data on F6, and we were happy to find that our data were in good agreement. The following year Tanji published an article in the Journal of Neurophysiology where he called the new mesial area (our area F6) the “presupplementary” motor area (preSMA; Matsuzaka, Aizawa, and Tanji 1992). This name is now largely used.

The issue of a possible parcellation of SMA into two areas was addressed by Karl Zilles in humans (Zilles et al. 1996). He found that the distinction between areas F3 and F6, which we found in the monkey, was also valid for humans and that there was a strong neurochemical similarity between human and monkey F3 and F6, respectively. I met Karl first in Cleveland, where there was an important meeting on the organization of motor cortex. It was a beginning of a long friendship and collaboration, which included Matelli and Luppino.

Neuropsychology and the Motor Theory of Attention

My interest in neuropsychology started in Pisa. With my new job in Parma, this interest did not decline. In fact, Giovanni Berlucchi and I met frequently and discussed various issues related to hemispheric specialization, selective attention, and stimulus response compatibility. Other people like Carlo Marzi participated in these discussions and among those working with me were Giovanna Bertoloni and Gian Paolo Anzola, two of the best medical students I ever had. Both subsequently decided to do clinical work.

In those years, I became also convinced that the teaching of some neuropsychological issues could enrich the course of neurophysiology and be useful for medical students. Professor Arduini agreed with me. This was, however, not the opinion of most of our medical colleagues who had a very low opinion of psychologists or at least of Italian psychologists. Arduini and I found a solution to this objection: Carlo Umiltà. Carlo was trained as a medical doctor and his CV showed serious experimental studies rather than vague speculations. Using all his prestige, Arduini was able to convince the most influential members of the Medical Faculty of the validity of our idea, and Carlo was appointed professor of psychology in our faculty.

Carlo Umiltà arrived in Parma in 1978. His arrival gave a new boost to the intellectual life of our institute. He had a good international reputation and this, plus our cognitively oriented neurophysiological experiments, attracted to Parma many visitors interested in our studies. Among them were Michael Posner, Alan Allport, a very young Jon Driver, and Steve Keele. Steve spent a sabbatical in Parma giving us a splendid course on motor systems considered from a psychological point of view.

Carlo had also a lot of charisma. When in 1989 Professor Arduini left Parma to return to Pisa, Carlo was elected director of the institute. He has been an excellent director. It was a sad day for me when he decided to leave Parma for strictly personal (nonscientific) reasons. I lost a great coworker (and an excellent tennis partner).

Carlo and I published together many papers, some also with Lucia Riggio, who came from Padua with Carlo and who is now professor of psychology in my department, and others with Luiz Gawriszewski, a very motivated and rather bizarre Brazilian professor.

My most important contribution in the field of psychology is the “motor theory of spatial attention,” originally conceived with Carlo Umiltà (Rizzolatti, Riggio, Dascola, and Umiltà 1987). Spatial attention is the capacity to improve the processing of sensory information coming from a specific space sector. The dominant view on spatial attention in those years was that advanced by Posner (Posner, Snyder, and Davidson 1980), which argues that attention depends on a dedicated supramodal control mechanism that is anatomically distinct from the modality-specific circuits underlying sensorimotor processing.

In the late 1980s, we published a paper (Rizzolatti, Riggio, Dascola, and Umiltà 1987) that challenged this view. We used a variant of the Posner paradigm. In the Posner paradigm (as most commonly used), subjects are seated in front of a computer screen and fixate at a central point on the screen, marked by a dot or cross. To the left and the right of the fixation point, there are two boxes. A cue is presented on the screen indicating where the imperative stimulus will be presented. The cue is then removed and the imperative stimulus appears in either the left or right box. The observer must respond to this stimulus immediately after detecting it by pressing a button, without moving the eyes. There are “valid” and “invalid” trials. In valid trials, the imperative stimulus is presented in the area as indicated by the cue. In invalid trials, the stimulus is presented on the side opposite to that indicated by the cue. Typically, a ratio of 80 percent valid trials and 20 percent invalid trials is used. Some trials, called “neutral” trials, have no cues prior imperative stimulus presentation. The comparison of performance on valid, invalid, and neutral trials allows one to establish whether cues direct attention to a particular area and benefit or hinder the subject performance. Since the participant is not allowed to move their eyes, differences in reaction time between imperative stimuli in the three conditions indicates that the subject oriented covertly their attention.

In our experiment the visual display comprised a central box, where a cueing digit was presented, and four boxes for stimulus presentation. The main result was that when an imperative stimulus was located in the hemifield contralateral to where attention was located, reaction times were longer than when the imperative stimulus and attention were deployed in the same hemifield, even when the distance from the unattended stimulus and the cued location was the same in the two hemifield conditions. We called this reaction time delay the “meridian effect” (Rizzolatti, Riggio, Dascola, and Umiltà 1987).

The meridian effect cannot be explained easily by the hypothesis that attention is a control system independent of basic anatomical and physiological circuits. There is no reason whatsoever why an anatomical landmark such as the meridian of the visual field could affect the function of a supramodal control mechanism. In contrast, the meridian effect can be easily accounted for by assuming that attention derives from preparation to move the eyes toward the cued location. When a cue indicates the future location of the imperative stimulus, an eye movement program is prepared toward the expected location. This program specifies the direction and the amplitude of the saccade. If a target does not appear in the cued location, a new eye movement program has to be prepared. This requires first a selection of the saccade direction and then the setting of the saccade amplitude. This determines a “cost” in reaction time. In contrast, changes in saccade amplitude alone imply only a readjustment of an existing program. The cost is, therefore, less than in the former case.

More direct evidence in favor of the premotor theory of attention came from a series of experiments that we carried out with Boris Sheliga (see Rizzolatti, Riggio, and Sheliga 1994). Boris arrived to my lab from Moscow and spent a couple of years with us before going for good to NIH. Boris is a very kind person and an extremely skillful scientist. Thanks to him we were able to measure the deviation of vertical saccades during attention tasks.

The basic experimental situation was the following. The visual display comprised three filled and two empty boxes. The three filled boxes were arranged horizontally, and the empty boxes were arranged below and above the central box. The central box was the fixation box. The cue was a thin line attached to this box. If the line was pointing to the left, the imperative stimulus was presented in the left filled box, and if pointing to the right in the right filled box. The imperative stimulus consisted of a white vertical line across one of the filled boxes. As soon as the imperative stimulus was presented, participants had to make a vertical saccade directed to one of the empty boxes, according to a previous verbal instruction. The major difference with standard Posner parading was that the measured variable was not a manual response but a vertical saccade directed to a box located below or above the fixation point. The main result was that, when participants paid attention to a given spatial location, the trajectory of a saccade triggered by an imperative stimulus deviated, possibly to prevent the natural tendency to look at the stimulus. Thus, allocating attention to a given position necessarily activates the eye movement system, even if the required ocular movement was a simple vertical saccade.

The predictions of the motor theory were confirmed by neuroimaging experiments. The results showed that spatial attention and eye movements share the same cortical neuronal network (Corbetta et al. 1998; Nobre, Gitelman, Dias, and Mesulam 2000). There is no system of cortical areas activated exclusively by covert attention or by a saccade.

It will be too long to present here the rich neurophysiological evidence that confirmed the motor theory of attention (see Rizzolatti and Craighero 2010). One experiment, however, deserves to be mentioned. In a brilliant electrophysiological study, Moore and Fallah (2001) showed that it is possible to enhance spatial perception by altering oculomotor signals within the brain. The authors trained two monkeys to make manual responses at the detection of a transient dimming of a peripheral visual target and tested the effects of FEF microstimulation on monkeys’ performance. They found that subthreshold stimulation of FEF determined a decrease in the psychophysical threshold for stimulus detection, only, however, when the target stimulus was positioned in the motor field corresponding to the stimulated point. This finding provided direct evidence that the programming of eye movements leads to the allocation of spatial attention.

The motor theory of attention raised a lot of controversy. In general, the field of psychology did not like it. The destruction of a “mythical” supramodal construct, which many psychologists adored, elicited furious reactions. A nice exception to these reactions was that of Michael Posner, with whom we discussed several times the advantages and weaknesses of my theory in constructive terms. We were friends and remained friends in spite of our differences of opinion.

Neglect and Perception

For many years the chairman of the Department of Psychology at University of St. Andrews was Malcolm Jeeves. His main scientific interests concerned the corpus callosum. Giovanni Berlucchi and I met him in a Congress on interhemispheric relations in Smolenice, near Bratislava, in 1969. Subsequently we obtained a small grant that allowed us to exchange visits. Malcolm was a great organizer. After his appointment as chairman, he hired, in a short period, a collection of brilliant young scientists who later became very famous. Among them were Richard Morris, Melwyn (Mel) Goodale, David Milner, and David Perrett. Thanks to our exchange grant, I met Malcolm many times and became friends with these young researchers from St. Andrew.

In 1995, David and Mel published their now-famous book, The Visual Brain in Action. David sent me a preliminary version for comments. I found the book exceptionally good. I have still a copy of it on my desk in which David wrote: ”For Giacomo. With many thanks for your help.” Yet there was a point in the book that did not convince me: Why is one of the most dramatic perceptual deficits in neuropsychology, visual neglect, not caused by lesions of the ventral cortical stream, which according to Milner and Goodale is responsible for perception? Neglect, in fact, occurs typically after lesions of the right inferior parietal lobe.

Neglect was one of the hot issues of those years. Edoardo Bisiach, one the most famous researchers in that field, suggested that one of his students could spend some time with me. This student was Anna Berti. Anna was a neurologist. She came to Parma in 1989 and remained with me four years while getting her PhD in neuroscience. Anna was an outstanding young scientist with a pleasant, warm personality. I liked to work with her. We wrote together several reviews and I still remember those days as a mere pleasure. With Anna (most of the merit is hers), we did an experiment that I consider fundamental for showing that perception does not necessarily depend on the ventral stream (Berti and Rizzolatti 1992).

The question we addressed was the following: Patients with neglect deny seeing objects in their “blind hemifield,” but can they process the presented objects without visual awareness? To address this problem, we required a patient with a “dense” neglect to respond as fast as possible to target stimuli (pictures of animals and fruits) presented to the normal field by indicating the category of the targets. We then studied the influence of priming stimuli, again pictures of animals or fruits, presented to the neglected field on the responses to targets. There were three different experimental conditions. In the first condition, “Highly Congruent,” the target and prime stimuli belonged to the same category and were physically identical; in the second condition, “Congruent,” the stimuli represented two elements of the same category but were physically dissimilar; in the third condition, “Non-Congruent,” the stimuli represented one exemplar from each of the two categories of stimuli. Our results showed that the responses were facilitated not only in the Highly Congruent condition, but also in the Congruent one.

This finding suggests that patients with neglect are able to process stimuli presented to the neglected field to a categorical level of representation, even when they deny the stimulus presence in the affected field. In other words the patients did not perceive stimuli in the neglected field in spite of the fact that the ventral stream was not only anatomically intact, but also functionally intact and able to process stimuli to a categorical level. My view from these experiments is that the ventral stream is a “storage of objects.” For perception to take place, however, the activity of the dorsal stream is necessary (or, to be precise, the activity of the ventral part of the dorsal stream; see Rizzolatti and Matelli 2003). Anna Berti is now professor of psychobiology in Turin. She is a productive scientist still interested in neglect and related phenomena.

The New Century: Personal Events

The beginning of the new century started with bad news. I used to go to work by bicycle. During the winter of 1999, I noticed that I sometimes had pain in the chest, especially when the road had an upward slope. I minimized the fact, thinking of an intercostal pain due to the Parma wet climate. In January 2000, however, I decided to have a cardiologic visit. There was no infarct, but my cardiologist wanted to check my heart more deeply with an angiography. The results were very bad. I had to be operated on as fast as possible. One of the best Italian cardiac surgeons was at San Raffaele hospital, the same hospital where we first demonstrated the existence of mirror neurons. Thanks to Feruccio Fazio, also a professor at San Raffaele, the surgeon visited me in the same afternoon of the day when the angiography was made. He confirmed that the situation was bad and fixed the operation for the beginning of the following week. The operation was rather complex, but I was always convinced of a happy end. This was the case. I was also sure that I could be back at work in a week. This was an optimistic view. Before going back to work, I had to spend one month in a rehabilitation clinic on Lake Garda. It was not a bad period. The improvements were evident day after day, and Leni was all the time with me. It was a kind of strange holiday after which I was ready to go back to Parma with renewed force and enthusiasm.

My return to the lab was characterized by a series of unexpected recognitions. The first was the Premio Feltrinelli, the most prestigious Italian scientific prize, given by the Accademia dei Lincei. This prize was followed, two years later, by my election to this Academy.

In 2000, a few months after my coming back from the hospital, I was called by Eric Kandel who invited me to write the chapter on the motor system for the new edition of Principles of Neurosciences. I accepted with great pleasure. The writing and rewriting of the chapter was an endless and sometimes unnerving story. Eventually the chapter became three, two of which I wrote with John Kalaska. The chapters are now out in the new (fifth) edition of the book (Kalaska and Rizzolatti 2013; Rizzolatti and Kalaska 2013). They are a bit longish but not bad.

The interest aroused by our discovery of mirror neurons led to another prestigious recognition: The election in 2002 as an associate member of the Neuroscience Research Program, directed by Gerald Edelman. The meetings were held in La Jolla, California, in Edelman’s beautiful center known as the Neurosciences Institute. The programs were very interesting as were the conversations with Gerry and the other associates, and especially with Joaquin Fuster, a good friend.

This series of recognitions was followed in 2002 by my election as a foreign honorary member of the American Academy of Art and Sciences and in 2005 to Academie Francaise de Sciences. The ceremony at Cupole, the site of French Academy, was very impressive and rendered even more beautiful by the presence of many members dressed in the famous traditional uniform. Finally, some years later (in 2012) I was elected foreign associate of the U.S. National Academy of Sciences, a very great honor for a foreign scientist.

Action Understanding

Macaque monkeys are poor imitators. So since the first papers, we proposed that mirror neurons of monkeys play a role in “understanding” the observed actions. By the term “understanding,” we meant the capacity of an individual to recognize the goal of an observed action, to differentiate it from other actions, and to use this information to act appropriately. The logic was the following: When the monkey decides to perform a given motor act, the mirror neurons become active. When the monkey observes the same action done by another individual, the same neurons fire. Thus, in both cases, the same motor representation is elicited. Because of this identity, the monkey understands what are the goals of others’ actions.

In order to test this hypothesis we carried out two experiments. In the first experiment, we tested whether F5 mirror neurons were able to recognize motor acts from their sounds (Kohler et al. 2002). In the second experiment, we asked whether the understanding of a motor act, based on memory cues, could trigger their activity (Umiltà et al. 2001).

In the first experiment, we recorded the activity of mirror neurons when the monkey was observing a motor act characterized by a typical sound (e.g., ripping a piece of paper), and when this sound was heard, but the action producing it was hidden from the monkey’s view. The results showed that many mirror neurons responded to the sound, even if the motor act was not seen (Kohler et al. 2002).

In the second experiment, neurons were tested in two conditions: In one, the monkey saw an object-directed action (“full vision” condition); in the other, the same action was presented but with its final part hidden (“hidden” condition). The results showed that many neurons responding to the observation of grasping in full vision also discharged in the hidden condition. Thus, the meaning of the observed actions and not their visibility triggered activity from mirror neurons (Umiltà et al. 2001).

Imitation

If macaque monkeys are poor imitators, certainly this is not true for humans. Thus, considering the properties of mirror neurons, it seems plausible that, when in evolution this function appeared in Homo sapiens, its neural basis was a set of mirror neurons encoding not the goal of an observed action but the elementary movements forming it. This hypothesis was indirectly corroborated by TMS experiments showing that the observation of intransitive movements activates, in the observer, the same muscles that are involved in movement execution (see Rizzolatti, Cattaneo, Fabbri-Destro, and Rozzi 2014).

We believed that more direct evidence in support of the hypothesized involvement of mirror neurons in imitation could be obtained using fMRI. At the end of the last century, however, an appropriate scanner for running human fMRI experiments was lacking in Parma. Fortunately, I found teams of scientists willing to collaborate with me. One team was that led by John Mazziotta at UCLA. In particular I worked with one of his young coworkers, Marco Iacoboni. Marco is an Italian neurologist who went to Los Angeles, about 20 years ago, for a short stay and is still there. He is now professor of psychiatry and biobehavioral sciences at UCLA.

An fMRI experiment that we carried out at UCLA concerned imitation. In the main experimental condition, participants had to observe a moving finger, a cross on a still finger, or a cross on an empty background. They were instructed to lift a finger as soon as possible in response to stimulus presentation. The main result was that the activation of the areas belonging to the mirror system was significantly stronger when the participants responded to the observation of the moving finger than when they had to respond to the other stimuli (Iacoboni et al. 1999). These data indicate that a mirror mechanism for imitating simple movements is present in humans. Neuron responses to the observation of simple movements have never been observed in monkey premotor cortex.

The second group with which I collaborated extensively in those years was the team working with Hans-Joachim Freund and Karl Zilles in Duesseldorf and Juelich. Thanks to an exchange grant, one of my students, Giovanni Buccino, went to Duesseldorf to learn functional brain imaging. For many years Buccino has been my main coworker in fMRI studies. He is now professor of physiology at the University of Catanzaro.

With Buccino and Stefan Vogt, who played an important role in the experiment, we investigated whether the mirror mechanism is involved in imitation learning. The participants were students who had never played guitar before. They were asked to imitate guitar chords played by an expert guitarist. There were four conditions: observation of the chords made by the teacher, pause, and execution of the observed chords, and rest. The main result was that during pause, when the students built internally the new chord pattern, the same circuit was activated as during observation, plus the middle frontal cortex (area 46). We proposed that imitation learning occurs in two steps: first, “mirror” activation of motor representations; second, recombination, thanks to the prefrontal lobe (area 46), of these motor acts (Buccino et al. 2004). A subsequent study carried out on expert and naive guitarists confirmed the fundamental role of area 46 in combining different motor acts encoded in the mirror circuit in a new motor pattern (Vogt et al. 2007).

Mirrors beyond Neuroscience: Philosophy

Although Ramachandran’s famous sentence—“Mirror neurons will do for psychology what DNA did for biology”—somehow predicted that mirror neurons will interest scholars in disciplines other than neuroscience, I was very surprised when I saw an article entitled “Constitution by Movement: Husserl in Light of Recent Neurobiological Findings” (Petit 1999). (Edmund Husserl is the early twentieth-century German philosopher who founded the phenomenology movement.) The article was written by Jean-Luc Petit, a phenomenologist. Jean-Luc invited me first to Strasbourg and then organized with Alain Berthoz a small meeting in Paris. It was a great success. Our ideas became very popular among the phenomenological philosophers.

At approximately the same time, Alvin Goldman, the famous philosopher (not a phenomenologist), wrote an article with Vittorio Gallese on mirror neurons (Gallese and Goldman 1998). The fact that interest in mirror neurons was not limited to phenomenologists was confirmed by an invitation that I received from Giulio Giorello, one of the most influential Italian philosophers of science. Giorello invited me to give a seminar in his Department in Milan. After the meeting, he suggested that I write a book together with Corrado Sinigaglia, his postdoc who had spent a period in Louvain working in the Husserl Archives.

I was initially a bit reluctant to accept this invitation, but Corrado liked the idea. With my surprise Corrado showed an incredible competence in neuroscience. So the book started and was finished in about one year. The Italian edition, So quello che fai (I Know What You Do) was very successful and, even now, is widely sold and read (Rizzolatti and Sinigaglia 2006). Soon after its publication, our book was translated into Spanish and French, and subsequently into English, German, and Russian and, more recently, in other languages including Japanese and Korean.

This collaboration with Corrado started in 2006 and is still going on. We published several articles together and introduced the concept of “understanding from inside” (Rizzolatti and Sinigaglia 2010). With this expression, we indicated that understanding others through mirror neurons is different from other forms of understanding, such as understanding using inferential reasoning. In the first case, understanding emerges from the fact that others are like you; in the second case, you understand them in the same way as you understand physical phenomena, such as why an apple is falling down from a tree.

Language

Already from the early PET experiments (Rizzolatti et al. 1996; Grafton, Arbib, Fadiga, and Rizzolatti 1996), it was clear that the observation of others’ actions activates a sector of Broca’s area. On the basis of this observation, Arbib and I (Rizzolatti and Arbib 1998) argued that this activation indicates a close link between gestures and language and, in more general terms, that it supports the previously advanced notion that human speech derived from human gestures rather than from animals’ calls (see ref. in Armstrong, Stokoe, and Wilcox 1995; Corballis 2002).

We proposed that mirror neurons provide the mechanism that creates a direct link between the sender of a message and its receiver. Thanks to this mechanism, actions done by other individuals become messages that are understood by an observer without any cognitive mediation. The novelty of our article consisted in the fact that we suggested a neurophysiological basis for a common nonarbitrary link between communicating individuals.

Our paper was published in Trends in Neurosciences. It was highly successful and received a large number of citations. Yet, other issues subsequently took my interest. Thus, the study of the relations between language evolution and mirror neurons was pursued by Michael, who went on to publish several important articles on this issue (e.g., Arbib 2005).

A different issue, also related to speech, that attracted my attention was whether the articulatory cortical system is endowed with the mirror mechanism. In other words, when I hear a phoneme is there an activation of the cortical motor areas involved in the production of that phoneme? With Luciano Fadiga and others (Fadiga, Craighero, Buccino, and Rizzolatti 2002), we presented words that, when pronounced, strongly involved tongue movements (e.g., birra) and others than, when pronounced, did not require these movements (e.g., baffo). While subjects listened to these words, we stimulated, using TMS, the mouth field of their motor cortex and recorded MEPs from tongue muscles. We found that listening to words (or even pseudo-words) containing “rr” increased MEPs, while this effect was absent when listening to words containing a double “f.” These results clearly indicate that the heard phonemes are transformed in their motor equivalence as suggested by the motor theory of Alvin Liberman (Liberman and Mattingly 1985).

From Mirror Neurons to the Mirror Mechanism

In the first years following the discovery of mirror neurons, our research was focused on the mirror properties of areas involved in the recognition of actions devoid of a clear emotional content (“cold actions”). What about emotions? Are they recognized through a mechanism similar to that of cold actions? In 2002, Christian Keysers, Vittorio Gallese, and myself discussed this issue. Christian was in Parma as a postdoc after getting his PhD with David Perrett in St. Andrews. Christian was very eager to start this research. He was an exceptional coworker and almost unique in his capacity to conclude satisfactorily any initiative he started.

Christian was a good friend of Bruno Wicker from Marseilles who had access to a scanner and was connected with Jane Plailly and Jean-Pierre Royet, both of whom were experts in using odorants as stimuli in psychological experiments. The experiment we carried out consisted of two parts. In part one, participants inhaled odorants producing a strong feeling of disgust; in part two, the same participants observed video clips showing the emotional facial expressions of disgust. The most important result was that observing emotional faces and feeling disgust activated the same sites in the anterior insula. Thus, as observing hand actions activates the observer’s motor representation of that action, observing an emotion activates the neural representation of that emotion. This finding suggested a unifying mechanism for understanding the behaviors of others (Wicker et al. 2003). In the following year, we wrote an essay, in which we maintained that the transformation of sensory information into a motor program was not limited to cold actions, but included emotions (Gallese, Keysers, and Rizzolatti 2004).

Although it is well known that emotions are linked to vegetative and motor behavior, one may wonder whether the rostral part of the insula encodes motor programs. I studied this issue with Vittorio Gallese and two PhD students in Parma: Ahmad Jezzini and Fausto Caruana. We examined the functional properties of the insula using prolonged (3 s) electrical intracortical microstimulation in behaving monkeys. The results showed that the insula is composed of several different functional subdivisions. A sensorimotor field occupies the caudal-dorsal portion of the insula, while, more rostrally, positive and negative ingestive motor behaviors are elicited. Finally, affiliative gestures (lip-smacking) and behaviors indicating distress are evoked by sites in the ventral insula. The most important finding of the experiment was our demonstration that the disgusted motor behavior (facial expression and arm movements for pushing food away) was elicited following stimulation of a rostral portion of the insula corresponding to that activated in the human brain during the presentation of a disgusting odorant or the observation of a disgusted face. Thus, the feeling of disgust occurs when the motor behavior of disgust is elicited (Jezzini et al. 2012).

Intention Understanding

The observation of a motor act performed by another individual allows the observer to understand the goal of the observed motor act, but also, typically, the intention behind it. Before my heart surgery, I planned with Marco Iacoboni to perform an fMRI experiment to define the circuits involved in understanding the intention of an observed motor act (i.e., “why” an action is performed). The concept is very simple. If I observe Mary grasping a cup of coffee, I immediately understand her motor intention from the way she grasps it. For example, if Mary grasps the cup using the handle, it is likely that her intention is to drink the coffee. In contrast, if she puts her hand on the top of the cup, her intention is hardly that of drinking coffee. Also the context in which the action is performed may clarify the intention of the observed motor act. If the cup is empty, it is hard to think that Mary’s motor intention is to drink, while if the cup is full, it is likely that her intention is to drink. Note that here we deal with motor intention, not with the reasons behind it (i.e., Mary wants to drink coffee because she is drowsy and wants to wake up).

In order to investigate motor intention, we performed an fMRI experiment. Normal subjects watched three kinds of stimuli: grasping actions without a context, context only (scenes containing objects), and grasping performed in two different contexts. In the context-with-action condition, the context suggested the motor intention associated with grasping (drinking or cleaning). The result showed that actions embedded in contexts, compared with the other two conditions, yielded a significant signal increase in the posterior part of the inferior frontal gyrus and in the adjacent sector of the ventral premotor cortex where hand actions are represented. Thus, premotor mirror areas, active during the execution and the observation of an action, are also involved in understanding the motor intentions of the observed action. To ascribe a motor intention to another person is an operation that the motor system does automatically through the mirror mechanism (Iacoboni et al. 2005).

Monkey experiments confirmed this conclusion at the single neuron level. We trained monkeys to grasp objects with two different intentions: eating or placing using the same grip. Neurons were recorded from inferior parietal lobule (IPL, mostly area PFG), and their discharge during grasping was studied. The results showed that two-thirds of IPL grasping neurons discharge with a different intensity according to the intention of the action in which a grasping motor act was embedded. We termed these “actionconstrained neurons.”

In a second experiment, monkeys observed the experimenter grasping an object. Two conditions were used to vary the intention of the grasping movement. If the experimenter had a container on his shoulder, he would put the object into it. If there was no container, the experimenter would bring the object into his mouth. The results showed that the intensity of the discharge of about two-thirds of IPL mirror neurons was modulated by the agent’s (experimenter, in this case) intention. Thus, mirror neurons not only represent the goal of the action, but also the motor intention underlying it (Fogassi et al. 2005).

In a subsequent study, Bonini et al. (2010) recorded neurons from F5 applying the same two-intention paradigms. The results showed that F5 also contains “action-constrained” grasping neurons that are active both during action execution and action observation. The authors concluded that the similarities between mirror neuron properties of the two areas indicate that they constitute a functional circuit underlying an observer’s understanding of the intentions of others.

In 2007, I carried out a further experiment on intention. In that year, Mike Gazzaniga invited me to spend a couple of months as a visiting professor in Santa Barbara. Santa Barbara is a very quiet place and the university campus near the ocean is the most relaxing place you can imagine. In Santa Barbara, I found Scott Grafton, my old coworker in the first PET experiments on mirror neurons and a prominent figure in brain imaging. The scanner, however, for doing fMRI experiments was not yet operational. Scott was working with a young Swiss researcher, Stephanie Ortigue, who was an expert in EEG. I was impressed by the potential of high-density EEG recordings and by the algorithms that had been elaborated for localizing the EEG sources and to transpose them subsequently onto the MNI brain, the widely used “standard” human brain template provided by the Montreal Neurological Institute.

With Stephanie and Scott, we examined the time course of cortical activations during intention understanding using a 128-channel EEG system. Volunteers saw two-frame video-clips. The first frame showed an object with or without context; the second showed a hand interacting with the object. The volunteers were instructed to understand the intention of the observed actions. We found an initial left hemisphere involvement that we interpreted as related to the understanding of the goal of object-directed motor acts. The successive right hemisphere activation suggested that this hemisphere plays an important role in understanding the motor intention of others (Ortigue, Sinigaglia, Rizzolatti, and Grafton 2010).

During my stay in Santa Barbara, I had a nice surprise. I received an important prize: the Grawemeyer Award in Psychology, which I shared with Leonardo Fogassi and Vittorio Gallese, for the discovery of mirror neurons. I was very happy to receive a prize for psychology, a fact indicating that our attempt to “naturalize” psychological function was appreciated also by psychologists. The prize gave me also the opportunity to visit Kentucky and to meet the nice friendly people who work at the University of Louisville.

Autism: Early Studies

The idea that the mirror mechanism could be impaired in autism was advanced in 2001 by Williams et al. (Williams, Whiten, Suddendorf, and Perrett 2001). Even before reading that article, however, I had also thought of a possible link between autism and the mirror mechanism. I made some timid attempts to demonstrate it. These attempts unfortunately clashed with the laziness (even more than with the skepticism) of the medical personnel caring for autistic children in Parma.

However, before my stay in Santa Barbara things changed. First, two of my PhD students, Luigi Cattaneo and Maddalena Fabbri-Destro, found the idea very appealing. Second, the new professor of child psychiatry, Giuseppe Cossu, agreed to collaborate with us on this topic. Third, Cossu found an autism care center in Tuscany where the doctors, Cinzia Pierracini and Annalisa Monti, enthusiastically agreed to collaborate with us.

The approach we used derived from our experiments on motor intention coding in monkeys (Fogassi et al. 2005). We asked typically developing (TD) children and children with autistic syndrome disorder (ASD) to perform two actions. One action consisted of grasping a piece of chocolate and bringing it to the mouth (eating), the other in grasping a piece of paper and putting it into a container (placing). We recorded EMG from mylohyoideus (MH) muscle, one of the muscles involved in the mouth opening. We found that, in TD children, the MH muscle became active in the eating condition as soon as the reaching-to-grasp action started, preceding by about 700 ms the moment at which the hand grasped the piece of chocolate. In contrast, in ASD children, the earliest MH activation was first observed when the hand was already grasping the chocolate. As expected, no MH muscle activation was observed in the placing condition. In other words, the overarching intention to eat the chocolate was not transformed automatically into motor intention. There was therefore in ASD children a fundamental deficit in action organization.

In the second part of this experiment, the conditions were the same as in the first (grasping for eating versus placing), but this time TD and ASD children did not act but rather observed the experimenter grasping for eating or for placing. The results showed that in TD children, MH muscle was active during the observation of the eating action. In contrast, in children with ASD, the observation of an experimenter grasping and eating chocolate did not elicit any muscular activation. In other words, in ASD children, the observation of others’ actions did not “intrude” into the motor system. We proposed that a basic deficit in ASD consists of impairment of the motor system, which in turn prevents the organization of intentional motor action. This last deficit is responsible for an impaired capacity of children with ASD to understand the intentions of others (Cattaneo et al. 2007).

We conducted additional experiments to test our hypothesis that children with ASD suffer from a deficit of intention understanding resulting from dysfunction of the mirror mechanism. In one study another student, Sonia Boria, played an important role (Boria et al. 2009). We tested the capacity of TD and ASD children to report the goal of the observed motor acts (i.e., what the actor was doing) and the intention underlying it (i.e., why he/she was doing it). We found that children with ASD recognize the “what” of the motor acts, but they fail to recognize the “why” (i.e., the intention behind the observed action).

Further evidence for a motor impairment in action organization of ASD children was provided by an experiment in which TD and ASD children were asked to perform two distinct actions. Each action consisted of two motor acts. The first act (grasping a small ball) was identical in both actions; the second (placing the ball in a hole) varied in its difficulty. In fact, in one action, the participant had to place the ball in a small container (difficult task), while in the other action, in a large one (easy task). The results showed that, in TD children, the difficulty of the second action (placing the ball in a small container is more difficult than in a large one) slowed the kinematics of the first motor act, while, in children with ASD, it did not affect it (Fabbri-Destro, Cattaneo, Boria, and Rizzolatti 2009). This indicates that while TD children programmed both the motor acts forming the actions from the outset, children with ASD performed them not as a sequence, but as two independent motor acts.

Some authors considered the fact that children with ASD can recognize the goal of motor acts as evidence against a link between mirror neurons and autism deficits. Our claim, however, was that children with ASD have difficulty in understanding the intention of an observed action, not the motor act forming it. In any event, the novelty of our study was in putting the stress on a deficit in the development of motor organization in children with ASD, and in considering the cognitive impairments, which emerge with age, as a consequence of this motor deficit.

A Political Interlude

My research with few exceptions was carried out in Italy in a public university. Can I say that the Ministry of Education, which my university depends upon for support, helped me in my discoveries? The answer is no. On the contrary, our discoveries in Parma occurred in spite of the Italian government. For years, Italy has had no PhD programs and public money for research has been minimal. To survive, the members of my research teams had to find paid employment outside of the university. For years, Matelli, for example, spent his weekends as a substitute of a general practitioner. Luppino and Gallese spent their nights in the Parma jail as substitutes for the official jail doctors. Fortunately, all my coworkers of those years were MDs; otherwise, no research would have been possible in physiology in Parma.

My team started to have money that allowed me to pay young people only at the end of the last century, thanks to the HFSP and to the European community. However, in the same year when we discovered the mirror neurons, the Italian government decided to take an “ecological” view on animal experiments, and for about one year, we could not continue our experiments on monkeys. Fortunately for us, Berlusconi won the next election and appointed a pharmacologist as vice-minister for health. Animal experiments started again.

Berlusconi was, however, little interested in research and the a priori opposition against him, composed mostly of intellectuals and academics, did not improve the situation. Thus, the academic circles were very happy when in 2006 Prodi won the elections and Fabio Mussi was appointed Minister of Education. Mussi had been a student of the prestigious Scuola Normale Superiore of Pisa, which he left, however, because of his heavy involvement in politics. His view of university was not that of a scholar, but a confused mixture of anti-elite claims and Marxist slogans. He decided that university must be reformed. In the meantime, he stopped the recruitment of new professors and implemented a compulsory retirement for those 70 years old. In Italy retirement was at 75. The result was the abrupt elimination of many of the most prominent academics and the emigration of young people to countries more supportive of academic research.

After two years of inefficient government, Prodi was compelled to resign. Berlusconi won the following election. It was a disaster. Maristella Gelmini, a second-rate lawyer with a very poor schooling curriculum, was appointed as Minister of Education. Although politically conservative, she continued the politics of Mussi against the university professors, which she considered corrupt. She implemented a chaotic reform that made the university dominated by a series of complex and idiotic bureaucratic laws.

After about 20 years of normal life, I found myself in a nightmare, forced to retire and with the prohibition to apply for and use government money, in spite of the fact that my research was going very well. Fortunately during this crisis I won a substantial European Research Council (ERC) grant. I was free to use this money in any European university. My rector was happy to allow me to remain in Parma and to use all facilities as before. In addition, thanks to the ERC money, I was able to hire a group of excellent postdoctoral fellows. Thus my situation came back to normality.

Ironically, in the same months in which the Italian government decided to compel me to retire, I received a very friendly letter from Joaquin Fuster, who invited me take the chair in cognitive neuroscience at UCLA that he was planning to endow. I was strongly tempted to accept, but my personal situation was improving. Furthermore, I was very reluctant to leave my growing grandchildren.

Mirror Neurons in Tübingen

Scientific interest in the mirror mechanism has grown with the years. A review that I wrote in 2004 (Rizzolatti and Craighero 2004) reached, in a couple of years, hundreds of citations (now it exceeds 5,000 citations). However, most of the work on the mirror mechanism had been carried out in humans. There were only few experiments in animals, where one can explore the mirror mechanism at the single-cell level. Thus, I was very happy when Peter Thier, at the University of Tübingen, proposed that we collaborate with the idea to make more quantitative the previous studies of mirror neurons. Involved in this project were, besides myself and Peter, Fogassi and two young Italian scientists, Vittorio Caggiano and Antonio Casile, who were compelled, because of the situation I described above, to emigrate to Germany.

The collaboration worked very well. In the initial paper, published in Science, we demonstrated that space was a fundamental factor for the activation of mirror neurons in F5. Some neurons could be triggered only if the stimuli were in the peripersonal space, others in extrapersonal space. Some were not space committed (Caggiano et al. 2009). We recently confirmed these results with a larger sample of neurons (Bonini et al. 2014).

In the study with Caggiano et al. (2009), we also investigated whether space-selective neurons encode space in a metric or in an operational format. By metric format we meant that there was a fixed boundary between peripersonal and extrapersonal spaces, while by operational format, we meant that the space was dynamic and the peri/extrapersonal boundary depended on the actor’s (the monkey, in this experiment) potential to reach the objects. The results showed that about half of the tested space-selective mirror neurons were “operational mirror neurons.” They responded only if the presented objects could be reached by the monkey (Caggiano et al. 2009).

A possible functional role of space-sensitive mirror neurons is that they may set the most appropriate behavioral response according to the location of the observed action in space. Peripersonal space suggests a possible immediate interaction with the action agent, while extrapersonal space implies a more complex behavioral pattern in order to interact with the acting individual. This interaction could be cooperative or competitive.

Among other interesting results of our collaboration with Tübingen, I think of particular importance are the findings that mirror neurons in area F5 are influenced by the visual perspective of the presented stimuli. Three perspectives were tested: subjective (0°), side (90°), and frontal (180°). The results showed that most mirror neurons were view-dependent, with responses tuned to one or, more frequently, two specific points of view. Among the neurons specific for only one view, there was a slight preference for the subjective view. Finally, a minority of the tested mirror neurons exhibited view-independent responses (Caggiano et al. 2011).

A classical view in visual physiology is that view-independent neurons are generated by convergence of several lower order neurons with viewdependent properties. Thus, one may suggest that view-dependent mirror neurons in F5 represent an intermediate step leading to the formation of the view-independent ones. However, one must remember that mirror neurons are motor neurons, and their output is always the same, regardless of what is the input triggering it. Thus, both view-independent and viewdependent mirror neurons encode action goals irrespective of the details of the observed motor acts. This raises the question of what may be the functional meaning of the view-dependent mirror neurons.

An interesting possibility is that the view-dependent mirror neurons send a backward projection, via parietal cortex, to neurons located in the higher order visual areas encoding the same actions that determined the discharge of F5 mirror neurons. This hypothesis would suggest that the understanding of the goal of an action is carried out by mirror neurons, but the details of the observed action are rehearsed, after goal comprehension, by visual neurons. A modulation of bottom-up processing by more abstract representations higher up in the processing hierarchy has been conceptualized in the context of reverse-hierarchy theory by Ahissar and Hochstein (2004). Likewise, this idea forms a central element in theories in computer vision (Ullman 1996).

Leuven and the Monkey Cortical Mirror Circuitry

Another important collaboration of the same period is that with Guy Orban. We met the first time in Erice at the end of the 1970s at a school on vision. The reason I started to collaborate with Guy was that his research team in Leuven had worked out a way to use a clinical scanner for performing fMRI studies in monkeys. It was a cheap and effective method.

Our collaboration started with an experiment, published in Science, in which we demonstrated that the observation of a hand-grasping objects activated four frontal areas—rostral F5, areas 45B, 45A, and 46—in the monkey cerebral cortex. Observation of an individual grasping an object activated, in addition, caudal F5 (Nelissen et al. 2005).

This paper was followed by a more extensive fMRI study of cortical activations of monkey brain during grasping observation. The results showed activation in three main nodes: STS, IPL, and the arcuate region (PFG). A subsequent Region of Interest (ROI) analysis showed that, in IPL, grasping observation activated specifically two cytoarchitectonic areas: areas PFG and AIP. In STS, grasping observation produced stronger activation than the observation of the same stimuli presented statically in all areas of the region. Thus, in order to elucidate which of the STS areas were connected with the parietal areas endowed with mirror properties, we injected tracers in areas PFG and AIP (Nelissen et al. 2011). The results showed that visual action information, encoded in the STS, is forwarded to ventral premotor cortex (F5) along two distinct anatomical routes. One route connects the upper bank of the STS with area PFG, which projects, in turn, to the premotor area F5. The other connects the lower bank of the STS with AIP and then to area F5. It is interesting to note that some of the fibers of this last route originate from the inferior temporal lobe, suggesting that the mirror circuit receives information on object semantics through this route.

Human Studies on the Mirror Mechanism: Parma and Leuven

The collaboration with Leuven is still going on. In 2012, Guy Orban moved to Parma. Besides the opportunity to continue our collaboration, Parma offered the possibility of an almost free access to a 3T scanner that has been given to me as a donation by a private foundation (Fondazione Cariparma). Guy also obtained an ERC grant that permitted him to form his own group and increased the critical mass of neuroscientists in Parma.

A theme that we addressed together was the cortical representation of actions made with a tool in human and monkey brains. Human subjects, untrained monkeys, and two monkeys previously trained to use tools, were scanned while they observed grasping hand actions and grasping actions performed with tools (e.g., pliers). The observation of an action, regardless of how it is performed, activated occipito-temporal, intraparietal, and ventral premotor cortex, bilaterally. In humans, however, the observation of actions performed with tools yielded an additional specific activation of a rostral sector of the left IPL (Peeters et al. 2009).

This IPL location was human specific, as it was not observed in monkey IPL, even after monkeys had become proficient, through extensive training, in using a rake or pliers. Thus, while observing a grasping hand activated similar regions in humans and monkeys, an additional specific sector of IPL devoted to tool use may have evolved in Homo sapiens.

The hypothesis we are testing now is that the whole posterior parietal lobe is organized in terms of motor programs and that action recognition is a rehearsal of these programs. Data from an experiment of Orban where a subject observed another individual climbing (Abdollahi, Jastorff, and Orban 2013), and our very recent common paper on arm actions performed with different goals (Ferri, Rizzolatti, and Orban 2015), appear to support this general principle.

Vitality Forms

Some years ago I presented our data on action observation at a psychology conference. After my talk, I was stopped by Daniel Stern, the famous psychologist and psychoanalyst. He asked me why we have not explored, in addition to the “what” and the “why” of an action, the “how” an action was performed. That is, using his terminology, the “vitality forms” of an action. I knew some of Daniel’s work, but very superficially. After this meeting I read his classic book The Interpersonal World of the Infant (Stern 1985), and I became interested in the neural basis of vitality forms.

We performed therefore an fMRI experiment in which we assessed the neural correlates of vitality form recognition, presenting participants with videos showing actions executed with two different vitality forms: energetic and gentle. The participants had to focus attention either on the goal of the presented action, or on its vitality form. As expected, in both cases, activations were found in the arm mirror circuit. However, the contrast of “how” versus “what” revealed a specific activation of the dorsocentral insula when participants focused on the vitality form of the action. This insular sector is functionally distinct from that related to emotion indicating that there is a specific part of the insula devoted to vitality forms.

This experiment was performed with the help of Daniel Stern and his wife Nadia Bruschweiler for the theoretical part and of Cinzia Di Dio and Giuseppe Di Cesare, my postdoctoral and graduate students, respectively, for the technical part. A few months after we finished writing the paper, Daniel died. We dedicated the paper to his memory (Di Cesare et al. 2014).

Very recently we continued this work investigating the neural correlates of vitality forms in three different tasks: action observation, action imagination, and execution. The main purpose was to see whether the insular sector that became active during recognition is active also during vitality form execution. Conjunction analysis showed that, in all three tasks, there was a common, consistent activation of the dorsocentral sector of the insula. These findings indicate that this part of the insula is a key element of the system that modulates the cortical motor activity, allowing individuals to express their internal states and to understand those of others through a mirror mechanism (Di Cesare, Di Dio, Marchi, and Rizzolatti 2015).

Autism Again

Our early study showed that children with ASD are impaired in the organization of their actions and, as a consequence, there is a deficit in the development of the mirror mechanism (see, in addition to studies mentioned above, Sparaci et al. 2014). Motor deficits, although well known to all people who deal with children with ASD, have been largely neglected by psychologists studying autism. In recent years, however, interest in this aspect of ASD has increased (see Mostofsky et al. 2006), especially because this aspect of the syndrome could lead to an early diagnosis of autism.

Recently, we decided to explore the motor deficits associated with this syndrome in more depth, using the Florida Apraxia Battery. Children with ASD showed low performance in all sections of the test. The greatest deficits were found, however, in pantomime execution both on imitation and verbal command, plus in imitation of meaningless gestures. The most interesting finding was, however, the presence of a correlation between performance in pantomimes and the severity of problems in social behavior. This finding clearly indicates that the motor deficits are not additional symptoms unrelated to the core ASD syndrome. On the contrary, they are a fundamental part of ASD (Gizzonio et al. 2015).

Early communication between mother and child occurs, in large part, via action vitality forms. Just before Daniel Stern’s death, we examined with him the recognition of vitality forms in children with ASD. Magali Rochat and Vania Veroni tested the children in the San Miniato Autism Center and in the Centre Hospitalier de Tours. The results showed that, unlike typically developing individuals, individuals with ASD exhibit severe deficits in recognizing vitality forms, and their capacity to appraise them does not improve with age (Rochat et al. 2013). A deficit in vitality form recognition appears, therefore, to be an important trait marker of autism.

Past and Future

I have no deep message to deliver at the end of my autobiography. I was lucky to have loving parents, a wife who has supported me for my entire career, and a nice family with two children and five nice grandchildren. I was also lucky to have good coworkers. I do not like working alone, as it happened to me when I first arrived in Parma. I like, instead, working with people with whom I can share the enthusiasm of discoveries and the disappointments of negative days.

I frequently present my data to audiences consisting also of laymen. The interest I have seen expressed by such audiences in the mirror mechanism, and the very positive reactions I have witnessed to the notion that we have a mechanism that renders us part of a community rather than isolated individuals, encourage me to continue my research. This encouragement is reinforced by scientific recognitions, such the recent Prince of Asturias Prize and the Brain Prize by the Lundbeck Foundation.

There are three lines that I plan to pursue in the next years. The first is intracerebral recording in humans. Intracerebral recordings are an exceptional scientific resource. The high-frequency gamma power, which one may monitor using this technique, is a robust electrical signal recorded directly from the brain and directly linked to spiking activity, rather than an indirect measure related to blood flow as fMRI studies. Most importantly, the temporal resolution of intracranial recordings allows very precise measurement of the temporal dynamics underlying the investigated functions. The limitations of intracerebral recordings include the difficulty of precisely localizing the positions of the recording leads and difficulty of merging results coming from different patients. We have solved these problems by developing software to recover the precise location of the leads on the cortical sheet of individual patients, and to warp the cortical sheet containing these sites to any human brain template. By this technique, we are able to transform intracranial recordings into a unique tool for brain mapping. This technical part has been worked out largely by my postdoc Pietro Avanzini. These experiments will be carried out in collaboration between my department and the surgical center for treatment of epilepsy in Niguarda Hospital in Milan, one of the most advanced centers in this field in the world.

The second line of research that I am going to pursue is to improve and render more efficient the action observation therapy for motor rehabilitation. Fadiga, Buccino, and myself started to develop this therapy many years ago. The principle is the following. Observing others’ actions activates in the observer the same neural structures that are responsible for the actual action execution. Thus this activation potentiates residual movements and might lead, with practice, to a recovery of lost movements. So far, this approach has been successfully applied in the rehabilitation of upper limb motor functions in chronic stroke patients, in motor recovery of Parkinson’s disease patients, and in children with cerebral palsy (see Buccino 2014). This approach also improves lower limb motor functions in postsurgical orthopedic patients. Up to now this technique has been used in a rather primitive custom-made way. A lot of technical improvements are possible such as controlled kinematics, the use of 3D stimuli, and the choice of stimuli most appropriate and even personalized for individual patients.

Finally, autism. It is now recognized that the real challenge in autism is to make an early diagnosis. Early diagnosis allows one, by using appropriate rehabilitation techniques, to achieve results that would be unthinkable if the treatment were delayed. Our data demonstrating that a fundamental deficit in autism is related to an impaired motor organization opens a new perspective for rehabilitation. Finally, the deficits we recently found in the mirror mechanism underlying vitality forms are another very promising avenue for advancing our knowledge about autism and for its rehabilitation. The future is interesting.

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Trevor W. Robbins

BORN:

London, U.K.

November 26, 1949

EDUCATION:

Jesus College, University of Cambridge, B.A., 1st Class Honors, (1971)

Jesus College, University of Cambridge, PhD (1975)

APPOINTMENTS:

University Demonstrator in Experimental Psychology, University of Cambridge (1973–1978)

University Lecturer in Experimental Psychology, University of Cambridge (1978–1992)

Reader in Cognitive Neuroscience, University of Cambridge (1992–1997)

Professor of Cognitive Neuroscience, University of Cambridge (1997–present)

Professor of Experimental Psychology and Head of Department of Psychology, University of Cambridge (2002–present)

HONORS AND AWARDS:

Spearman Medal of the British Psychological Society for Outstanding Research, 1981

Fellow of the British Psychological Society, 1990

Fellow, Downing College, Cambridge, 1990

DM Marquis Prize of the American Psychological Association for Best Paper in Behavioral Neuroscience, 1997

Chair, Neuroscience and Mental Health Board of the Medical Research Council, 1996–1999

President of the European Behavioural Pharmacology Society (EBPS), 1992–1994

President of the British Association for Psychopharmacology, 1996–1998

Fellow, Academy of Medical Sciences, 1999

ISI Most-Cited Neuroscientists List, 2001

Distinguished Achievement Award EBPS, 2002

IPSEN Foundation Prize for Neuronal Plasticity, 2005

Fellow, Royal Society, 2005

Fred Kavli Distinguished International Lecturer Society for Neuroscience, 2005

President, British Neuroscience Association, 2009–2011

Distinguished Scientific Contribution, American Psychological Association, 2011

European Brain and Behaviour Society, Behavioural Brain Research Award, FENS, 2012

Angharad Dodds John Fellow in Mental Health and Neuropsychiatry, 2012

Commander of the British Empire (CBE), 2012

Grete Lundbeck European Brain Research Foundation: Brain Prize, 2014

Lifetime Achievement Award, British Association for Psychopharmacology, 2015

Trevor Robbins has striven to synthesize cognitive and behavioral neuroscience with neuropsychopharmacology. He has defined cognitive and behavioral functions of corticostriatal and limbic-striatal systems, as well as their chemical neuromodulation by the monoamines (dopamine, noradrenaline and serotonin) and acetylcholine. He has achieved bidirectional cross-species translation of findings from experimental animals to patients using the CANTAB computerized neuropsychological battery, which he co-invented. has pursued possible pharmacological treatments in patients with neuropsychiatric and neurodegenerative disorders ranging from ADHD and schizophrenia to Alzheimer’s and Parkinson’s diseases. He is responsible, with BJ Everitt, for a theory of drug addiction that proposes that transitions from goal-directed to habitual responding underlie compulsive drug-seeking and taking behavior and that these transitions are paralleled by a devolution of control from the ventral to the dorsal striatum, as well as a loss of “top-down” control from the prefrontal cortex.

Trevor W. Robbins

Early Life and Education: From Dopamine in South London to Inner Space at Cambridge

I was born in south London in 1949, first child of parents William and Eileen in a conventional family later to include my younger sister, Rita. Neither parent was able to attend University; both had had to leave school early because of World War II, which devastated London and left an aura of austerity over my early years. Among my first memories are watching the English cricket team winning the Ashes against Australia on a grainy black-and-white television at my grandparents’ house, while mother was at work. From about four years of age, we lived close to one of those oasislike green parks that provide sanctuary from the urban reality of south London. Bizarrely, I was to discover in later life a remarkable coincidence associated with this space, which I used throughout childhood as a playground that presumably enhanced my synaptic plasticity. The Georgian house that dominated the park and served as an elegant café for Sunday revelers had a scientific history. Dopamine was first synthesized there. I later read in an article by Hornykiewicz (1986), who had inspirationally applied neuroscientific discoveries by Carlsson and others to test effects of L-Dopa in Parkinson’s patients, that dopamine had been synthesized in south London, and naturally I wanted to know exactly where. A piece of Web-based research, leaning on biographies of Fellows of the Royal Society gave me the answer. Burroughs-Wellcome had used the Georgian House in Brockwell Park as a physiological research laboratory, under the leadership of no less a figure as Sir Henry Dale, famous for his early research into neurotransmitters and the dictum (now since disproven) that each neuron has but one transmitter. One of his research assistants, Arthur Ewins, had synthesized dopamine, which then was known by its chemical name of 3-methoxytyramine, publishing a paper with Barger in the Journal of the Chemical Society in 1910. The chemical initially was concluded to be a weak sympathomimetic substance of no obvious significance (Barger and Dale 1910). It was later to gain in importance, and especially for my own career.

Another neuroscientific coincidence illuminated my early life, as I played with my cousins in an apartment close to Holborn in central London. My aged aunt in her 80s reminisced with me about those times and when I asked where the apartment was she said it was in Queens’ Square, “opposite the famous hospital.” The famous hospital was in fact the National Hospital, the leading center for neurology in the United Kingdom, where all of the famous British neurologists (and many others from overseas) trained and practiced (and where I later took a period of sabbatical leave in the 1980s to gain experience in clinical neuropsychology). In fact, the apartment in which they lived across the Square was Alexandra House, now home of the Institute of Cognitive Neuroscience of University College London, another later source of intellectual stimulation from neuropsychologists such as Tim Shallice.

I was academically good at school and managed to pass the dreaded 11-plus (at age 11) examination by which children were streamed into those attending grammar schools and those attending secondary modern (high) schools. Rather than aiming high and seeking a scholarship at the élite Dulwich College (a significant public, i.e., fee-paying, school), I decided to sample state education at Battersea Grammar School, situated in the suburb of Streatham, south London, which turned out to be an excellent choice. I tried my hand at everything, including drama, sports, and also chess, as the school was blessed with a number of young chess prodigies. I later led our school team to win the prestigious Sunday Times British Schools Chess Championship, won the London Junior Championship (under 14s), was ranked in the top 20 players in the country and even represented England Juniors at Board 1 before winning a succession of “half-blues” for representing Cambridge versus Oxford in varsity matches. Becoming strong at chess was a definite influence on my later interest in cognitive psychology and later became a focus of an interesting diversionary study into chess and working memory with the distinguished cognitive psychologist Alan Baddeley (Robbins et al. 1995).

On the academic side, I was good at both sciences and the humanities, eventually opting for the former—as the trend then and now in U.K. education was specialization and focus, rather than the liberal arts of the United States or the Baccalaureate-style European education. You were expected to maintain intellectual breadth by your vocational activities rather than through formal training. (I have endeavored ever since to maintain those vital interests in literature, drama, music, and visual arts in this way). The school generally had at most one or two pupils going to Oxbridge every year, and I used these role models to shape my future career goals. I plumped eventually for biology as my main interest, followed by chemistry. I had been inspired by reading in the London Evening Standard an article about the genetic code—probably about the time that the codons were identified. I understood that much of the work was being done in Cambridge, beginning of course with Crick and Watson, and immediately set my sights on biochemistry and molecular biology and Cambridge—to understand how living things actually worked.

To apply to Cambridge in those days, you had to have two languages, other than English. I had kept up with French, but had to give up classics, being in the science stream. So I had to study Latin in my spare time to pass the exam necessary for qualification for Cambridge. (I passed, although just before the exam they waived this requirement.) I took the Cambridge entrance exam in the last year at school, which was a little early; (most candidates take an extra year). To my astonishment, I was offered an interview at Jesus College (I had no idea which college I should apply to and just took after the example of my history teacher). Fortunately, after recovering from an early trap of my own making in the interview, I was offered a place to read the Natural Sciences Tripos (NST).

The NST was a flexible course, and I homed in on biological options. To be honest, I was slightly disappointed with the course material, which seemed to go over old ground that I already had covered at school (but probably did not really understand as well as I had thought). The second year offered an intriguing option of experimental psychology, which I took with biochemistry and zoology and instead of physiology, to make up my three offerings. The supervision or small-group tutorial system at Cambridge (whereby students are taught generally in twos or threes and write essays or do work for discussion) already had exposed me to some superb teachers in biology, but I met up with a lasting influence at this stage—Dr. Susan Iversen. Susan Iversen combines charisma with high intelligence in every domain, including the all-important social one; she is a truly inspirational and warm person. Susan Iversen actually had read zoology but had assimilated large parts of experimental psychology, which she taught with élan and enthusiasm. The result was that I was attracted to specialize (major) in psychology in my final year, and I did a research project with her on the effects of d-amphetamine on exploration in rats. I realized about this time that Susan Iversen was married to another important influence, Leslie Iversen, a master neurochemist who had remarkably assumed directorship of the Medical Research Council (MRC) at Cambridge at an early age and who had lectured with some gentle skepticism on his part on the molecular basis of memory and learning.

The final undergraduate year went quickly and I was enraptured by psychology, especially as it related to the brain—Susan Iversen’s course was quite important. I also enjoyed the discipline of animal learning and the brilliant Michael (later Professor) Morgan’s maverick approach. I was fortunate to attend the late Donald Broadbent’s guest lecture series, which revolved around chapters of his yet-unpublished masterwork on Decision and Stress (1971), which has remained another major influence in several ways (although it has been surprisingly undervalued by experimental psychologists). The head of department was Oliver Zangwill, one of the fathers of British neuropsychology, and one of the main forces that had introduced the likes of Larry Weiskrantz and nonhuman primate work to Cambridge (and the United Kingdom). Zangwill was to play an important part in one of my personally momentous decisions—not to become a clinical psychologist. I had obtained a place on the prestigious master’s course in clinical psychology at the Institute of Psychiatry in south London, close to my birthplace at Dulwich Hospital. My mother had suffered from panic attacks and agoraphobia and had been well treated at this renowned center, and in a sense, that experience had motivated my interest in psychopathology. I was also more generally interested in motivation, that is, what made people tick. I was fortunate enough to get a first class result in the final exam, and this led Zangwill to ask, in his inimitably understated way, whether I would like to take up a place to read for a PhD at Cambridge, with Susan Iversen. Earlier, I had considered doing a PhD and had traveled to the University of Sussex to meet the redoubtable Professor Stuart Sutherland who was building an outstanding department in experimental psychology, especially learning. Decisions, decisions—one of the few real decisions you have to make throughout life—I plumped for research in Cambridge with Susan Iversen, although I did not really have a good idea of exactly what was entailed.

Graduate Life at Cambridge and Denmark: Early Studies on Psychomotor Stimulant Drugs

Thus ensued an ultimately happy but somewhat chaotic time. There were no taught courses in those days and you essentially had to pick up research techniques as opportunities arose, and also had to adopt a thematic approach to research that ultimately would generate a PhD thesis within three years. I was in laboratory with several of Susan Iversen’s other research students. Particularly helpful and a constant source of inspiration and enthusiastic motivation was Ian Creese who later worked with Solomon Snyder to discover the dopamine receptor. Arjun Sahgal was completing a major thesis on memory systems in rhesus monkeys and baboons and later became a prominent U.K. neuropsychologist and psychopharmacologist. My early predoctoral period at Susan Iversen’s direction was rather like a modern lab rotation doctoral course—I also spent time in Leslie Iversen’s laboratory investigating the biochemistry of amphetamine metabolites and found I was just about competent to perform such studies but this was not likely to be my main strength (and I’m sure that Leslie Iversen would have agreed.). I also had a clinical project with Susan Iversen working with the neurologists in Cambridge on Parkinson’s disease. We used a sophisticated way of measuring motor function in these patients based on Fitt’s Law to quantify the possible benefits of a drug called amantadine. I learned an important lesson that for all the sophistication, I could not detect when amantadine was added to the usual L-Dopa theory or not. One of the patients found that he couldn’t actually get up from bed upon amantadine withdrawal, however; that was a big effect, but it appeared in only one of the patients studied, which provided another early lesson in terms of clinical heterogeneity. Susan Iversen was a tremendous mentor and her and Leslie Iversen’s extensive U.S. contacts arising from their time at NIH and Harvard Medical School meant that a constant succession of luminary neuroscientists visited them at home where Susan Iversen’s enormous networking skills came to the fore in a most exciting and fortunate manner for a graduate student. I remember meeting people like Julius Axelrod, Brenda Milner, Mortimer Mishkin, Karl Pribram, and Snyder all from their visits to Cambridge over lunch at the Queens’ Head pub or chez the Iversen soirées. Particularly thrilling was a personal communication Leslie Iversen relayed to us via Susan Iversen that “Sol has discovered the opiate receptor.”

My thesis went quite well; I expanded my undergraduate project to publish my first paper in the journal Psychopharmacologia (Robbins and Iversen 1973a). That first paper is always a little mysterious and exciting. I was focused on ways of affecting the central dopamine systems, beginning with the (rather dirty) method of simply investigating effects of systemic injections of amphetamine and dopamine agonist drugs in rats. I had the idea from the Broadbent book of using signal detection theory to characterize effects of the drug on performance, before I realized that David Warburton at Reading University already had had the same idea and had published on the method with cholinergic drugs. Nevertheless, I was able to publish a paper with Susan Iversen in a new journal from the Nature stable, Nature New Biology, which applied the method (Robbins and Iversen 1973b).

One of my first experiments from that period was never published except for being mentioned in chapters. I had looked at the effects of high doses of amphetamine and was especially interested in the cascade of behavioral changes that occurred to culminate in a bizarre syndrome of repetitive behavior, called stereotypy. I was fascinated that this occurred in all vertebrate animal species studied from human stimulant addicts to the lamprey and that it provided a potential model of psychopathology, relevant perhaps to psychosis (Randrup and Munkvad 1967). My experiment investigated how learning interacted with stereotypy. What I found was that in rats trained to work under a fixed ratio schedule of lever pressing to collect water from a dipper, this behavior often was suppressed. There would be, however, periods in which the learned behavior itself became stereotyped and repetitive—that is, the rats would continue to approach the empty dipper or, even more dramatically, they would continue to press the lever without bothering to collect the earned water reinforcement. The behavior was clearly abnormal, but rather than being random and arbitrary, it was based on the animal’s previous experience and training. Later studies showed similar effects of the dopamine agonist apomorphine (see Figure 1). This seemed to be a remarkable model of psychopathology—what appeared to be grossly abnormal behavior with little apparent purpose, dependent on the drug effect (presumably on striatal dopamine) interacting with the animal’s past history. (I later investigated with Guy Mittleman possible coping, stress-reducing response properties of stereotypy, although somewhat inconclusively).

Fig. 1.  The effects of the dopamine direct agonist apomorphine to produce stereotyped operant behavior. Rats are trained to respond across two levers, which unpredictably produce food reward. The normal pattern of responding on the levers is shown by the increments in cumulative pen record, with responses on the left lever incrementing on the y-axis and responses on the right lever causing downward ticks. Visits to the food magazine to collect earned food pellets are shown in the bottom record. Apomorphine treatment results in a focusing of responding onto one (the left lever) and a reduction in food magazine responses; the result is stereotyped lever pressing with no apparent purpose. This behavior is occurring at doses that normally cause typical oral stereotypy by this drug but evidently can be extended to incorporate previously learned responses (Robbins and Watson, unpublished data circa 1979).

This stereotyped instrumental behavior, although never published in full, and a persistent challenge for explanation throughout my career, led me to what I initially thought was an intriguing idea that behavior could be supported just by stimuli that previously had been associated with reward, that is, conditioned reinforcers, and I found that an industrial behavioral pharmacologist called Ronald Hill had had a similar idea, which he had published in an Amphetamine Symposium volume (Hill 1970). I developed the idea in my thesis using what I had learned from animal learning theory, and although the results were good enough for a thesis, I never did quite nail this idea to my satisfaction until my postdoctoral period when I was able to publish a single-authored paper in Nature (Robbins 1976) on this topic.

One consequence of my research into stereotypy is that I became interested in a Danish laboratory led by Axel Randrup that had published those intriguing cross-species studies alluded to earlier and that was embedded in what I came to learn was one of the largest mental hospitals in Europe. The ready availability of short travel grants from the European Training Program enabled me to spend six months at this center in the town of Roskilde some 20 miles from Copenhagen, Denmark. I stayed in a guest room in a research laboratory and thus had first-hand experience of in-patients sometimes hallucinating as they wandered through the hospital grounds. In addition to Randrup, who was a positive, original thinker with some mildly eccentric qualities, the laboratory housed talented neuropharmacologists who were to become influential to the field: Claus Braestrup, who later participated in the discovery of the benzodiazepine receptor; Mogens Nielsen; and Jorgen Scheel-Kruger, who completed some important early studies on the different neuronal mechanisms by which amphetamine and methylphenidate produced their effects.

I also met Melvin Lyon, an American behavioral neuroscientist who had settled there and quickly began to work with him in designing some operant studies, as I had been intrigued by his similar findings of learned influences on stereotyped behavior produced by amphetamine in dramatic studies of avoidance learning (Lyon and Randrup 1972). In fact, although these started in a promising way, the laboratory was hit by a rodent infection halfway through the studies, and I therefore had the frustration of not being able to do much laboratory work for a portion of my visit. This setback, however, did give me the opportunity to spend much time in intense and friendly discussion with Lyon, which led to a major review we undertook of the behavioral studies of effects of stimulant drugs. We came up with the generalization that such drugs (and by implication striatal dopamine activation) produced “an increasing rate of responding in a reducing number of response categories.” I was encouraged in this theorizing by the dramatic and pioneering account by O. Sacks in his book Awakenings (1973) of effects of L-Dopa in Parkinson’s patients (e.g., especially Rolando P.) who had developed the disease through the encephalitis lethargica epidemic. We found a home for the somewhat lengthy article in a new book series of reviews (Lyon and Robbins 1975). I was grateful for this future fodder for my PhD thesis and also for future citations to the Lyon and Robbins synthesis by the likes of one of my heroes, Urban Ungerstedt. Ungerstedt had crowned the efforts of the seminal work completed by the Karolinska group on the neurobiology of dopamine systems in a now-legendary series of studies using the selective neurotoxin 6-hydroxydopamine (6-OHDA; e.g., Ungerstedt 1971). A highlight of my trip was the visit he hosted for me to the Karolinska Institute in Stockholm. Another, at the end of my stay, was a trip to Rotterdam to attend my first international meeting of the European Brain and Behaviour Society (EBBS), where I gave my first oral presentation; Edmund Rolls, then at Oxford, was a helpful mentor during this mildly stressful episode.

I had two enormous life-changing events on my return to Cambridge. First, amazingly, I was appointed to the faculty of the Department of Experimental Psychology as a Demonstrator—a sort of junior lecturer post specializing in practical teaching (I helped, sometimes counterproductively, in Zangwill’s spell-binding hypnosis demonstrations). This was a kind of five-year research plus teaching fellowship, which no longer exists in Cambridge, but which invaluably gave young scientists the opportunity to develop a career platform before generally moving on. Second, soon after my return, I met an amazingly clever and stunningly beautiful woman with the somewhat exotic name of Barbara Sahakian, Susan Iversen’s first-ever U.S. graduate student who had come to Cambridge to work with the Iversens on the effects of postweaning social isolation in rats. These animals, which were essentially deprived of social play during adolescence, developed striking patterns of behavioral hyperactivity and stereotypy that resembled effects of amphetamine. Sahakian thought that the isolated rats’ behavior potentially modeled the human attention deficit/hyperactivity disorder (ADHD) and was keen to show that the stimulant drug therapy may lead to stereotypy in these adolescents. Indeed, the rats showed dramatic increases in stereotyped responses to amphetamine that suggested changes in brain dopamine function caused by this early social experience (Sahakian et al. 1975). (Only later, when we had established a neurochemistry laboratory in the department, working with graduates Graham Jones and Scott Hall and postdoc Lawrence Wilkinson were we able to demonstrate this in fact to be the case; see Wilkinson et al. 1994). I became interested in Sahakian’s project and indeed we became interested in one another in what would become a lifelong partnership and collaboration, which has culminated with us living together as full professors at Cambridge.

The next couple of years were of consolidation of personal and professional life. The PhD thesis was duly submitted (and accepted) with my feeling that it was really a sketch toward the studies I really wanted to do. I bought a house in Cambridge for £8,100 (about $12,000) on a salary of £2,500 per year (homes in Cambridge now cost nearly 60 times as much). The laboratory saw new graduate students such as Michael Petrides, later director of Cognitive Neuroscience at the Montreal Neurological Institute; Nicholas Tye, who shared our house and later worked with Eli Lilly and Company to produce the successful antipsychotic olanzapine; and Peter Kelly, a dynamic and enterprising postdoc of Susan Iversen’s from Oxford who was soon to produce some compelling evidence using 6-OHDA that the locomotor hyperactivity produced by amphetamine was due to dopamine release from the nucleus accumbens within the ventral striatum (Kelly et al. 1975), whereas the behavioral stereotypy had already been shown by Creese and Iversen (1975) to be due to dopamine in the dorsal striatum (I having expertly observed and provided behavioral ratings for that study). Other influential colleagues included two bright graduate students of Susan Iversen’s, Stephen Mason and Paul Fray. Between them and Arjun Sahgal, they managed to help the lab develop new sophisticated methods for controlling experiments by computers, online partly through an inspirational link with new microprocessor-based technologies in collaboration with exciting new computer-based industry in Cambridge (Silicon Fen) through companies such as Acorn, led by the brilliant entrepreneur (and my friend) Hermann Hauser.

My major experimental thrust was to follow up the idea that stimulant drugs enhanced the effects of stimuli associated with reward, that is, conditioned reinforcers, an idea that much later became renamed incentive salience by Kent Berridge and Terry Robinson (1998) at the University of Michigan. The key paradigm, of several I tried, was first to associate an arbitrary conditioned stimulus with a reinforcer, such as food or water (or rewarding brain stimulation, or a drug) and then to determine whether rodents would learn new responses to obtain these conditioned reinforcing stimuli. Amphetamine-like drugs greatly potentiated the rate of responding on the novel lever providing the conditioned reinforcer. One unusual drug with which Hill had worked, called pipradrol, originally developed as a drug to enhance cognitive performance in the elderly, produced particularly strong and less (frustrating) individual variation of effects than d-amphetamine, and I used this for all my early studies of this striking phenomenon. Even then, I was struck by the pathological nature of this behavior—rats sometimes would respond thousands of times for these stimuli, which no longer signaled water reward, and they no longer bothered to visit the former location where the reinforcer water had been delivered. If required to learn a two-response operant chain (e.g., press left and then right) to turn on the conditioned reinforcer, they ended up increasing their response on the response closest to the former reward—thus not resulting in any feedback stimuli at all, except for whatever proprioceptive and kinaesthetic feedback they obtained from their own behavior. This seemed to me a profound model of psychopathology under what was presumably a high dopamine state. It reminded me not only of my earlier observations of stereotyped behavior in rats but also of accounts I had read in Bleuler’s classic work Dementia Praecox (1950) of patients with schizophrenia, whose sometimes bizarre and apparently irrational behavior was driven by events and associations formed in their past. Bleuler had stated in his great work that stereotypy was in the thoughts and stereotypy was “in the thinking and in the desires of the hallucinating patients” desires of the hallucinating patients (1950, p. 185). These data and ideas were submitted to Nature in the single-authored paper referred to above which to my great surprise was accepted for publication (Robbins 1976) and almost certainly contributed to my 1978 appointment to a tenure-track lectureship at Cambridge and to my eventual long-time commitment to the place (although only after quite a few second thoughts).

I managed to sneak in a period of personal leave to visit the United States for the first time with Barbara Sahakian to meet her distinguished parents in Boston, William and Mabel Sahakian, both professors of psychology and philosophy, as well as church ministers. In a mini-tour of the East Coast, during a visit to Johns Hopkins to see Creese and Snyder, we met up with another major influence, George F. Koob. Koob was to take up a postdoctoral visit to work with Susan and Leslie Iversen and wanted advice on how to live at Cambridge, England. He was to become an intellectual and practical mentor, initiating me into the rigors of stereotactic surgery, brain stimulation reward, and electrochemistry, while also becoming a lifetime friend and influential scientific colleague. We saw Koob in frequent visits and interchanges between Cambridge and San Diego, where he was to settle first at the Salk Institute, working with Floyd Bloom, and later at the Scripps Research Institute.

This period was followed a year or two later by a return, sabbatical stay in Boston, after Sahakian had completed her PhD, to work at Harvard Medical School with the “fathers of behavioral pharmacology,” Peter Dews, Bill Morse, and Roger Kelleher—with whom Susan Iversen had earlier worked. I learned much in this brief stay, which was salutary for a humble psychologist—as this group was wedded to a brilliant but strictly no-nonsense behavioristic perspective inspired originally by B.F. Skinner and combined with equally no-nonsense classical pharmacology. The principles of rate (or baseline-dependency, Law of Initial Values) and the critical difference between concepts such as reward and reinforcement was soundly learned. I also was initiated into the then-influential behavioral pharmacology group in the United States being introduced to such luminaries as Joe Brady and Charles Schuster.

Functional Studies of the Central Monoamine Neurotransmitters in Cambridge, England

One practical lesson I learned from my studies of mice using Galen Wenger’s apparatus at Harvard was that it might be feasible to train rodents in a multiresponse operant task in which they had to detect brief flashes of light presented randomly in space to earn food. I found that it was possible to use such an apparatus for rats and to quantify two somewhat-independent measures of performance, accuracy of detection, and premature responses as an index of response vigor (see Robbins 2002). This task was inspired by my readings from Broadbent’s Decision and Stress (1971) of a set of studies done at the Cambridge Applied Psychology Unit on the “five-choice serial reaction time” for humans, directed at assessing the effects of such human factors as stress; extremes of noise, temperature, and incentives; and drugs, such as stimulants and barbiturates. Broadbent had theorized about the famous curvilinear (inverted-U-shaped function supposedly linking efficiency of performance to hypothetical levels of arousal in the central nervous system. His insight had been that you needed different inverted-U-shaped functions to explain all of the effects of these stressors; they simply did not add up in a straightforward way. My later insight was that these different functions probably were mediated by the different chemical neurotransmitters affected by the various drugs—notably the monoamines, including dopamine, noradrenaline, and serotonin, and the substituted amine, acetylcholine (Robbins and Everitt 1995). Over my subsequent career, I developed the theoretical idea, including studies in humans as well as experimental animals, that different states (e.g., of mood or arousal) optimally favored particular fronto-executive functions, thus enabling a refined and sensitive tailoring of cognition that was most appropriate to the prevailing internal state or environmental conditions (see Robbins 2007).

The ambition to work on these ideas was greatly enhanced by my future scientific collaborations initially with Koob, and later with another Cambridge colleague, Barry Everitt, whom I had met at another EBBS meeting in Copenhagen 1976. It was a source of embarrassment to both of us in socializing with other delegates that we actually had not met in Cambridge, as we were working not more than 100 meters apart on different floors of the Departments of Experimental Psychology (myself) and Anatomy (Everitt). We resolved in the future to try working together on common interests, Everitt also having developed research on the monoamine systems from his own previous postdoctoral stay at the Karolinska Institute. This collaboration, one secret of which has been to retain our distinctive individual identities and contributions, has led to some inspired interactions. It has now lasted nearly 40 years, recently being marked by a joint award, specifically for the collaboration, from the American Psychological Association. The immediate products of the interaction were some of my first jointly funded grants with Everitt by the MRC to investigate the comparative roles initially of noradrenaline (reviewed in Everitt et al. 1990), and then (in the late 1980s and 1990s) acetylcholine and serotonin. This work eventually led to data showing quadruple dissociations of behavioral effects among these transmitters in their effects, for example, on the five-choice serial reaction time task described above, which were compatible with the type of theory concerning the differential functions of these transmitters (Robbins and Everitt 1995). I also gained some support from the Parkinson’s Disease Society to investigate further the roles of dopamine using other behavioral paradigms, including one that postdoc Mirjana Carli and a smart graduate student John Evenden invented to examine the Ungerstedt-Marshall and Teitelbaum idea that unilateral striatal dopamine depletion led to sensory neglect. We refuted this hypothesis by suggesting instead that it was in reality a response or intentional neglect (Carli et al. 1985) that possibly was caused (from results of further studies; e.g., Brown and Robbins, 1989) by impairments in representing egocentric space.

We also explored which of the dopamine systems (i.e., the dorsal or ventral striatum) were responsible for the enhancement of conditioned reinforcement. Early experiments using the 6-OHDA dopamine depletion techniques with Everitt suggested that it was the dorsal system, consistent with my theoretical view that it was a form of stereotypy. A brilliant and bold graduate student, Jane Taylor, confounded this view by showing with our first use of intracerebral infusions of drugs that the key area was the nucleus accumbens (Taylor and Robbins 1984). Moreover, further collaborations with a postdoc from Bordeaux, Martine Cador, and Everitt showed that the behavior was likely driven by the basolateral amygdala, which appeared to be responsible for encoding the conditioned stimulus-unconditioned reinforcer interaction (Cador et al. 1989). Together with other studies with Koob on food-associated incentive activity (Koob et al. 1978) and the exotic phenomenon of the acquisition of schedule-induced polydipsia (Robbins and Koob 1980), a form of compulsive drinking perhaps induced by overarousal, we began to hypothesize distinct roles of the ventral (i.e., nucleus accumbens) and dorsal (i.e., caudate-putamen) striatum for incentive motivation and stimulus-response coupling and execution, and under pathological circumstances, motor stereotypy (dorsal striatum; Robbins and Everitt 1992). I like to think that the former idea, which was consistent with views of the Tony Phillips–Chris Fibiger collaboration at the University of British Columbia (Fibiger and Phillips 1988), and owing something to Tim Crow’s early provocative speculations (Crow 1973), presaged to some extent the seminal discoveries of Wolfram Schultz (1996) on the roles of midbrain dopamine neurons in reinforcement learning. These studies also stimulated Everitt and I to start thinking about how these systems might be implicated in drug addiction (see the following).

Translational Studies of Human and Animal Neuropsychology: The CANTAB

Another significant development for myself in the 1980s was my foray into work with nonhuman primates and humans. I have always had an interest in the translation of research into clinical utility, beginning with my early career aspirations in clinical psychology and fueled in the United Kingdom by an intense drive ethically to justify work with experimental animals by showing potential human benefit in relation to the costs to the animals themselves. The perfect opportunity to pursue this pipedream was made possible by a grant competition of the Wellcome Trust for a Major Award in relating neuroscience to mental health disorders. Stephen Dunnett had joined the Department of Experiential Psychology as a lecturer to investigate effects of neural transplants in experimental animals in Parkinson’s, Huntington’s, and (early) Alzheimer disease-type models, and this focused our attention on therapeutic strategies for ameliorating the profound cognitive deficits of these disorders. Most ambitiously, we also proposed to extend the analysis not only to the nonhuman primate (marmoset) model, but also to human patients by using cognitive tests that could be generalized from animals to humans (a concept also popularized by Larry Weiskrantz at Oxford). We also borrowed another idea from Oxford researcher David Gaffan, to use touch-sensitive screens, to test not only monkeys (Gaffan’s innovation) but also human patients. For a program that almost certainly now would be considered by many granting agencies as overambitious and lacking focus, we were amazed to be funded. This Wellcome Trust support, which has now lasted for some 30 years, has been instrumental in my development as a cognitive as well as behavioral neuroscientist, as it funded the development of what came to be called CANTAB (the Cambridge Neuropsychological Test Automated Battery; http://www.cambridgecognition.com/academic/ cantabsuite/tests).

The CANTAB (Robbins et al. 1994, 1997) arose as a series of brainstorming discussions about new neuropsychological tests with members of the Wellcome Trust team we had brought together: Sahakian, Evenden, Angela Roberts, and Robin Morris. Sahakian, then a lecturer at the Institute of Psychiatry, London, led the piloting of these tests in patients with early Alzheimer’s disease in one of the first memory clinics in the United Kingdom. We made sure that they could at least attempt the easiest forms of the tasks, which were based partly on tests that had been employed by Mishkin and others to map the neural systems implicated in visual recognition memory in rhesus monkeys. Other tests derived from the reverse perspective of decomposing a standard human neuropsychological instrument such as the Wisconsin Card Sorting Test (WCST), commonly used to test patients with frontal lobe damage, and presenting it in a form that could be learned by our chosen New World monkey, the marmoset. The WCST required subjects to learn a concept or rule on the basis of trial-and-error feedback from the clinical neuropsychologist before the rule was suddenly changed to require re-learning. Milner’s famous (1963) finding had been that patients with frontal lobe damage, while learning the initial rule normally, perseverated in applying it when it was no longer correct. I had realized that the WCST was related to a paradigm that was then still influential in animal and human learning theory (Mackintosh 1983); the distinction between intradimensional (id) and extradimensional (ed) shift learning; the rule-shift in the WCST was equivalent to an analogous shift in which stimuli had to be attended in experiments with pigeons, rodents, and children. With Roberts working in our first studies in marmoset monkeys, we were able to show that marmosets apparently solved these rule-learning and shifting tasks in ways similar to those found in humans (Roberts et al. 1988). We later were able to exploit this similarity to test the precise neural substrates of attentional set-shifting in marmoset monkeys; one of the major aims of the CANTAB was to achieve this type of bidirectional translation from animal to clinical studies.

Fig. 2.  Double dissociation of effects of lesions of the lateral prefrontal and orbitofrontal cortex in the marmoset on two forms of cognitive flexibility: extradimensional set-shifting and reversal learning. Reproduced with permission by Nature Neuroscience (Dias et al, 1996).

The CANTAB id/ed set-shifting task also incorporated yet another type of shift, in reversal learning. An id shift required the animal or human to continue to use a rule learned for one set of compound stimuli (i.e., stimuli varying in at least two dimensions) when confronted with a new set of discriminations. By contrast, for an ed shift, the subject had to shift to use the previously irrelevant cues to predict reward again when confronted with new stimuli over which to generalize the rule. For reversal learning however, the stimuli remained the same, but their significance for reward or punishment was shifted. Working with Rebecca Dias, Angela Roberts and I found that discrete lesions to different parts of the marmoset prefrontal cortex (PFC) produced doubly dissociable effects on ed shifting and reversal learning (Dias et al. 1996). Lateral PFC lesions produced ed shifting deficits but no effects on reversal learning, whereas orbitofrontal lesions produced deficits in reversal learning (as was already known) but no effects on ed shifting (see Figure 2). Thus, different circuits appeared to underpin these forms of cognitive flexibility and these findings have had a major effect on our thinking as well as an impact in several areas. Thus, for example, we also have used this paradigm to differentiate the roles of the catecholamine and serotonin neurotransmitters in the PFC for these different aspects of cognition; the former affects id and ed shifting (see Robbins and Roberts 2007), whereas serotonin in the orbitofrontal cortex selectively influences reversal learning (Clarke et al. 2004). Moreover, former student Verity Brown and colleagues ingeniously turned the id/ed test for humans and monkeys into an assay for rodents but using different sensory modalities (smell and touch) rather than visual dimensions (Birrell and Brown 2000), which has been much used in the pharmaceutical industry. Another former graduate student, Timothy Bussey, has successfully developed a touchscreen behavioral test battery for rats and mice, based originally on work he initiated in the lab with discarded human touch-screens (Bussey et al. 1994, 2012). More generally, this work with marmosets stimulated an interest in defining the precise components of fronto-executive functioning.

A further example of a CANTAB test with pharmaceutical relevance was the five-choice serial reaction time task (5CSRTT). Originally adapted for rats from the classic human task, we back-translated it to humans, specifically patients with early Alzheimer’s disease. The experimental program with Everitt on functions of the chemical transmitters had thrown up an interesting discovery about the functions of the cholinergic basal forebrain. Many investigators had been testing effects of destroying these neurons in the rodent brain to model more selectively the profound cortical cholinergic depletion that had been shown for patients with dementia. Although there were many reports of impaired learning and memory following such destruction, Everitt and I were skeptical that these impairments were entirely due to cholinergic loss because of the considerable ancillary damage caused to neural systems adjacent to the nucleus basalis magnocellularis (the likely homologue of the cholinergic nucleus basalis of Meynert in humans), such as the globus pallidus. This was particularly the case when the lesions were made with the nerve fiber-sparing excitotoxin ibotenic acid. For some reason, the cholinergic neurons themselves were apparently rather resistant to the effects of this neurotoxin in comparison with other cell groups. Experimentation and serendipity revealed that the cholinergic neurons were more susceptible to the excitotoxins quisqualic acid and later AMPA. The latter actually produced an apparent relative sparing of the noncholinergic cell groups, with a greater impact on cortical acetylcholine function and less evidence of significant behavioral deficits, at least in tests of memory and learning, such as the Morris water-maze and passive avoidance (Page et al. 1991). This was not true of performance on the 5CSRTT, in which robust attentional impairments were found that were reversible even by cholinergic agonists, such as the acetylcholinesterase physostigmine and nicotine and also remarkably by cholinergically enriched neural grafts obtained from rat embryos (Muir et al. 1992). The exciting parallel human study was being carried out by Sahakian and colleagues who were finding in one of the first ever trials of an anticholinesterase, tacrine, that the only objectively measured aspect of performance to show improvement following chronic treatment with the drug in patients diagnosed with Alzheimer’s disease was on the human CANTAB version of the 5CSRTT. The drug did successfully show small improvements on the standard clinical scales but not on objective measures of memory function. Thus, this translational rodent project successfully predicted the likely small, although significant, effects that cholinergic drugs can have on patients with dementia, that were mainly confined to enhancing alertness and attention, consistent with clinical findings (Sahakian et al. 1993).

I also learned several lessons from the animal part of this project; notably the importance of the necessity of specificity and selectivity of any manipulations designed to test the causal role of neural circuits in the brain—and in parallel, the importance of carefully assessing the consequences of such manipulations using appropriate histological and neurochemical assessments. Although we had achieved greater selectivity attacking the cholinergic neurons by varying the nature of the chemical neurotoxin we were using, presumably because of subtle differences in the molecular constitution of membranes of the cholinergic cell bodies, the achieved specificity was far from perfect. Indeed, a few years later, an even more selective immunotoxin (192-IgG saporin) was developed, and we were fortunately able to show that our basic findings held (Dalley et al. 2004). The constant refinement of techniques, however, means that further evolution of viewpoints is likely; the emergence of optogenetic and chemogenetic techniques, such as DREADDs, means that future hypotheses about the roles of the cholinergic system in attentional processing in the cortex are likely to be tested to the limit.

A second lesson was that converging evidence, where possible, using other techniques is also important to support working hypotheses. Thus, we were later able to show with Jeffrey Dalley using in vivo microdialysis, that acetylcholine is released during performance of the 5CSRTT in rats—and these findings have been further qualified by elegant work by Martin Sarter at Michigan using in vivo voltammetric techniques to quantify choline transients (Parikh et al. 2007). I recall that Martin and I first exchanged ideas about the functions of the nucleus basalis upon my consultancy visits to the Schering AG in Berlin, initiated by their scientific director and subsequent friend Dai Stephens, around the time of the falling of the Berlin Wall.

To strengthen my own experience in human neuropsychology I decided to take a period of sabbatical leave at the Institute of Neurology in London working with the eminent clinical neuropsychologist Professor Elizabeth Warrington, which I found to be an exciting and unique experience. My interest in Parkinson’s disease, especially the suspected cognitive deficits in that disorder also led me into a crucial collaboration with the late Professor C. David Marsden and his group, which enabled me to test the utility of the CANTAB battery in an intense clinical setting. Marsden was then the leading expert on Parkinson’s disease in the world and had strong views on the motor functions of the basal ganglia and whether Parkinson’s disease patients had significant cognitive disorders. He generously allowed me access to a tiny testing room situated just off his main office in the institute, and I was referred a large variety of clinical patients with all sorts of neurological impairments, ranging from idiopathic Parkinson’s disease to a new malign syndrome called multiple system atrophy that resembled Parkinson’s disease but was unresponsive to L-Dopa therapy and in fact etiologically was quite distinct. I was able to witness clinical phenomena such as bradyphrenia (slowed thinking) and even measure it using a CANTAB adaptation (the Stockings of Cambridge test) of Tim Shallice’s Tower of London planning task that made it possible to measure the apparent speed of thinking. One patient I tested could solve almost all of the problems but only after a seemingly interminable period of reflection.

Fig. 3.  Three CANTAB tests for three components of executive function: Tower of London planning task (also called the Stockings of Cambridge), the id/ed attentional set-shifting test, and spatial working memory. Reproduced with permission of Cambridge Cognition, plc.

Using CANTAB, and with aid of a new talented and hard-working graduate assistant Adrian Owen, we were able to chart the course of Parkinson’s disease from its earliest stages even before medication to its later stages during which it was clear that general cognitive intellectual deterioration was taking place (Owen et al. 1992). Owen also was testing patients with localized brain damage—for example, to the frontal or temporal lobes—to validate that the CANTAB tests indeed were probing the expected neural substrates and that our attentional set-shifting test was sensitive, like the WCST, to frontal damage in humans (Owen et al. 1990, 1991). The CANTAB tests (see some examples in Figure 3) especially probed what we decided to be the most salient executive components, including cognitive flexibility, response inhibition, and working memory (Friedman et al. 2006; Robbins 2007; Robbins et al. 1998).

Of particular interest to me was whether L-Dopa medication prescribed for the motor impairments was of any additional use in treating cognitive impairments. We already had found that just-diagnosed, never-medicated patients did have significant problems with attentional set-shifting, suggesting to us that the nature of the cognitive impairments was reminiscent of a frontal disorder (we coined the notion of a “fronto-striatal” dementia) and demonstrating, at least for this function, that the drug could not be exerting significant deleterious effects. We tested the hypothesis that L-Dopa had significant effects on cognition in Parkinson’s disease by testing patients on and off L-Dopa therapy, finding that performance on certain tests, planning as well as spatial working memory (using a human adaptation of the delayed alternation type tests in animals), was profoundly impaired by L-Dopa withdrawal, whereas performance on other tests (e.g., visual recognition memory) was not (Lange et al. 1992). The findings on spatial working memory were entirely consonant with Patricia Goldman-Rakic’s seminal studies of the role of prefrontal dopamine in spatial working memory in monkeys, which had been a guiding inspiration for the CANTAB (Brozoski et al. 1979). These findings with Parkinson’s disease patients were later to be complicated by several other intriguing results that reinforced a future lesson that, although informative and clinically useful, it is unwise to rely on findings obtained from studying a neurological disorder to study the functions of neural structures, such as the basal ganglia, or a chemical transmitter system, such as dopamine. Neurodegenerative diseases have far too many nonspecific and generalized effects to be effective “experiments of nature.”

Firm evidence for these generalized effects came from studies much later in the 1990s by gifted graduate students Roshan Cools and Rachel Swainson, who both found essentially that whereas some aspects of cognition in Parkinson’s disease, such as working memory, were improved by dopaminergic medications, other aspects were made worse (Swainson et al. 2000; Cools et al. 2001). We related these puzzling differences to differences in the degree of disease-related dopamine loss in parallel, functionally segregated fronto-striatal pathways of Alexander, DeLong, and Strick (1986), which hypothetically mediated different aspects of cognitive function. Thus, those pathways, predominantly in the dorsal striatum, that were most dopamine depleted exhibited the most therapeutically beneficial responses in terms to L-Dopa (most noticeably in motor function and also in spatial working memory), whereas those least dopamine-depleted, in the ventral striatum, tended to show impairments in behavior that we had come to associate with the ventral striatum (aspects of reversal learning and risky gambling behavior; Cools et al. 2001).

Further studies conducted with consultant neurologist and basal ganglia expert Roger Barker and colleagues, together with Danny Weinberger’s group at NIMH, were to show even greater complexity. Thus, a genetic polymorphism associated with the regulation of dopamine function in the PFC (catechol-o-methyl-transferase) conferred on some Parkinson patients, who expressed the met-met genotype (associated with high prefrontal dopamine levels) paradoxical cognitive impairments on such tasks as the Tower of London planning task when early in the course and also on L-Dopa medication (Foltynie et al. 2004). It seemed from these studies that too much, as well as too little, dopamine could result in cognitive deficits in Parkinson’s disease. Several other lines of evidence supported this dopamine overdose hypothesis; it was also clear that these fronto-striatal impairments did not necessarily predict Parkinsonian dementia, and other evidence now encourages the view that this may be a consequence of an entirely distinct nondopamine (not-striatal) pathology. We thus now have a dual-syndrome hypothesis of Parkinson’s disease pathology: the first refers to a dopaminedependent fronto-striatal component, and the second to another more posterior cortical syndrome possibly related to Lewy bodies and tau inclusions that is especially sensitive to the influence of other chemical transmitter deficits in Parkinson’s disease, notably acetylcholine and noradrenaline (Kehagia et al. 2010).

This work on Parkinson’s disease was paralleled by other work on neurodegenerative disorders, such as Huntington’s disease (e.g., Lawrence et al. 1998) and fronto-temporal dementia (e.g., Rahman et al. 1999), that again had been inspired by our work on experimental animals, especially marmosets. But perhaps the most exciting breakthroughs were provided by our work on the early detection of Alzheimer’s disease with Sahakian and John Hodges. Another of the CANTAB tests, visuo-spatial paired associate learning (PAL), turned out to be exquisitely sensitive to the memory impairments observed in early Alzheimer’s disease (Swainson et al. 2001). This task had been inspired by several influences, including an early study by Smith and Milner (1981) on object-location memory in patients with hippocampal lesions and by parallel studies on monkeys in Mishkin’s laboratory (Parkinson et al. 1988). The basic rationale of the task was to remember the location of several objects, a cognitive capacity apparently requiring the hippocampus, where visual and spatial streams of information converge for potential association. Thus, several boxes on the screen are opened successively one after the other to display a distinct visual icon in each one. Before each icon is displayed in the center of the screen, the subject merely has to touch the white box in which it originally was associated toward the margin of the screen. The task begins with six boxes, but with only two objects to be remembered, before becoming six and then eight objects over a short number of trials. Working in our group, Swainson found that patients with questionable dementia, attending a memory clinic for the first time, were divided into two groups by this task, some performing normally and others showing impairments as great as those of many early Alzheimer patients (Swainson et al. 2001). Many of these latter patients subsequently were shown to exhibit further deterioration and eventually were diagnosed as having probable Alzheimer’s disease. This finding, conducted with the aid of a joint grant held with GlaxoSmithKline provided an enormous boost to the foundation of a company, Cambridge Cognition, to develop CANTAB further. Most recently, Cambridge Cognition was launched on the London Stock Exchange upon the release of a product, CANTAB Mobile, which provides the PAL tests as an objective screening instrument for general practice doctors who have patients complaining of memory loss. In this way, we have endeavored to overcome the two major translational gaps: from animals to humans, and from the research clinic to bedside.

From Actions to Compulsions: Studies of Fronto-Striatal Systems in Neuropsychiatry; Drug Addiction and Other Impulsive-Compulsive Disorders

The CANTAB also provided impetus into our investigations of the functions of the fronto-striatal systems and their chemical neuromodulation. Although Everitt and I continued into our grand overall project of comparing the roles of the major chemical systems into motivational as well as cognitive systems, we were focused especially on apparent parallels and differences in functioning between the ventral and dorsal striatum in the context of drug addiction. Major strides already had been made in this field that promised to provide the most convincing neuroscientific underpinning of all of the neuropsychiatric disorders (with the possible exception of anxiety). We had focused on the role of the projections from the basolateral amygdala to the nucleus accumbens in forming conditioned associations (both appetitive and aversive) that guided behavior (Cador et al. 1989; Killcross et al. 1997) and came to recognize, along with others, that the chronicity of drug exposure in addiction made it highly susceptible to conditioning influences, consistent with much human addiction phenomena. Our early studies, with Athina Markou from San Diego and others, concentrated on redeploying the so-called second-order schedule of reinforcement, an acquaintance with which I had gained in my time at Harvard, by which instrumental responding for drugs, such as cocaine and heroin, is maintained in part by the delivery of brief stimuli associated with the drug infusions. The importance of this procedure is that it enables some measure to be made of the animal’s motivation to obtain the drug before the drug is actually on-board, when, naturally, instrumental responding is further exacerbated, especially with drugs such as cocaine and amphetamine that already had been shown to enhance the effects of such conditioned reinforcing stimuli (Arroyo et al.1998). We initially employed this procedure to establish the roles of the basolateral amygdala and different subregions of the nucleus accumbens (core and shell) in cocaine-seeking behavior (Whitelaw et al. 1996). Later studies with Rutsuko Ito and Dalley also employed in vivo microdialysis to show in well-trained rats that dopamine was released in the nucleus accumbens following cocaine infusion, but not generally during the initial period of receiving only the conditioned stimuli. The most exciting result, however, was that dopamine was released in the dorsal striatum during this phase, almost to the same extent as the drug itself (Ito et al. 2000, 2002). This result, together with others, led to the hypothesis in what is now our most-cited review article that addiction involves a shift of control, initially from the ventral striatum and ultimately to the dorsal striatum (Everitt and Robbins 2005). We speculated that this corresponds to the shift often observed from goal-directed to habit-based learning, which already was surmised from the work of White, Mishkin, Balleine, Graybiel, and others to be mediated by the dorsal striatum, and that addiction also could be understood in this light. Recent reviews have surveyed the relevant evidence one decade on for this hypothesis (Everitt and Robbins 2016). Another important component of the theory is that a gradual loss of top-down control from the PFC over these striatal domains results in the development of compulsive sequences of actions built up from habits (see Figure 4). One important question that we have pursued is whether this loss of top-down control is produced by exposure to the possibly neurotoxic effects of drugs of abuse or, alternatively, whether it is a consequence of individual predisposing factors that could result from genetic or experiential factors. We think that the answer is a mixture of both influences, at least in the case of stimulant abuse.

Earlier developments in our human neuropsychological test battery enabled us to monitor influences of top-down control in decision making relevant to drug abuse and other psychiatric disorders. We were especially interested in cognitive or response inhibitory control mechanisms and had developed several tests in animal and humans to measure these, including the stop-signal reaction time task (Logan et al. 1984), temporal reward discounting, and the so-called Cambridge Gamble Task (Roger set al. 1999a). We also had begun to employ brain imaging methodologies using both fMRI and PET to highlight the neural circuits that were engaged by such tasks in healthy volunteers (Rogers et al. 1999b). A key example was the slowed stop-signal performance of patients with lesions of the inferior frontal cortex, especially in the right hemisphere, that had been shown by Sahakian’s outstanding graduate student Adam Aron, working with what were then sophisticated means of measuring the extent of structural loss in different sectors of the frontal lobe employed by Ed Bullmore and Paul Fletcher (Aron et al. 2003). I was astonished at the selectivity of this impairment and its implications, which I think remains central to the debate on the nature of PFC functioning (cf. Aron et al. 2014). Another key paper was one with Robert Rogers comparing performance on the Cambridge Gamble Test of patients with frontal lesions and drug abusers, as well as healthy volunteers with transient putative 5-hydroxytryptamine (5-HT) depletion caused by tryptophan depletion, thus mimicking the loss of brain serotonin that has been observed in stimulant abusers post mortem), and showing clear parallels in decision-making impairments (Rogers et al. 1999a).

Fig. 4.  Neuropsychological scheme to explain stimulant drug addiction as shown in Everitt and Robbins (2005). Note the role of ventral striatum in conditioned reinforcement, the dorsal striatum in habitual behavior, and the prefrontal cortex in top-down control. Reproduced with permission from the publishers of Nature Neuroscience.

In rodent experiments, we had shown that basic decision-making impairments were caused even by manipulations of the nucleus accumbens itself. Rudolf Cardinal, with Everitt and myself, showed that damage to the core subregion produced impulsive responding on a temporal discounting procedure for rats that had been pioneered by Evenden (1999); the lesioned rats consistently chose the small immediate reward over the larger delayed one (Cardinal et al. 2001). A later study by Dawn Eagle found that a rat analogue of the stop-signal task was not impaired by similar lesions, although damage to the dorsal striatum was effective in slowing stopping performance (Eagle and Robbins 2003). Thus, it appears that different aspects of top-down control are mediated via different fronto-striatal connections and possibly by distinct neuromodulatory influences. Thus, for example, noradrenergic and serotoninergic drugs appear to exert distinct actions. One finding of especial significance is that the stop signal reaction time task appears to be rather impervious to effects of serotonin manipulation in both humans and rodents (Eagle et al. 2009). In fact, the classical notion that 5-HT mediates behavioral inhibition has been quite severely constrained by our recent studies (e.g., Winstanley et al. 2004), although this neurotransmitter has been shown to exert ramifying actions in sophisticated areas of social cognition (e.g., Crockett et al. 2010).

Perhaps the most significant finding we have had in this area involved a third form of impulsive responding, the premature responding measure on the rodent 5CSRTT. Dalley had noticed the wide individual variation for this particular measure in Lister hooded rats and discovered that it corresponded to their individual susceptibilities to develop cocaine binge-taking behavior. Moreover, when these high-impulsive rats were screened for their striatal dopamine D2 receptors, which Nora Volkow et al. (2007) had shown convincingly to be reduced in human chronic stimulant abusers, they were shown to be significantly reduced in numbers even though they had not been previously drug exposed (Dalley et al. 2007). The high-impulsive rats were later shown to have compulsive drug-seeking behavior, as indicated by their willingness to experience punishing electric foot-shock in order to earn i.v. cocaine infusions (Belin et al. 2008). These findings suggested that impulsivity associated with low D2 dopamine receptors may be a predisposing factor for stimulant drug abuse, leading to addiction.

To test this hypothesis in humans, we have adopted a number of approaches. Karen Ersche has employed both neuroimaging and behavioral measures in an endophenotype strategy, by which not only chronic dependent stimulant abusers, but also their unaffected sibling probands, have been tested. In several studies, we have been able to show that impulsivity is present in these siblings, whether measured in terms of impulsivity self-rating (Ersche et al. 2010) or by objective tests, such as the stop-signal reaction time task. In addition, the impaired performance in the stop task is associated with reduced integrity of the white matter in the frontal lobe, probably innervating the inferior frontal cortex, which is known to participate in these functions (Ersche et al. 2012). Ersche also has shown that some of the changes in grey matter in the temporal and frontal lobes are not present either in siblings (Ersche et al. 2011) or in recreational stimulant abusers who have not received a diagnosis of substance use disorder, but they may be correlated with the duration of stimulant drug use. This finding supports the concept that frontal control in these patients is compromised both by the predisposing constitution of the drug abusers and also by the effects of the drugs themselves, although whether the latter effects are permanent or reversible remains to be seen. A converging approach has been in the form of a massive, EU-funded prospective study, IMAGEN, which has sought to obtain predictive markers for drug abuse in a large (n = 2,000) population of healthy adolescents, using brain imaging, behavioral, and genetic markers. Intriguingly, the pattern of neural network activations produced by the stop-signal reaction time task was indeed related to early abuse of nicotine, alcohol, and illicit substances (Whelan et al. 2012).

The studies on drug addiction recently have led us to the more general phenomenon of “impulsive-compulsive disorders,” including ADHD and obsessive-compulsive disorder (OCD). Our studies of ADHD stemmed from the original interest in the effects of stimulant drug medication and their apparent cognitive-enhancing actions. This finding that methylphenidate could improve spatial working memory even in volunteering Cambridge students (Elliott et al. 1997; Mehta et al. 2000) suggested to us that the drug was basically a cognitive enhancer rather than remediating a basic deficit, a hypothesis buoyed by our recent findings using PET to measure D2 receptors in adult ADHD (del Campo et al. 2013). Other studies have focused on the relative contribution of the effects of dopaminergic and noradrenergic actions of methylphenidate and their neural location. This has led us to compare other atypical stimulant drugs with methylphenidate, notably atomoxetine, the relatively selective noradrenaline reuptake blocker (Chamberlain et al. 2006), and modafinil, the neurochemical actions of which are quite obscure but have definite cognition-enhancing effects in healthy volunteers on CANTAB tests, such as the Tower of London, and even in patients with schizophrenia (Turner et al. 2003, 2004).

Most recently, I have been investigating OCD with Naomi Fineberg, Sahakian, and others as a prototypical example of compulsive behavior and in comparison with drug abuse and other compulsive disorders. The same notions of dysexecutive control and a drift to habit-based learning have permeated our thinking on this devastating condition, which bears relationships with anxiety disorders, schizophrenia, and depression as well as behavioral addictions. Thus, Sam Chamberlain in our group has shown that ed attentional set-shifting is significantly impaired in the unaffected siblings of OCD patients as well as in the OCD patients themselves, suggesting a general tendency to rigid behavior (Chamberlain et al. 2007). Additionally, both siblings and OCD patients exhibit reduced orbitofrontal activation during reversal learning (Chamberlain et al. 2008), which is consistent with our earlier findings of deficits in reversal following excitotoxic lesions to such regions or depletion of serotonin to those same regions in marmosets (Clarke et al. 2004). These reductions may contribute to OCD symptoms and may be remediated in patients following treatment with high doses of selective serotonin reuptake inhibitors. Impairments in goal-directed behavior to the apparent advantage of habit-based learning have emerged by applying the principles of diagnosing habits using reward devaluation methodology that originally were proposed by Anthony Dickinson (1985), whether applied to appetitive or aversive learning (Gillan et al. 2011, 2014). Our most recent attempts are to relate these behavioral findings to the operation of discrete fronto-striatal systems using a range of neuroimaging paradigms. Overall, and consistent with our previous CANTAB strategy, we are keen to continue to employ new behavioral paradigms and neuroimaging methods to better define phenotypes within neuropsychiatry, consistent with our studies of the functions of neural systems in experimental animals. This work may result in the fractionation and neural dissection of several neurobehavioral constructs into further components on the way, including impulsivity and compulsivity.

I perceive some persistent themes in my intellectual interests from the earlier parts of my career; I am still fascinated by the notion of loss of control over subcortically mediated behaviors and their adaptive motivation, if any. These behaviors extend from stereotypies to deficits in cognitive rigidity and habit-based learning, representing an apparent hierarchical organization over cognitive and behavioral output that appears to dominate the output of the frontal lobes mediated by structures such as the basal ganglia, under the differing states of arousal or activation reflected by environmental influences and dispositions imposed by the interplay of the major ascending monoamine transmitters. I suspect that neuroscientists such as myself never lose intellectual commitment to anything they once began to study; they simply add them into an ever-increasing and intoxicating intellectual mix into which they can but hope to embroil and fascinate their younger colleagues.

Epilogue

The bare bones of my career are summarized at the start of this article; they do not necessarily represent the highlights. It was wonderful, however, to be appointed full professor at Cambridge in 1997 at the same time as Everitt and also, for our collaboration, to be jointly honored by the American Psychological Association in 2011. Other highlights have included being elected to a fellow of the Royal Society, the most prestigious of the U.K. scientific bodies. I remember with excitement the Discussion Meetings I helped to organize for the Royal Society on Prefrontal Cortex Function and the Neurobiology of Drug Addiction in 1996 and 2009 and the accompanying edited books. I also have much enjoyed editing the journal Psychopharmacology since 1980. My service to “medical research” and U.K. Research Councils was marked by an appointment as Commander of the Most Excellent Order of the British Empire in 2012. A crowning honor was the award of the Grete Lundbeck Brain Prize with S. Dehaene and G. Rizzolatti in 2014.

Acknowledgments

I acknowledge over the course of some 40 years the support of the Department of Experimental Psychology (now Psychology) and its esteemed faculty who have provided continuous intellectual stimulation and inspiration: I was honored to be elected to be head of department in 2002, succeeding the luminaries Bartlett, Zangwill, and Mackintosh. I also acknowledge the generous and continuous support of the MRC and Wellcome Trust, including the formation of the Behavioural and Clinical Neuroscience Institute, with Ed Bullmore as clinical director. I am grateful to generations of Cambridge undergraduates, graduates, and postdocs who have been part of the lab. It has not been possible to acknowledge all of their individual contributions to my work; I have had to be selective in describing its main themes and my failure to incorporate reference to their own often independent and brilliant contributions in no way implies that I regard their own efforts as being of any less significance or importance to me.

Finally, I acknowledge with extreme gratitude the support of my extraordinary partner Barbara Sahakian, who has had an eminent career in her own right, while also bearing the major burden of family life and children. Our daughters Jacqueline and Miranda are now both graduate students in the field of neuroscience, although working in areas quite separate from behavioral and cognitive neuroscience.

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Crockett, M.J., Clark, L., Hauser, M.D., and Robbins, T.W. (2010) Serotonin selectively influences moral judgment and behavior through effects on harm aversion. Proceedings of the National Academy of Sciences, USA 107, 17433–17438.

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Dalley, J.W., McGaughy, J., O’Connell, M.T., Cardinal, R.N., Levita, L., and Robbins, T.W. (2001) Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task. Journal of Neuroscience 21, 4908–4914.

Dalley, J.W., Theobald, D.E.H., Bouger, P., Chudasama, Y., Cardinal, R.N., and Robbins, T.W. (2004) Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-saporin-induced lesions of the medial prefrontal cortex. Cerebral Cortex 14, 922–932.

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Eagle, D.M., and Robbins, T.W. (2003) Lesions of the medial prefrontal cortex or nucleus accumbens core do not impair inhibitory control in rats performing a stop-signal reaction time task. Behavioural Brain Research 146, 131–144.

Elliott, R., Sahakian, B.J., Matthews, K., Bannerjea, A., Rimmer, J., and Robbins, T.W. (1997) Effects of methylphenidate on spatial working memory and planning in healthy young adults. Psychopharmacology 131, 196–206.

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Ersche, K.D., Turton, A.J., Pradhan, S., Bullmore, E.T., and Robbins, T.W. (2010) Drug addiction endophenotypes: impulsive versus sensation-seeking personality traits. Biological Psychiatry 68, 770–773.

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Foltynie, T., Goldberg, T.E., Lewis, S.J.G., Blackwell, A.D., Kolachana, B.S., Weinberger, D.R., Robbins, T.W., and Barker, R.A. (2004) Planning ability in Parkinson’s disease is influenced by the COMT val158met polymorphism. Movement Disorders 19, 885–891.

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Gillan, C.M., Papmeyer, M., Morein-Zamir, S., Sahakian, B.J., Fineberg, N.A., Robbins, T.W., and de Wit, S. (2011) Disruption in the balance between goaldirected behaviour and habit learning in obsessive-compulsive disorder. American Journal of Psychiatry 168, 718–726.

Gillan, C.M., Morein-Zamir, S., Urcelay, G.P., Sule, A., Voon, V., Apergis-Schoute, A.M., Fineberg, N.A., Sahakian, B.J., and Robbins, T.W. (2014) Enhanced avoidance habits in obsessive-compulsive disorder. Biological Psychiatry 75, 631–638.

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Ito, R., Dalley, J.W., Howes, S.R., Robbins, T.W., and Everitt, B.J. (2000) Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. Journal of Neuroscience 20, 7489–7495.

Ito, R., Dalley, J.W., Robbins, T.W., and Everitt, B.J. (2002) Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drugassociated cue. Journal of Neuroscience 22, 6247–6253.

Kehagia, A.A., Barker, R.A., and Robbins, T.W. (2010) Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in Parkinson’s disease. Lancet Neurology 9, 1200–1213.

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Killcross, S., Robbins, T.W., and Everitt, B.J. (1997) Different types of fearconditioned behaviour mediated by separate nuclei within amygdala. Nature 388, 377–380.

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Lange, K.W., Robbins, T.W., Marsden, C.D., James, M., Owen, A.M., and Paul, G.M. (1992) L-Dopa withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests of frontal lobe dysfunction. Psychopharmacology 107, 394–404.

Lawrence, A.D., Hodges, J.R., Rosser, A.E., Kershaw, A., ffrench-Constant, C., Rubinsztein, D.C., Robbins, T.W., & Sahakian, B.J. (1998) Evidence for specific cognitive deficits in preclinical Huntington’s disease. Brain 121, 1329–1341.

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Mehta, M.A., Owen, A.M., Sahakian, B.J., Mavaddat, N., Pickard, J.D., and Robbins, T.W. (2000) Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain. Journal of Neuroscience 20, RC65 1–6.

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Muir, J.L., Dunnett, S.B., Robbins, T.W., and Everitt, B.J. (1992) Attentional functions of the forebrain cholinergic systems: effects of intraventricular hemicholinium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task. Experimental Brain Research 89, 611–622.

Owen, A.M., Downes, J.J., Sahakian, B.J., Polkey, C.E., and Robbins, T.W. (1990) Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 28, 1021–1034.

Owen, A.M., Roberts, A.C., Polkey, C.E., Sahakian, B.J., and Robbins, T.W. (1991) Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia 29, 993–1006.

Owen, A.M., James, M., Leigh, P.N., Summers, B.A., Marsden, C.D., Quinn, N.P., Lange, K.W., and Robbins, T.W. (1992) Fronto-striatal cognitive deficits at different stages of Parkinson’s disease. Brain 115, 1727–1751.

Page, K.J., Everitt, B.J., Robbins, T.W., Marston, H.M. and Wilkinson, L.S. (1991) Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesion of the basal forebrain in rats: differential dependence on cholinergic neuronal loss. Neuroscience 43, 457–472.

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Rahman, S., Sahakian, B.J., Hodges, J.R., Rogers, R.D., and Robbins, T.W. (1999) Specific cognitive deficits in mild frontal variant frontotemporal dementia. Brain, 122, 1469–1493.

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Wolf Singer

BORN:

Munich, Germany

March 9, 1943

EDUCATION:

Ludwig Maximilian University (LMU), Medicine (1962–1968)

Sorbonne, Faculté de Medicine et des Sciences (1965–1966)

State Examination in Medicine and Defense of MD Thesis at LMU Munich (1968)

Approbation as General Physician (1970)

Habilitation for Physiology (PhD), Technical University (TU) Munich (1975)

APPOINTMENTS:

Independent Group Leader at the Max Planck Institute for Psychiatry, Munich (1975–1981)

Professor for Physiology at Technical University Munich (1980)

Director at the Max Planck Institute for Brain Research, Frankfurt (1981–2011)

Founding Director of the Frankfurt Institute for Advanced Studies (FIAS), Frankfurt (2003–present)

Chairman of the Ernst Strüngmann Forum (2006–present)

Founding Director of the Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with the Max Planck Society, Frankfurt (2008–2011)

Senior Fellow at the Ernst Strüngmann Institute for Neuroscience (2011–present)

Director emeritus at the Max Planck Institute for Brain Research (2011–present)

HONORS AND AWARDS (SELECTED):

Warner Lambert Lecture, American Society for Neuroscience, 1989

Neuronal Plasticity Prize of the Ipsen Foundation, 1991

Member of the Pontifical Academy of Sciences, 1992

Founding Member of the Berlin-Brandenburg Academy of Science, 1992

Ernst Jung Prize for Science and Research (Zuelch Prize), 1994

Hessischer Kulturpreis, 1998

Koerber Prize for the European Sciences, 2000

Chevalier de la Légion d’Honneur, 2002

Krieg Cortical Discoverer Award of the Cajal Club, 2003

Betty and David Loetser Prize, University Zurich, 2003

Communicator Prize, German Research Council, 2003

Dr. honoris causa, University Oldenburg, 2005

Dr. honoris causa, Rutgers University, N.J., 2008

Order of Merit (First Class) of the Federal Republic of Germany, 2011

Cothenius Medal, Leopoldina, 2013

Fellow of the European Molecular Biology Organisation (EMBO), 2014

Fellow of the American Association for the Advancement of Science, 2014

The early work of Wolf Singer concentrated on signal transmission in the visual thalamus and cortex and its modulation by nonretinal projection systems. Subsequently, he studied the synaptic mechanisms mediating experience dependent modifications of cortical architectures combining in vivo experiments in kittens with in vitro analyses of rodent cortical slices. Following the discovery of synchronized oscillatory responses in the visual cortex in the mid-1980s, his research focus shifted to the analysis of cortical dynamics in cats and monkeys. This work led to the proposal that the brain uses precise temporal relations between distributed neuronal responses for the encoding of semantic relations. This approach has later been extended to patients, using fMRI, EEG, and MEG technology and revealed characteristic disturbances of temporal coordination in patients suffering from psychiatric disorders. His current research tests the hypothesis that cortex exploits for its computations the highdimensional, nonlinear dynamics of recurrent networks.

Wolf Singer

Early Years

Born during a horrendous and volatile period of history, I spent the first night of my autonomous life in the hospital’s bomb shelter separated from my mother Sieglinde Singer, for my birth (on March 9, 1943) coincided with the first comprehensive air strike on Munich, one that left the clinic’s roof ablaze. Reunited the next morning, a completely unanticipated knock at our hospital room’s door introduced me to my father Joachim Singer. He was a medical doctor who, because of his expertise in mountain climbing, had been assigned to an army division in the Caucasus Mountains. Wounded by friendly fire, he appeared unexpectedly due to medical leave. This furlough was not to last, for soon he was ordered to return to the Eastern Front. On his way there, he learned that his unit had been destroyed in battle, and thus he headed back to Germany. En route he encountered, completely by chance, his younger brother Peter, a physicist who had been studying with Heisenberg, and who was being deployed to the Crimea with his unit. As with many families at that time, my father’s family straddled two continents: His older brother, Hermann, had immigrated to Pennsylvania years before the war to join my paternal grandmother, a U.S. citizen and former cultural attaché in Berlin, who by that time had divorced from her German husband, my grandfather. The other brother, Peter, disappeared sometime after that chance encounter under unknown circumstances.

For the remaining years of the war, I lived with my mother and her parents in Soyen, a tiny village in upper Bavaria close to Wasserburg/Inn, where my grandfather was the head of a primary school. When the Third Reich collapsed, my father was in the eastern section of the Alps. To escape Russian captivity, he set off for home by foot, taking with him a wounded comrade. Despite several critical encounters with Russian soldiers, he was able to continue unhindered, for they took him to be an American army surgeon because of his perfect English. Once again, he appeared, most miraculously, at our door.

I grew up immersed in the idyllic setting of that small Bavarian village. The oldest of three siblings—a sister (Katrin, born in 1946 and living in the United States since 1988) and younger brother (Peter, born in 1954)—my grandparents lovingly cared for us while our parents struggled to secure our existence. My father abandoned his earlier dreams of an academic career to work as a general practitioner. Fragmented memories remain from those early years of American soldiers; care packages; excursions into the woods to gather berries and mushrooms; visits to farmers to collect much-needed sustenance (given in exchange for my father’s medical assistance); the daily way to school, which took close to an hour on foot but far less on skis in the winter, and the freedom to choose which way to take; the odors of hay, dung, and moss; holy mass on Sundays; and long evening walks to remote chapels, where I was drawn to the solemn chants, accompanied by my grandfather on the organ, the candles, and the wafting scent of incense.

This idyll came all too abruptly to an end when I turned 10 for one simple reason: There were no secondary schools within reach of my village. Thus, I needed to go to boarding school.

The Landschulheim Neubeuern, founded by Baroness von Wendelstadt and Countess Degenfeld-Schonburg at the beginning of the 20th century, educated its pupils in the humanistic tradition. Situated in the Schloss Neubeuern, perched on a solitary rock in the middle of the valley overlooking the river Inn, the school offered not only a spectacularly beautiful view of the Alps but also a rich cultural history. Countess Degenfeld was a cultivated lady. She was host to the George-Kreis, a literary group named after the poet Stefan George that included many highly regarded German writers and academics. Richard Strauss and Hugo von Hofmannsthal were her guests when they conceived of the opera Rosenkavalier. The school was quite exceptional for its day. From the outset, it was open to girls as well as boys and students from around the world. Religious freedom was guaranteed and facilities provided to accommodate all practices. Not surprisingly, the school was closed by the Nazis during the war, but it reopened in 1948 with a renewed commitment to humanistic education.

My departure from home left me feeling lonely and vulnerable. The stunning beauty of the school’s surrounding landscape, though, served as my main source of consolation. Thinking back, I realize now how much my daily encounters with such beauty shaped and influenced me. Fortunately, school left little room for self-pity, for in addition to our academic courses, we were required to learn a trade. Any “free” time was spent honing the necessary skills to qualify as a metal or wood worker. The rationale behind this technical training was not entirely educational: the school was in dire need of furniture and other goods. We were also expected to master a musical instrument, but I promptly abandoned piano lessons because I detested the methodical translation of notes into finger movements. With the help of my classmates and a decelerated tape recorder, I managed to teach myself how to play the string bass and later the clarinet, joined the jazz band, and greatly enjoyed playing by ear.

My true passion during this time—one that held and perhaps drove my professional orientation later in life—was bricolage. At school, I built a fleet of gliders and motor-driven airplanes and boats, some of which were controllable using self-made, tube-based remote controls, all of which had limited lifetimes. Once transistors became available, I was able to build much lighter remote controls as well as tiny radios, which could be hidden in hollowedout books—precious items, since we were not allowed to listen to the radio at school. During my visits back home, I gradually transformed my bedroom into a lab equipped with primitive versions of many of the same “toys” that I would encounter much later in real labs. Because holiday excursions were the exception rather than the rule, I devoted as much time as possible to my experiments—probably too much, as might be said for later years as well. A lesser passion, but nonetheless tangible goal while at school, was to climb all the mountains visible from the terrace of Schloss Neubeuern. My father had succeeded in passing along his love for rock climbing and hiking to me, and I was eager to explore.

I completed my secondary studies in 1962. In Germany, it is tradition to take a break after one completes the Abitur (or baccalaureate) and before university studies begin. So, together with three friends, I set off for eight weeks to camp my way through Finland, up to the North Cape, and back down via Norway and Sweden. This experience not only taught us the wonder of being entirely free and self-paced but also exposed a far darker truth: When speaking to people along the way, we witnessed how our enthusiastic chatter—spoken with the intent of getting to know people—had the complete opposite effect. Our accents evoked terrible memories in those who had suffered at the hands of the Nazis, inextricably binding us to this dark period of German history. I had learned of the atrocities that Germany had perpetrated during the war. My parents were very articulate, as were the educators at the boarding school. But this experience left its indelible mark on me.

First Steps in Academia

Although, or perhaps because, my father had been such a shining role model of a practicing MD, I was determined not to pursue medical practice. I did, however, believe that the study of medicine could teach me about life and the human condition by revealing its biological underpinnings as well as the causes of failure.

The transition from the protected and in many respects artificial microcosm of boarding school to Munich, with all its temptations and anonymity, troubled me, as did the overwhelming course offerings provided by the university. I discovered countless alternatives to medicine, and after the first two semesters of basic courses, doubts grew ever stronger as to whether I had chosen the right area of study. My medical studies introduced me to most of the natural sciences and gave me the opportunity to see what was inside a human body through hours of meticulous dissection. Still, I felt that it afforded only glimpses into a universe that we were discouraged from exploring in depth. So I took courses for physicists and became fascinated by abstract and quantitative models, only to discover that this offered limited insight into the secrets of living matter. Philosophy seemed to be the way out, as I perceived it to be the meta-discipline that attempts to combine the knowable into a unified framework. So I enrolled in seminars of philosophical propaedeutics under the direction of Wolfgang Stegmüller (an analytical philosopher), and for a while was fully absorbed by the rigor of thought. Soon I began to realize that different options existed to interpret that which I previously viewed as facts. Unifying worldviews as proposed by Teilhard de Chardin, whom I had read with enthusiasm during boarding school, now appeared as only one of many possible stances. I felt unable to decide between naturalistic, constructivist, or phenomenological positions, and thus after a period of cerebral gymnastics, I humbly resumed my medical studies.

Focal Experiences

A sequence of three closely spaced events terminated this period of trial and error. The first involved my participation in a special course in anatomy, in which we were allowed to dissect human brains and trace macroscopic fiber tracts. Picking apart the organ that supports cognition, consciousness, and culture, and whose malfunction is at the root of mysterious psychiatric diseases, was a seminal experience—one that fully reconciled me to my studies. I chose to work in neurosurgery wards for the requisite internships during university breaks, first in Munich and then later at the Hôpital Foch in Paris, where earlier I had worked as an auxiliary nurse. I thought that nothing could be more fascinating than directly interfering with the brain in the context of therapeutic interventions. In Munich, where I was allowed to assist operations with large craniotomies to remove tumors, I remember being shocked by the crudeness with which brain tissue, whose delicate structure we had studied in the dissection course, was removed through suction. In Paris, I worked in the ward of Professor Guillot, a leading expert in stereotactic surgery who specialized in the treatment of Parkinson’s. At that time, the method of choice was the coagulation of the subthalamic nucleus, and the difficulty was to locate this small structure. Neither computer tomography nor magnetic resonance tomography existed at this time; localization relied on X-ray films and arteriography. In the latter, film cassettes needed to be removed from the stack quickly and at regular intervals to obtain time-resolved representations of arterial and venous compartments—a procedure that constituted one of my jobs at the Hôpital Foch. I still can hear the command feu to which I had to respond enlevé. Surgical interventions were performed in lightly sedated patients because target location was complemented by electrical stimulation and subsequent evaluation of the patients’ responses. For the first time, I saw how artificial activation of neurons in the brain can cause sensations and complex movements. I remember vividly how puzzled patients were when they realized that some agent, which they were unable to locate, had moved their limbs.

At the time of these initial concrete encounters with the mysteries of the brain, I was admitted to the Studienstiftung des Deutschen Volkes, a prestigious organization that supports select students with stipends, tutorials, and interdisciplinary schools. This brought me into contact with a network of brilliant students and academic mentors from all walks of science. We interacted intensely at summer schools and organized study groups throughout the year on such themes as “symmetry,” “time,” and “equilibrium.” Through this, I experienced for the first time the joy of joint intellectual adventures.

The third event, which determined the rest of my life, came in 1964. Two directors from the Max Planck Institute (MPI) for Psychiatry—Paul Matussek (a psychoanalyst and orthodox Freudian) and Otto Creutzfeldt (a neurophysiologist)—offered a seminar on the neuronal underpinnings of consciousness. I signed up immediately, for my greatest wish was to understand how mental phenomena could result from the interaction of material elements. Matussek approached the issue from a firstperson perspective, whereas Creutzfeldt concentrated on results from Sperry and Gazzaniga’s work on split-brain patients. I learned that stimuli presented to the nondominant hemisphere can undergo extensive processing and even trigger actions in a person who is unaware of the stimulus, thus believing that the actions were self-initiated. Herein lay the deep questions concerning the relationship between mind and matter, the conscious and the subconscious, the conundrum of top-down causation, agency, and free will. I doubt that these terms or concepts were explicitly mentioned at that seminar, yet somehow my intuition led me to think that the exploration of such questions would constitute a most fascinating challenge. I approached Creutzfeldt after the seminar to ask whether there was a chance to do research on such topics under his mentorship. Only in my second year of medicine, he smiled and told me that I needed to learn a lot more beforehand and that once I had passed the preclinical exams, we should reconsider the issue. I took his statement to be a “yes.”

Shortly after this brief encounter with my future mentor, and my firm decision to engage in brain research, I received confirmation that my application to study for one year at the University of Cambridge had been approved. I finished my preclinical studies in Munich, passed the required exams, and took another eight-week break with my friends (the same ones from the Scandinavian trip) to travel to Greece. Our in-depth exploration of the cradle of European civilization culminated in a one-week retreat at the monasteries of Mount Athos, thus concluding our tour d'Europe. When I returned to Munich, I officially withdrew from the university and moved to Cambridge to attend a language course at the Bell School, arranged by the Studienstiftung for foreign students who had been admitted to British universities.

Stolen Moments

The move to Cambridge in 1965 turned out to be as pivotal an experience as the seminar on consciousness, in terms of my private life. At the Bell School, I found myself in a vast community of students from all over Europe and shared with them the overwhelming experience of freedom, to which the insular character of England certainly contributed. In my class there was one particular French girl—a sophisticated, cultivated individual—who piqued my interest greatly, but she seemed well beyond my reach. For several weeks I even ignored that she could understand all of our German conversations, having studied in Heidelberg. On some evenings, I organized hypnosis sessions with several students, the French girl included, having learned the technique in Munich from a pupil of J. H. Schulz, who invented autogenic training. It was great fun, and the hypnosis worked. Some of the subjects reliably executed posthypnotic commands without being aware of them and gave explanations in an intentional format: “I opened the window because it is hot in here.” This direct evidence for the power of subconscious processes impressed me deeply, reinforced what I had heard about the split-brain patients, and contributed to my burgeoning interest in the conundrum of free will.

At the end of the language course, the school organized a trip to London, including a Prom concert at the Royal Albert Hall. Preferring to take my own car (an old Volkswagen) rather than ride the bus, I invited the French girl to join me. We arrived early and went for a cup of tea, during which time some petty thief promptly cleaned out my car. At the time, this could hardly be viewed as a serendipitous event: Francine lost her handbag, complete with passport, money, and plane ticket, and thus unable to leave the island, as planned, the next day. It took countless trips to the French consulate, switchboard-mediated phone calls, and numerous telegrams (there were no fax machines at that time) to restore her identity. These additional weeks together, however, enabled us to become close friends, and for the next three years, we chased each across Europe. Had that thief picked a different car, our lives would have progressed on entirely different paths, perhaps never to see each other again.

Eventually Francine flew back to her world and I proceeded to the matriculation office at the University of Cambridge. For reasons that still aren’t clear, my entire dossier detailing my acceptance was missing, leaving no possibility to begin my studies. Returning to Munich was not an option, since I had officially withdrawn from the university. I could have waited around in Cambridge for the next term, but instead decided on the spot to drive to Paris and register as an étudiant libre at the Sorbonne, where I was able to take all the courses that I would need later to continue my studies in Munich. Free to work in hospitals of my choice, I opted for St. Anne, to gain experience with psychiatric patients, and for the Salpétrière, which at that time was the mecca of neurology. I attended seminars by Professor Garcin, who analyzed patients and derived sophisticated diagnoses based solely on anamnesis (medical history), observation, and standard neurological examination. One of his diagnostic features that I clearly remember is la main thalamique.

Because I had interpreted Creutzfeldt to say that I eventually could study with him, I wrote to him to ask what I should study to qualify for work in his department. The reaction to this naïve question was overwhelming and a testimony to the admirable mentorship that this great scientist exhibited throughout his life. He contacted his friend and colleague, Pierre Buser, another icon in neuroscience, who generously allowed me to enroll in his course for neuroscience. This course was part of the troisième cycle, a level reserved for postgraduates wishing to specialize in a particular area. Much too young and inexperienced, I joined a small group of about 10 students and was introduced to electrophysiology through courses that took place every afternoon at Jussieu (now Université Paris 6). I was allowed to perform surgery on cats and practice field potential and intracellular recordings from motor neurons in the spinal cord. Professor Pearl, an expert in spinal cord physiology, happened to be spending a sabbatical in Buser’s lab and volunteered to supervise the course. During these decisive months, I learned all the steps required to conduct a complex in vivo experiment in a mammal. The preamplifiers, which we built ourselves, were based on the principle of cathode followers to minimize the grid currents of the tubes. Because Mosfet transistors did not yet exist, the challenge was to come up with high input impedance and low noise.

These truly exceptional opportunities to study in Paris, along with the city’s cultural offerings (through a quirk of fate I attended the legendary 1965 performance of Norma, with Maria Callas and Fiorenza Cossoto at the Opera Garnier), quickly negated all regrets I may have had about not staying in Cambridge. Paris and France became my second home. My only regret during this rich phase of life was that Francine was not there. She was studying in Geneva, which at that time was far away, thus precluding any spontaneous rendezvous. In addition, contact with my French peers was limited to discussions in bistros, as inviting me home was considered problematic, because of my German accent. In the midst of all the excitement, I often felt quite alone.

Back to Munich

In the summer of 1966 I returned to Munich to resume my medical studies and discussed with Creutzfeldt a possible thesis topic: I wanted to pursue split-brain research and he proposed that I examine whether commissurotomy would interfere with interhemispheric synchrony. This would involve electroencephalogram (EEG) recordings from implanted electrodes and commissurotomy. At the time, I had no idea what synchrony meant. Creutzfeldt suggested that I investigate whether transitions between synchronized and desynchronized states or the occurrence of alpha spindles would be less coordinated after commissurotomy. First, however, I needed to learn how to produce split-brain preparations, so Creutzfeldt wrote to Giovanni Berlucchi, a leading expert in split-brain experiments. Berlucchi who worked at the Moruzzi School¹ in Pisa, together with other eminent scientists, immediately agreed to teach me how to cut the commissures. In Pisa, Berlucchi patiently instructed me for several weeks in his method, guided my hands, and, at the end, presented me with a collection of the special spatulae he had engineered to retract the hemispheres. He also taught me how to section the chiasm using a transbuccal approach. I will forever be grateful to him for his hospitality and generosity during my stay.

After Pisa, I started to work in Creutzfeldt’s lab at the MPI for Psychiatry. Because of flexible curricula, I was able to complete the clinical portion of my medical studies while working on my thesis. I entered Creutzfeldt’s lab in its golden age: Creutzfeldt worked with Hans-Dieter Lux and guests from Japan (Ito, Watanabe) on the visual cortex, obtaining intracellular recordings with sharp electrodes and comparing these with field potential recordings in search of the underpinnings of the EEG; Max Straschill and Peter Hofmann were working on eye movements and the optic tectum; Bert Sakmann and Heinz Wässle were recording from the optic nerve; Henning Scheich and Uwe Heinemann worked in the EEG lab; Erwin Neher joined a bit later and teamed up with Lux to prepare the grounds for whole-cell recordings from snail neurons with fire-polished electrodes; and there was a continuous influx of guests from around the world who contributed their know-how. Together with the departments of anatomy, pharmacology, biochemistry, and the primate lab of Detlev Ploog, all of the classical disciplines of neuroscience were represented in-house. In addition, the institute was composed of an integrated research clinic for psychiatry and neurology. This remarkable density of expertise provided the most amazing fertile ground for research and collaboration.

Creutzfeldt’s style, in terms of running a department, was quite unique. He granted us maximal freedom and let us learn by doing. He was always available when we needed his advice and took whatever time was necessary (which explains perhaps why he was always late). The lab was a common source platform. In principle, this was great as it permitted us to swap equipment. But it did, on occasion, result in unexpected problems (more than once a BNC cable was removed from the depths of a rack, and it took hours to discover what had happened). Considering the remarkably successful careers of all of those who were nurtured in Creutzfeldt’s department, it is tempting to conclude that freedom and creativity are causally related.

Once I had collected my data (which today would be recognized as electrocorticography (ECoG) recordings of resting state activity and evoked potentials), I needed to find a way of processing it. Since we had no computers, evoked potentials could be visualized only by superimposing traces on the scope and taking pictures; evaluation of the continuous signals required inspection of traces produced by an EEG machine. Because the synchrony of the arousal-related state transitions was not influenced to a high degree by commissurotomy, I looked for more subtle markers, such as phase synchronization and co-occurrence of spindles. This required cross-correlation analysis. The only way to achieve this was to cut the EEG recordings, mark the zero crossings with a pencil, select a bin width, align several meters of continuous EEG records on the floor, shift them manually bin by bin against each other, and count the coincidences. This worked and showed a decrease in phase synchrony after commissurotomy. This analysis, however, was limited to the low-frequency bands, not only because of the archaic method but also because the ink pens could not cope with frequencies above 20 Hz. It took 20 more years before I resumed such analyses, albeit in an entirely different context. Only at the very end of my thesis was I able to obtain use of the first computer that could average evoked potentials as well as compute auto- and cross-correlations: the famous computer of average transients (CAT). It had ferrite magnets for memory, one could see the individual bits on the memory card, and altogether it had 4 K of memory—two seconds of data with one millisecond resolution for a cross-correlation. It was sensational, but of little help.

Upon completing the experimental portion of my research, I needed to shift attention slightly and complete another term of clinical work. I chose to do this in Paris and took with me the processed data (essentially films and EEG paper) to finish my evaluation. On the way back from Paris, during a brief stop at a restaurant along the French–German border, my car (the same old Volkswagen) was broken into again. This time, all the material for my thesis as well as the textbooks needed to prepare for my imminent final exams were taken. After two days of combing through all the garbage depots in the region, I reconciled myself to the fact that this material was gone forever. It was hard to find a serendipitous effect from this theft. Thus, more experiments needed to be conducted. By the time I submitted my thesis, I had compensated for most of the lost material. The thesis was published in Experimental Brain Research, in German with an English abstract—a common practice at that time (Singer and Creutzfeldt 1969).

The Phase Transitions toward Independence

After passing the final exams for my medical studies and defending my thesis in the autumn of 1968, Francine and I accomplished what we had apparently been striving for since Cambridge: we married on December 31. Much, of course, had happened in the interim. Francine had finished her studies of German literature in Geneva and cooperated with the historian Saul Friedländer on the history of the Third Reich, before moving to Paris where she worked as a translator for the publishing house Casterman. And although my medical studies were now behind me, two years of clinical training at the Munich university hospital were required before I could be licensed as an MD. Thus, our life together needed to begin in Munich, rather than Paris—a decision made even more attractive because of an offer from Creutzfeldt to let me finish various projects that I had undertaken after the commisurotomy experiments. What could have easily erupted into a dual-career problem was avoided due to Francine’s willingness to move to Munich, for which I will forever be grateful.

Although I relished my thesis project because it involved delicate surgery and the handling of awake animals, major conclusions about brain functions could not be drawn, other than that commissures play a role in the temporal coordination of low-frequency oscillations. There were just too many unresolved questions with regard to the cellular correlates of the EEG and the functional implications of the conspicuous frequency changes. So, I began to record from the lateral geniculate body of cats with pipettes, hoping to be able to obtain intracellular recordings, as others were able to do in the cortex, and to look for stimulus-dependent changes in transfer functions. This turned out to be quite challenging, but one peculiar and encouraging observation emerged: after electrode resistance increased, as one probed for neurons, the spikes became positive and monophasic and one could see what looked like excitatory postsynaptic potentials (EPSPs), the frequency of which was clearly resembling that of ganglion cell discharges. There was no clear DC shift, but I observed depolarizing and hyperpolarizing fluctuations of the membrane potential that correlated well with the discharges. These recordings, which we called “quasi-intracellular” recordings, allowed me to get reasonably comprehensive samples of cells to study the dynamics of signal transmission and inhibitory interactions. For the first time, I had seen parts of the brain work in an interpretable way and experienced the excitement of having uncovered something that no one had ever seen. These observations formed the basis of my first publications in English (Singer and Creutzfeldt 1970).

One conspicuous finding from these first “quasi-intracellular” recordings of geniculate cells was that transfer functions did not only change as a result of stimulus conditions, they did so, even more, in conjunction with global state changes that occurred despite constant levels of anesthesia. When the EEG displayed delta waves, cells hyperpolarized and failed to transmit retinal EPSPs, they exhibited enhanced inhibition by other retinal channels and changed from a sustained to a bursting discharge pattern. From Morruzzi and Magoun’s as well as Jouvet’s seminal studies, it was known that the projections from the mesencephalic reticular formation, the ascending reticular arousal system (ARAS), were responsible for a suppression of slow EEG waves and that this suppression caused desynchronization (i.e., an increase of low-amplitude high-frequency oscillations that occur at the expense of large-amplitude slow oscillations). Because all of these signatures of arousal could be elicited by electrically stimulating the reticular formation, I set out to study the effects of stimulating the reticular formation on intracellularly recorded responses in geniculate neurons. Initial experiments were performed together with Ursula Dräger, who had come to Creutzfeldt’s lab before moving to Harvard to work with Hubel and Wiesel (Singer and Dräger 1972). Perfecting our approach, we obtained true intracellular recordings with the appropriate negative DC shift and overshooting spikes, and saw that reticular stimulation caused a complete blockade of IPSPs, irrespective of whether they occurred spontaneously or were induced by light stimuli or electrical stimulation of the chiasm or the optic radiation. This explained the changes in transfer function and gave rise to a long series of studies that continued well into my first years at Frankfurt. The first review of this line of research appeared later in Physiological Reviews (Singer 1977) and served as the basis for my habilitation² at the Technical University of Munich.

Phase transitions of all sorts were under way, but one particular event marked my life more than any scientific discovery: the birth of our twin daughters, Nathalie and Tania, in December 1969. This intended expansion of our family changed our lives and priorities in a profound and wonderful way, far beyond anything that could have possibly been previously imagined—a fact that remains constant and unchanged to this day. As parents, we learned that the girls could not only survive but thrive, even if we were not omnipresent, and so Francine began to work for the Bayerische Rundfunk (Bavarian Broadcasting), taking care as an editor and presenter of the program in French language. Even as infants, the girls had clear agendas, irresistible charm, and, if required, were able to insist on what they needed. When necessary, we were able to rely on experienced and caring grandparents on both sides, and so somehow our lives transitioned without too much worry.

Around this time, I received a grant to pursue the basics in behavioral and cognitive psychology in another country. Having completed my clinical training in internal medicine, obstetrics, and surgery, I was free to move and chose the department of psychology at Sussex University, headed by Stuart Sutherland, because it seemed to combine behavioral approaches with neuroscience, at least on a conceptual level. So, in the winter of 1970–1971, the four of us moved to Brighton. It was the year of the miners’ strike, which meant that there was no coal to be had for the furnace and, most of the time, no power for the electric heater. On more than one occasion, we went to bed fully dressed. Using the children’s buggy to collect wood in the nearby forests, we embraced the situation as an adventure rather than a nuisance. My mentors in the department were Fred Miles and Bill Phillips. I learned to shape and condition pigeons in Skinner boxes and to compile training schedules with analogue circuits consisting of relays and all sorts of logical gates. Above all, I became acquainted with the psychophysical experiments of Bill Phillips—an encounter that proved crucial for my further orientation. With his access to a huge computer, he could produce checkerboard patterns on a cathode ray tube (CRT) screen. He examined the phenomenon of iconic memory—the ability to store information of complex pictures beyond the offset of the picture so that even small changes introduced in a subsequently presented picture could immediately be detected. As test patterns, he used sequences of random checkerboards, to which he either added or deleted one of the squares. Bill found that subjects easily detected changes of either polarity if the second pattern followed the offset of the first by no more than about 150 milliseconds. The effect depended critically on a precise retinotopic alignment of the patterns and showed only little interocular transfer. This suggested a retinal or thalamic mechanism. Because I had found powerful retinotopically specific inhibitory interactions between ON and OFF channels in the lateral geniculate nucleus (LGN) through my quasi-intracellular recordings, I was able to predict how the offset of a bright square would influence the responses to the reappearance of the same square, and how this response would differ from that of a newly appearing square. Under the assumption that these differences in ON responses supported change detection (the same would be true for OFF responses of disappearing squares), Phillips and I set off (with pencil and paper) to formulate a set of 12 predictions on how performance should depend on the temporal parameters of stimuli. Some of these predictions were extremely counterintuitive—for example, if the first pattern is flashed only briefly, detection of an added square should become possible only after longer interstimulus intervals, but then over a longer time period. The reason is the long latency of OFF responses to short stimuli. Step by step we tested these predictions and were able to confirm all of them. After returning from Sussex in summer 1971, I tested whether the responses in the geniculate actually behaved as predicted and found a perfect quantitative match between cellular responses and human performance (Phillips and Singer 1974; Singer and Phillips 1974). We had found a function for the inhibitory interactions between ON and OFF channels. Just as lateral inhibition between channels of similar polarity enhances spatial contrast and suppresses redundancy, inhibition between channels of opposite polarity enhances temporal contrasts and suppresses redundant responses to unchanged contours of briefly interrupted or occluded patterns. This synergetic experience between behavioral and neurophysiological approaches was eye-opening and has henceforth influenced much of my work; psychophysics has remained a complementary tool that I draw on to this day. Equally rewarding is my close friendship with Phillips, whose deep knowledge of cognitive neuroscience and genuine interest in neuronal mechanisms has been and still is a precious source of inspiration. We continued to cooperate and discovered a strange long-range effect between magno- and parvocellular-processing streams (Wilson and Singer 1981; Leonards and Singer 1997), which strongly suggested that the brain establishes semantic relations between precisely synchronized stimuli—a notion that gained importance later in my work on the binding-by-synchrony hypothesis. Phillips sent brilliant students to my lab, the last being Peter Uhlhaas, who joined me in Frankfurt in 2006 and led most of our work with psychiatric patients. My stay in Brighton exposed me to an entirely new sort of academic culture, one that differed in many respects from what I had experienced in Paris and Munich. Discussion seemed to be the top priority, catalyzed by sacred tea breaks and joint ventures to the pub. I vividly remember how surprised I was to learn that the huge computer at the institute—which must have cost a fortune at the time—was not used around the clock, even though there was ample competition for its use. It sat idle during tea as well as over the sacred weekend. It took me until much later before I discovered the virtues of discourse and the primacy of thinking over doing. My only regret is that I did not pay sufficient respect to these priorities earlier.

In 1971, another remarkable event took place that brought me into contact with virtually all the famous neuroscientists in the field of systems neuroscience. Creutzfeldt organized a large international neuroscience symposium that was to take place in August at an Austrian resort. Unfortunately, shortly before the meeting, the resort went bankrupt, and thus another location capable of accommodating close to 200 participants needed to be found quickly. Immediately my thoughts went to my boarding school at Schloss Neubeuern, knowing that the school would be closed in August for summer holidays. Discussions with the school’s administration followed, personnel were called back from holidays, and the conference was moved to the castle. It was probably the first and last time that the world’s most eminent neuroscientists had to share rooms with up to six beds and use common bathrooms. Such were the conditions imposed on David Hubel, Torsten Wiesel, Sir John Eccles, Janos Szenthagothai, Peter O. Bishop, Peter Schiller, Masao Ito, Larry Weiskrantz, Vernon Mountcastle, and Konrad Akert as well as many others. It was my first encounter with the “grand world.” The intimate setting of this week-long conference—complete with its necessary improvisations and inspired by the surroundings—allowed us as young researchers to get to know these top-level scientists from their best side. The Neubeuern Meeting was a historical event, as all those still alive will certainly attest.

Shortly thereafter, Creutzfeldt accepted an offer from the Nobel laureate Manfred Eigen to join him as a director of the newly founded MPI for Biophysical Chemistry in Göttingen. Creutzfeldt offered me a position in his new department, but I hesitated, partly because I felt the need to forge my own way. Also, the ability to combine clinical research in neurology and psychiatry with basic research—a distinguishing feature at the Munich institute—was particularly important to me. Munich offered unique chances for collaboration, some of which later bore fruit. But perhaps the real reason behind the decision to stay in Munich happened on a more personal level: We loved our life there, and Francine had just begun to grow roots in this town.

Ambiguous feelings began to surface about my decision to remain at the institute. Most of my colleagues had left or were about to leave. The farewell party for Creutzfeldt late in 1971 was a particularly sad event, although it also marked the beginning of a new epoch in many ways. Bert Sakmann, who had made a detour to the lab of Bernhard Katz before moving to Göttingen, joined Creutzfeldt’s new department together with Erwin Neher. (The consequences of their teamwork—logical continuations of the approaches Neher had practiced with Lux and Sakmann with Katz—led to the 1991 Nobel prize, awarded for the invention of the patch clamp technique and the discovery of single channel gating currents.) Lux was named the new director of the MPI neurophysiology department and accepted me as a postdoc. He made it clear that he valued my cooperation but he also encouraged me to independently pursue my research interests, which differed from his. He allowed me to build my own lab in an annex, where I had use of three adjacent rooms. Because Creutzfeldt had generously left behind most of the needed equipment, I was able to continue my experiments within a short time.

Another decisive event that spurred me along the path toward independence involved my recruitment into the Sonderforschungsbereich Kybernetik (collaborative center for cybernetics). Financed by the Deutsche Forschungsgemeinschaft (German Research Council), this consortium of physiologists, mathematicians, physicists, and behavioral psychologists aimed to apply methods developed in the young field of cybernetics to the investigation of the nervous system. It was created to unite behavioral work being done at the MPI for Behavioral Research in Seewiesen³ with psychophysics and mathematical modeling from the physics departments at the Technical University of Munich. My participation in this long-term project (which lasted 12 years) profoundly influenced my thinking, kindled my interest for theoretical approaches, and provided a rich intellectual environment. It also ensured my growing independence by providing me with the necessary funding to hire personnel and buy my own equipment. Most important, the consortium required me to teach neurophysiology to students in nonmedical disciplines. This forced me to structure formal lectures, chair oral and written exams, and eventually to recruit PhD students on my own.

These academic activities ran parallel to my duties at the medical faculty, where I was required to conduct practical courses in preparation for the Venia Legendi (certification to teach at the university level). These practical courses aimed at exposing medical students to in vivo experiments on anaesthetized rabbits. Even in the 1970s, fierce discussions erupted over the ethical use of in vivo demonstrations to explain physiological processes. Sometimes, students would refuse to participate, thus prompting the need for in-depth discussions. The most efficient argument that changed their mind was not that something useful would be learned that could affect their performance as an MD but rather that such rabbits usually are eaten and sacrificed under much less humane conditions. For many students, these courses provided the first, and for many the only, opportunity to study live critical processes in a controlled setting and to experience the extent to which cardiovascular functions need to be coordinated by the nervous system to support life. Despite the options that virtual reality simulations are able to create, I am convinced that a minimum of such direct, hands-on experience is necessary in medical training, especially for MDs who do not go into surgery but may still have to cope with critical situations.

Excursions from Science

As of about 1974, the immediate future seemed reasonably secure and I was well situated to pursue my own research agenda. Before describing the directions that this took, I wish to highlight several nonscientific events that contributed to my development.

The first event concerns the dichotomy between medical practice and scientific enquiry. Almost immediately after I completed my clinical training and was licensed as an MD, I began to regret the distance from patients that research demanded. At times I doubted whether I should do something more useful and less frustrating than science and become a clinician. In search of a compromise, I arranged to work in my father’s practice as a general practitioner twice a week: on Monday and Friday evenings, when his practice was open to those who could not come during the day. I continued this routine until I moved to Frankfurt in 1982, not only because it was extremely rewarding on a personal level, but because it provided a much-needed balance to research.

The second concerns a series of collaborations that emerged out of the neurological department of the institute, which I attribute to the openness and charisma of Yves von Cramon, a neurologist (and later director at the MPI for Cognition and Neuroscience in Leipzig). Yves was a walking encyclopedia of human brain anatomy and neurological syndromes, and, as a passionate clinician, he encouraged me to delve deeper into neurology. His passion was infectious, so I donned a white coat and took over a neurology ward with 12 beds, under the naïve assumption that I could accomplish my clinical duties in the morning and conduct research in the afternoon. The ward was run by excellent nurses, and I had no acute patients. This experiment lasted for about a year and could have lasted longer, even though it did slow down my research and divert my attention. The main problem, however, was that I was unable to cope with the daily switches between roles. In the morning, as a clinician, I had to reach clear and definitive decisions, often on the basis of weak evidence, and stick to them for the sake of therapeutic continuity. I also needed to conceal my doubts so as not to jeopardize any positive effect of the patient–doctor relationship. Then as a scientist, in the afternoon, I needed to transform into a skeptic who doubts, despite robust evidence, and constantly worries about alternative interpretations. I experienced why it is so difficult to nurture, in one and the same person, the different mind-sets required for clinical and scientific work (for an extended discussion on this topic, see Bleuler 1970).

The third incident unfolded after I received an entirely unexpected letter from the army. Informed that I had been passed over for military duty after I completed high school, I was now being called up to fulfill my military service as a medical doctor for the next 18 months. The army desperately needed licensed MDs. The fact that I was running a lab and was responsible for my first PhD students was completely irrelevant to the army. What eventually confined this disaster to a period of six months was the fact that I was engaged as an academic teacher. I was sent to an army post in Munich, where, to my great delight, I ran into Bert Sakmann and a few others with whom I had studied. After the usual march-and-stand-still routine, we were instructed in the duties of a military MD; in particular, triage and the top priority of reestablishing combat fitness. This all happened at the peak of the Vietnam War, and much of the film material used for instruction had been produced by the U.S. Armed Forces. We found ourselves in an absurd and surrealistic world, yet it was all too real. After two months of basic training, I was promoted to the grade of a captain and ordered to the army hospital, where I was to serve as second-in-command at the psychiatry division. To my great surprise, I was my own boss, with my own adjuvant. I could dispose over an official car including a driver (something which has never happened to me since), and I could discharge soldiers from the army without asking anyone’s permission. All in all, the episode was highly instructive and much less catastrophic than I initially imagined it would be.

The First International Invitations

After my early work on the intracellular analysis of the retinal and extraretinal control of thalamic transmission made it over the Atlantic, I received two wonderful invitations that had long-lasting consequences. The first was an invitation to attend a symposium of the Neuroscience Study Program in Boston.⁴ This trip, my first to the United States, brought me into contact with eminent colleagues. I recall one remarkable discussion between János Szenthagothai and David Hubel: Szenthagothai presented his fantastic Golgi pictures of the cerebral cortex, showing for the first time the horizontally spreading axon collaterals of pyramidal cells in the visual cortex, which could span several millimeters. Hubel and Wiesel had confirmed, in the visual cortex, the columnar organization first described by Mountcastle in the somatosensory cortex. Both this strict topographical organization and the small size of the receptive fields seemed incompatible with any lateral interactions. Thus, Hubel argued that these long collaterals could not have a function in information processing but rather they probably served some mechanical or trophic purpose. Cortex was considered a feed-forward filter network, and the contextual integration of signals from outside the classical receptive field was not thought possible. Szenthagothai postulated such integration, but it took several decades before the evidence was forthcoming. Charles Gilbert, working with Torsten Wiesel at Rockefeller, was among the first to analyze with modern tracing techniques and electrophysiological methods the anatomy and function of these tangential connections and demonstrated their critical role in shaping the responses of cortical neurons to contextual stimuli.

The second set of invitations took me around the world: I was invited to a satellite symposium organized by Peter O. Bishop in Canberra, Australia, as well as to the main meeting of the IUPS (International Union of Physiological Sciences), which was to take place in New Delhi in 1974. An additional invitation followed from the Instituto Venezolano de Investigaciones Científicas (IVIC in Caracas, where an impressive number of prominent neurobiologists were to gather, among them Horacio Vanegas, who had spent some time at the Munich institute). These invitations were too tempting to pass up so, although the children were only about four, Francine and I decided that I should go. I booked a ticket on PanAm flight number 1 (the designation for an around-the-world flight) and departed for Caracas. In addition to the IVIC meeting, I met the family of Ernst Poeppel’s wife. (Ernst and I shared a miniscule office in Creutzfeldt’s lab before he left to be the head of the medical psychology department at Munich University.) From Caracas I flew on to Mexico, where Francine joined me for two weeks. We explored the Yucatan and the Sierra Madre mountains, and visited Pablo Rudomin, the famous electrophysiologist, and his wife, who was a painter. After Francine returned home, I continued along the West Coast, stopping in San Diego to give a talk at the Salk before going to San Francisco and Stanford to visit Christian Guilleminault (a sleep researcher and friend), who worked in William Dement’s lab (one of the pioneers of sleep research). From there, I flew on to Australia where I met up with Creutzfeldt and became acquainted with the Canberra school. After Canberra, I originally had planned to go hiking in Nepal before the IUPS meeting. Because my hiking gear had been stolen in Mexico, I accepted Creutzfeldt’s proposal to spend a few days with him in Thailand. Our visit in Bangkok was fascinating for many reasons, not the least due to Creutzfeldt’s offer to address him by his first name.⁵ From there Creutzfeldt went straight to Delhi, while I took a side trip to Kathmandu (which was still a medieval village) to explore its surroundings by bike. Over the course of this trip, my European chauvinist prejudices diminished greatly as a result of these fascinating encounters with different ancient cultures. It left me to ponder, on more than one occasion, the relevance of my highly focused science, the mosaic stones of which I carried with me on slides, which seemed so completely disconnected from the marvels I witnessed. After spending the required bribe, I took a flight to Delhi that had a long stopover in Calcutta—an experience that left me deeply depressed, even more so after I participated in the luxurious reception ceremonies that awaited in Delhi, which exceeded anything that I could have possibly imagined.

Eight weeks after my departure, I returned home. My view of the world and my place in it had profoundly changed. Everything had shrunk and become unfamiliar, and it took time to figure out what really mattered.

Difficult Decisions

During these formative years in Munich, I received two offers for tenured chairs. The first came, in 1972, from the University of Bielefeld to lead the Department of Human Biology. Although I did not have a permanent position in Munich, I declined the offer straight away because I felt that it had come too early in my career.

The second followed in 1976 from the Brain Research Institute in Zurich, which was headed up by Konrad Akert and Michel Cuenod. The decision surrounding the Zurich offer, however, was much more difficult. This process began with my participation at an international conference in Davos, Switzerland, at which all the principal investigators from the Zurich Institute were present. Unaware that the conference was a type of exam or interview, I embraced the scientific discourse and enjoyed the surroundings.⁶ I was drawn to the offer, not the least because of the charisma of both Akert and Cuenod. The research environment was excellent, and I already knew many of the colleagues (e.g., Klaus and Marie Claude Hepp), which would have helped the transition. Those who I consulted all advised me to take the offer, as it was clear that Munich could not offer a long-term perspective. However, I felt that I had what I needed (at least for the present) in Munich: My lab was the right size and cooperation with the clinic was excellent. Above all, my family was well adjusted. The decision was made in Dubrovnik, at the International Neuropsychology Symposium (in 1979), just after I had been elected to the society. Thus, we continued to live and work in Munich.

The Shift to Developmental Neuroscience

My research into the lateral geniculate was drawing to an end because I had gone as far as I could (and would not resume until after I moved to Frankfurt and had the means to investigate in detail the mechanisms underlying the nonretinal modulation of thalamic transmission). For the final experiments in the thalamus, I greatly profited from the extraordinary expertise in membrane physiology of Lux, who taught me how to build highimpedance preamps and bridge circuits for current injection as well as how to fabricate ion-selective electrodes. We used these to measure extracellular potassium concentrations to explain the origin of the depolarization of optic tract terminals associated with reticular stimulation, which was considered to be an indication of presynaptic inhibition. Showing that this depolarization of primary afferents was caused by increases of extracellular potassium, we were able to disprove the hypothesis of presynaptic inhibition, which was popular at the time (Singer and Lux 1973).

My next goal was to trace the flow of visual responses beyond the geniculate, applying the same combination of methods as before. Aided by a real computer—the famous PDP-8 with 8 K core memory and DEC (Digital Equipment Corporation) tapes for data storage—my group performed current source-density analysis of field potentials evoked by light and electrical stimulation, a method implemented in the lab by my first postdoc, Ulla Mitzdorf (Mitzdorf and Singer 1978). This procedure greatly facilitated the laminar analysis of signal flow in cat and monkey visual cortex and enabled us to confirm the serial flow of signals from layer IV to supraand infragranular layers. It also led to the discovery of monosynaptic activation of complex cells. The greatest surprise came from area 18, which was thought to be a higher order visual area: We found that it was activated by a direct input from the geniculate, similar to area 17. Conduction time analysis indicated that this input was provided exclusively by ganglion cells of the Y-type, the homologue of the magnocellular pathway in primates. Because of the nonlinear properties of this ganglion cell type, monosynaptically driven cells in layer IV of area 18 looked like complex cells. This observation led Hubel and Wiesel to suggest that area 18 was a secondary area, similar to monkey V2. According to our research, however, area 18 was a primary area that worked in parallel to area 17 and is specialized in the processing of fast movements. This work, conducted with my first PhD student, Felix Tretter, and my second postdoc, Max Cynader, was reported in the Journal of Neurophysiology (Tretter et al. 1975a). We were overwhelmed by the difficulty of establishing clear relations between receptive field properties and the complex interplay of excitatory and inhibitory potentials. The methods that had worked well for the geniculate were insufficient to address the complexity of cortical circuitry. We lacked both theory and techniques. Thus, I decided to change strategy and delve into the development of this structure, under the assumption that studying the maturation of functions would facilitate the approach.

Around this time, Pettigrew (1974) and Blakemore (Blakemore and van Sluyters 1975) published data on the effects of selective rearing in the orientation selectivity of cortical neurons of kittens, triggering a fierce controversy with those who claimed that the cortex was hardwired and not susceptible to experience-dependent modification. If everything is determined right after the eye opens and can degenerate only as a result of deprivation, as shown by Hubel and Wiesel (1970), studying development would only serve to complicate, rather than simplify, the search for principles. Clarity was needed, and we decided to verify to which extent orientation and direction selectivity were expressed at birth and modifiable through experience. In our experiments, dark-reared kittens were placed for a few hours each day on a stationary chair positioned in the center of a rotating drum, the inside of which had been painted with regularly spaced stripes. We observed that this selective experience induced a strong bias in the distribution of orientation and direction preferences (Tretter et al. 1975b). We also found, quite unexpectedly, that about 30 percent of the cells in supragranular layers developed multiple receptive fields, the spatial separation of which corresponded precisely to the spacing of the stripes of the grating. We hypothesized that this was due to selective strengthening of long-range reciprocal excitatory connections between the coherently activated columns according to a Hebbian mechanism (Singer and Tretter 1976). This finding greatly influenced our future projects, for it suggested that experience has a constructive effect on the development of cortical circuitry, that the modification of cortical circuitry followed Hebbian learning rules, and that the long-range collaterals (described earlier by Szenthagothai) actually had a function (see above) and served lateral integration. Together with Joseph Rauschecker (my second PhD student), we set out to prove that the selective strengthening of excitatory connections depended on correlated pre- and postsynaptic activity using monocular deprivation, restriction of vision to contours of a single orientation with cylindrical lenses, interocular rivalry, and strabismus as paradigms (Rauschecker and Singer 1979, 1981). To derive a more comprehensive picture of columnar remodeling, we applied the recently introduced C14 deoxyglucose method, which revealed that most of the functional remodeling occurred outside layer IV, most likely at the level of intracortical connections (Singer et al. 1981). This finding was confirmed with the current source-density method (Mitzdorf and Singer 1980; Kossut and Singer 1991). Because there were no image-processing systems at the time, we reconstructed serial sections by staggering photographically magnified autoradiographs or hand drawings between stacks of acrylic glass plates. These compact blocks created impressive three-dimensional representations of the columnar system of cat visual cortex and clearly revealed the massive influence of experience on the functional architecture.

In the mid-1970s, Ruxandra Sireteanu and Michael von Grünau joined the lab and we complemented the electrophysiological studies in selectively reared kittens with behavioral testing. We discovered that strabismic kittens had strongly reduced numbers of vertically oriented neurons and that this coincided with reduced visual acuity and contrast sensitivity for vertical gratings in both kittens and strabismic human subjects (Sireteanu and Singer 1980). Thus the relative number of feature detectors seemed to matter for perceptual functions.⁷ Psychophysics in human subjects with altered visual experience became an important line of research in the lab that nicely complemented the electrophysiological studies in kittens and attracted experts from abroad, such as Daphne Maurer.

In humans, we attempted to find perceptual correlates of the experiencedependent modifications that we had observed in kittens. One of Sireteanu’s students, Maria Fronius, suffered from strabismic amblyopia but was nonetheless an expert tennis player. To approach this apparent conundrum, we assumed that her peripheral visual field had preserved binocular functions. We knew that neurons in the suprasylvian cortex of strabismic kittens retained binocular receptive fields, presumably because these fields are large and overlap despite squinting (Sireteanu et al. 1981), thus allowing for partial fusion. We tested binocular functions in Fronius and found that she was perfectly able to perceive motion in depth, although she had no stereopsis for stationary patterns.

Having observed the dramatic functional and structural consequences of deprivation, we wondered why nature made development dependent on experience, thereby exposing it to the fatal consequences of deprivation. Because we had observed that activity-dependent changes in circuitry followed a Hebbian correlation rule, we proposed that experience-dependent pruning was used to ensure precise convergence of afferents from corresponding retinal loci on common binocular target cells in visual cortex—the prerequisite for binocular fusion and stereopsis. This convergence cannot be achieved with the necessary precision by genetically encoded markers because retinal correspondence depends on the final size of the skull and interocular distance. Our assumption was that afferents coming from precisely corresponding retinal loci should convey highly correlated responses because they are driven by the same contour in the visual field. Thus, we hypothesized that experience serves to select from a repertoire of overlapping afferents, those that exhibit the best correlated activity patterns, and that it does so using a Hebbian correlation rule. Such a selection mechanism would only work, however, if plasticity was supervised, because it requires that the eyes are still and fixating. Therefore, we began to search for mechanisms that could gate developmental plasticity.

Michel Imbert and his group in Paris had established that ocular dominance changes could not be induced in anesthetized, paralyzed kittens, thus suggesting that driving cortical cells with light stimuli is insufficient to induce synaptic changes. Reasons proposed were that the Hebbian process had a threshold that is reached only once the excitability of cortex is raised by the ARAS or that more specific corollary signals are required about the state of the oculomotor system or the position of the eyes. Together with Pierre Buisseret, we tested the latter and disrupted the proprioceptive input from the extraocular muscles bilaterally by severing the ophthalmic branches of the trigeminus intracranially as they exited the Gasserian ganglion. This did not interfere with eye movements, which are ballistic and thus not controlled by feedback from the muscles. It did, however, completely prevent ocular dominance shifts following monocular deprivation and strabismus (Buisseret and Singer 1983). We concluded that input from the extraocular muscles enabled plasticity, in agreement with our working hypothesis. Later I found that stretching the extraocular muscles after detachment from the eyeballs caused short latency responses in cortical neurons: (a) stretching the lateral rectus muscles activated cells with vertical receptive fields; and (b) stretching the superior and inferior recti triggered responses in cells with horizontal orientation. Unfortunately these findings have not been validated, by me or others, although it might clarify the enigmatic role of this proprioceptive system.

Rather than investigating further the pathways that mediate these proprioceptive effects, I pursued the stated hypothesis to see whether it was possible to reinstall plasticity by pairing reticular stimulation with monocular light stimulation in anesthetized, paralyzed kittens. This worked, and we obtained ocular dominance changes after a few hours. We were able to follow the time course of these changes by repeated comparison of evoked potentials elicited with electrical stimulation of the two optic nerves (Singer and Rauschecker 1982). These results suggested that the overall level of excitability or some internally generated permissive signals also played a role in gating synaptic plasticity, a hypothesis that we continued to investigate in detail in Frankfurt.

In the late 1970s, Uri Yinon contacted me to ask whether we could help him record from the visual cortex of cats in which he had induced a rotation of one eye while they were young to study compensatory processes. To our great surprise, these animals displayed no ocular dominance shift toward the open rotated eye, even though the other eye had been sutured closed to ensure use of the rotated eye: neurons in the visual cortex responded to stimulation of either eye and had normal receptive fields. This suggested that retinal signals are able to induce Hebbian modifications only when identified as appropriate in a more global visuomotor or polysensory context. Because of the heterogeneous history of these cats, we repeated the experiments and confirmed the findings (Singer et al. 1982a, 1982b). A more quantitative analysis of response properties revealed, however, that cell responses were more sluggish and less well-tuned than in normally reared animals, conditions resembling to some extent those previously observed in binocularly deprived cats. This substantiated the outcome from behavioral tests: Initially, the animals exhibited ocular and head nystagmus, but after a few days, they appeared to neglect vision altogether, although they kept their rotated eye open, walked over visual cliffs, and showed strongly reduced visual-orienting behavior. They got along very well in the colony, however, apparently relying on their whiskers and auditory cues. We hypothesized that the mismatch between retinal signals and eye, head, and body movements as well as other sensory maps (especially the vestibular coordinates) would prevent the generation of permissive extraretinal signals, which seemed to be required to gate experience-dependent plasticity. This evidence for the implementation of such supervising systems motivated much of the developmental work that was later continued in Frankfurt.

The Move to Frankfurt in 1982

The MPI for Brain Research in Frankfurt has a long history. It is considered to be the continuation of the Kaiser Wilhelm Institute for Brain Research, which was established in 1914 by Oskar Vogt and housed in Berlin-Buch until the end of World War II. After the war, its various departments were dispersed throughout Germany. In 1948, the Max Planck Society was founded to succeed the Kaiser Wilhelm Society and in 1962, the MPI for Brain Research was established in Frankfurt to reunite the departments of neurobiology and neuropathology under the direction of Rolf Hassler and Wilhelm Krücke, respectively.

In keeping with its statutes, the Max Planck Society sought advice on possible future scientific directions for the institute in advance of Hassler and Krücke’s retirement. An international commission was convened, chaired by the neuroanatomist Max Cowan, and in 1981, the decision was reached to reorient the institute’s focus toward basic neuroscience by creating departments in neuroanatomy, neurophysiology, and neurochemistry. Heinz Wässle (who headed up an independent research group in the Miescher lab at Tübingen) and I were chosen to establish departments in neuroanatomy and neurophysiology, respectively, and Heinrich Betz joined us in 1991 to initiate the neurochemistry department.

For me, to be nominated as a Max Planck director at the age of 39 years was the fulfillment of the boldest dream any young scientist could dare to have. Equally, however, it was also the source of many doubts: Would I be able to fill the lab and run a department, could I continue running experiments myself, would there be close cooperation with clinical partners, would Francine be able to find a job to match the one she had in Munich, could the twins cope with losing their friends and successfully enter a very different school system,⁸ would such a move represent what we truly wanted and needed at this stage of our lives? This time, the decision was clear: I did not hesitate to accept the honor.

Most of the members from my Munich lab were unable to move to Frankfurt for personal reasons. The only experienced scientists that accompanied me were Sireteanu and von Grünau, both experts in psychophysics.

The move brought changes on many levels, and I cannot emphasize enough my gratitude to Francine during this time: Her support, compassion, and determination steered our family through this turbulent phase and put all my worries to rest. It did not take us long to recognize and value the open-minded culture in Frankfurt—its tolerance, progressive cultural scene, novel brand of friends—and the freedom that this new start enabled. Francine and I adapted well, but the move proved difficult for the twins, who even to this day consider Munich (and Bavaria) to be their home. Francine kept her position at the radio, a decision that introduced mobility and new perspectives into our lives. To carry out her professional duties, she needed to be physically present in Munich for one week every month. During this time, I assumed full responsibility for our teenage daughters, from age 12 onward until they left for the university. A few years after our move, Francine also was appointed as lecturer at the university of Frankfurt.

Institutional Legacies

Upon arrival, Heinz Wässle (who had started work a few months earlier) and I encountered a functional institute: The animal house, the electron microscopy (EM) group, the administrative units, and the workshops were all staffed and functional. We immediately began by integrating the scientists and technicians whose contracts exceeded those of the retiring directors into our departments. Among these, Manfred Klee and Wolfgang Precht moved into my department. Klee, a highly renowned neurophysiologist, was one of the pioneers of slice preparations and investigated the cellular mechanisms and the pharmacology of epilepsy. Precht studied the vestibular system. From the onset, my department had considerable and complementary depth in expertise and, for a while, the majority of staff positions in the department were filled by colleagues who were already at the institute. I also inherited technical staff with great expertise in histology.

The institute was located in Niederrad (a district of Frankfurt positioned along the southern banks of the Main River), directly across from the medical complex of the Goethe University. The critical mass of the institute was enhanced through its association with the Edinger Institute.⁹ Originally a part of Kruecke’s department during his tenure as a MPI director, this neuropathological institute became part of the Goethe University upon his retirement. Led by Professor Schlote (an expert electronmicroscopist), it retained office space in our institute, occupying one complete floor. Another group that was carried over from the previous directors was the research unit of Professor Heinz Stephan, a renowned comparative neuroanatomist who studied the evolution of the vertebrate brain and had a fantastic collection of brains and histological sections from a large variety of vertebrates.

The institute also contained various artifacts throughout the building. The walls of the corridors on each floor of the five-story building, for example, were lined with wooden cabinets that contained thousands upon thousands of histological slides from patients. These slides had been collected over the entire course of the institute (i.e., from its beginnings in Berlin-Buch to the present). When Wässle and I arrived, we delegated the responsibility for these collections to the Edinger Institute, oblivious to the horrible legacy concealed therein.

A few years after our arrival, the historian Goetz Aly obtained evidence that made him suspect that some of the specimens in these collections had been prepared from the brains of victims of the “euthanasia” program carried out by the Nazis. Aly came to the institute, studied the dossiers, and proved by correlation (using data from the respective clinics) that our collections included slides from at least 34 people who had been killed by the Nazis and whose brains had then been examined by scientists at the Kaiser Wilhelm Institute for Brain Research in Berlin-Buch. Recent research carried out by Heinz Wässle revealed that these collections most likely contained samples from several hundred victims of the euthanasia program.

Once again, the indelible mark from Germany’s horrendous past came back into full focus—this time accompanied by an abyss created under the guise of scientific enquiry.

Alexander Mitscherlich, one of the founders of psychosomatic medicine and a member of the Frankfurt School, has written extensively about the crimes committed by our colleagues in the name of science during the Third Reich (e.g., Mitscherlich and Mielke 1949). However, the presence of concrete evidence to these odious crimes, housed in the wooden cabinets that lined the very halls of our institute, came as more than a shock to us. Although earlier we had delegated responsibility for the collections to the Edinger Institute, Heinz Wässle and I assumed full responsibility. It proved impossible to determine which slides were taken from the victims versus those that been extracted from patients who had died from disease. Thus, all material that had been collected between 1933 and 1945 was locked away in steel cupboards until a proper course of action could be determined. Concurrent with our experience, several other neuropathological institutes in Germany reported similar findings, and the matter quickly escalated to an issue of national concern.

In 1990, all slides prepared during the years 1933 and 1945 were buried in a grave at the Waldfriedhof in Munich, and a commemorative stele was erected to bear witness to the horrors that were committed in the name of science. Far beyond this, the true testimony to these atrocities must be reflected in how each and every scientist—present and future—approaches our craft: Our actions, and the knowledge that may result, hold great potential to do good, but we must be ever vigilant to protect its potential use from destructive purposes.

History continues to be made at the MPI for Brain Research. In 2014, the institute celebrated its 100th anniversary. For this occasion, Wässle and I worked together with our successors, Erin Schuman and Gilles Laurent, to document its full history. This publication (in German and English) provides, in more detail than is possible here, an in-depth analysis of the abhorrent actions that were conducted in the name of neuroscience in Germany during World War II (Max Planck Institute for Brain Research 2014). It also presents a vision for future directions, as the institute looks to engage in the next exciting episode of research.

Science during the First 10 Years in Frankfurt

Once settled in Frankfurt, my primary goal was to wrap up the studies on extraretinal control of visual transmission and extend the ongoing developmental studies. We set out to elucidate the mechanisms underlying the central gating of use-dependent synaptic plasticity, to find markers determining the time course of the critical period, and eventually to study in vitro the synaptic mechanisms that mediate the Hebbian modifications of synaptic efficiency. As in Munich, my lab combined psychophysics and electrophysiology to which immunocytochemistry and various axonal tracing methods were added. Polyclonal antibodies had become available for an ever-increasing number of proteins and neurotransmitter systems and fluorescent beads allowed tracing of cytochemically identified neuronal projections. In parallel, I wanted to investigate in more detail the synaptic mechanisms responsible for disinhibition in the LGN and the massive facilitation of polysynaptic responses in cortex induced by reticular stimulation. I wanted to conclude the earlier studies on the extraretinal control of thalamic and cortical transmission by identifying the synaptic mechanisms. I also had the intuition that the reticular-activating system might play a critical role in the central gating of developmental plasticity.

The new resources available in the department allowed us to expand our methodological repertoire. Still lacking the expertise in immunocytochemistry, I invited Vicky Chan Palay (whom I had met previously at F. O. Schmitts Fourth Neuroscience Study Program in Boulder, CO) to join us. An expert in cytochemistry and EM, Chan Palay came from Günter Baumgarten’s group in Zurich and generously taught us the basics. Once we were at ease with this technique at the light microscopic level, we were able to benefit from the immense expertise present in our institute’s technicians from the EM unit. We then ventured into combined light–EM immunocytochemistry with Vicente Montero, with whom I was acquainted in Munich, and Anna Dolabella de Lima. Later, after Alain Artola arrived, we implemented an in vitro lab to investigate synaptic plasticity with intracellular recordings in cortical slices and fluorescence-based calcium measurements in dendrites. Here, we profited from the generous help of Manfred Klee and Walter Zieglgänsberger, a personal friend from our common time in Munich. Sireteanu established a state-of-the-art lab for psychophysical studies and pioneered the preferential looking technique to study visual functions in toddlers. Last but not least, improvements were made to our computational infrastructure: We implemented a digital image-processing system for the quantification of deoxyglucose autoradiographs and equipped the physiology labs with PDP-11 computers and custom-made amplifiers, which allowed parallel recording from several electrodes.

During the time in which we set up a cat colony with comfortable darkrearing facilities, we concentrated on the extraretinal gating of thalamic and cortical transmission. The main advances achieved were the ultrastructural identification of the targets of cholinergic, serotonergic, and noradrenergic projections originating in the brainstem and innervating the LGN and the visual cortex. The location of the respective synapses in the synaptic glomeruli of the LGN and at the dendrites of putative inhibitory interneurons within the main laminae and the reticular nucleus of the thalamus agreed well with the disinhibitory action of the ascending projections (de Lima et al. 1985), and we were able to confirm (with iontophoretic studies and intracellular recordings) that acetylcholine inhibited intrageniculate inhibition (Francesconi et al. 1988). The preferential, partially paracrine innervation of supragranular cortical layers by these “modulatory” projections agreed with the strong facilitation of polysynaptic cortical responses that we had identified previously using current source-density analysis. In addition, in the visual cortex, iontophoretic studies confirmed the substantial contribution of acetylcholine to disinhibition and facilitation of polysynaptic responses (Müller and Singer 1989; Lewandowski et al. 1993).

We interpreted these results in the context of the dual action of reticular stimulation. One effect is tonic and leads to a long-lasting desynchronization of the EEG, the electrographic signature of arousal. The other is phasic, lasts for about 200 milliseconds, and closely resembles the pontogeniculo-occipital (PGO) waves associated with saccadic eye movements in rapid eye movement (REM) sleep. Waves with a similar topology and morphology also occur with voluntary saccades and have been addressed as eye movement potentials by Jeannerod and Jouvet. Jeannerod and Sakai (1970) had proposed that the eye movement potentials reflect corollary signals that suppress vision during saccades to avoid perception of selfinduced motion. PGO waves actually had been shown to produce primary afferent depolarization of retino-geniculate terminals, which was taken as evidence for presynaptic inhibition. If reticular stimulation mimics PGO waves, however, our findings suggested a different interpretation. We observed that reticular stimulation facilitates transmission, erasing inhibition, and that the afferent depolarization was caused by activity-dependent increases in extracellular potassium (Singer and Lux 1973). Therefore, we proposed that this corollary modulation of transmission in retinotopically organized visual structures served two functions. First, it appeared to gate transmission as a function of the sleep-wake cycle and arousal by shifting the network from a correlated burst mode into a decorrelated sustained firing mode—a favorable condition for signal transmission and processing. Second, disinhibition appeared to reset the system with each change of fixation by erasing the inhibitory traces left over from the processing of the previously processed image. Saccadic suppression, we thought, simply could be accounted for by the retinal image shift. As the y-system (the equivalent of the magnocellular pathway in primates) inhibits the x-system (the parvocellular pathway) in the LGN (Singer and Bedworth 1973) and as the magnocellular ganglion cells respond vigorously to fast-moving contours, we reasoned that they would shut down transmission of signals in the parvocellular system during saccades.

Development and Synaptic Plasticity

Once our cat colony began to produce offspring, we were able to resume developmental work. One line that we pursued was the search for histochemical markers during the critical period: We concentrated on developmental changes of the modulatory projections from the brainstem and the basal forebrain, synaptic recognition molecules, calcium-binding proteins, glial markers, and nerve growth factors. We observed changes in virtually all the candidate markers examined. Some correlated with the time course of the critical period and might have played a role in its initiation or termination; however, we were unable to differentiate between global maturational processes and specific mechanisms that gated the critical period. These descriptive results reflected well the plethora of molecular changes associated with the early postnatal development of the visual cortex and provided the baseline for subsequent, more targeted studies. They did not allow us, however, to single out the relevant factors. Christian Müller, who investigated glial markers, continued this line of research after he left the lab and made the important discovery that injection of cultured glial cells could restore ocular dominance plasticity in the adult (Müller and Best 1989).

Exciting work followed, as we looked to identify the systems involved in the central gating of experience-dependent synaptic plasticity and to obtain causal evidence for the involvement of these systems. When Mark Bear joined the lab, we combined pharmacological lesions of modulatory pathways with local blockade of receptor systems, using implanted osmotic minipumps for prolonged intracortical delivery of drugs. First, we found that unilateral sectioning of the cingulum prevented ocular dominance plasticity in the lesioned hemisphere. This lesion disrupted the modulatory pathways that ascend from the brainstem and basal forebrain and project to occipital cortex. It also depleted the visual cortex of cholinergic and noradrenergic afferents. At that time, we were not aware of the massive projection from the anterior cingulum to the visual cortex. It is thus conceivable for this projection to have a gating function as well. Similar results were found, but never published, for the fornix: Unilateral sectioning blocked plasticity selectively in the lesioned hemisphere. Thus, a complex network of gating systems may evaluate the adequacy of sensory information and then activate the “printnow” command. Our approach, however, was to search for the final common path. We found that pharmacological lesion of the noradrenergic projection alone was not sufficient to block plasticity, whereas combined blockade of cholinergic and noradrenergic transmission did (Bear and Singer 1986). This accounted well for the earlier finding that reticular stimulation facilitated plasticity, because this stimulation activates both cholinergic and noradrenergic projections. Proceeding a bit further, we tested (with minipump infusion of receptor blockers) the participation of other modulatory transmitter systems and found that serotonergic pathways also had a facilitatory effect (Gu and Singer 1993, 1995).

A major step toward the identification of mechanisms was the discovery, again with minipump infusion of receptor blockers, that inactivating NMDA receptors completely abolished ocular dominance shifts in response to monocular deprivation without affecting the neurons’ responses to light stimulation (Kleinschmidt et al. 1987). Evidence obtained earlier in Munich (Rauschecker and Singer 1981) provided the motivation for this investigation; namely, that synaptic modifications followed a Hebbian correlation rule that evaluated the temporal contingency between pre- and postsynaptic activity. Thus, we were looking for a mechanism that could translate this temporal contingency into a metabolically relevant signal. Phillipe Ascher had just discovered the voltage dependence of the magnesium block of the NMDA receptor (Nowak et al. 1984) and thus this receptor appeared to be an ideal candidate.

The proof that the NMDA receptor played a critical role in mediating developmental plasticity had multiple and exciting consequences. It explained the correlation rule and suggested calcium as the relevant second messenger for both homosynaptic strengthening of active synapses and the competitive heterosynaptic suppression of less active inputs. It also suggested that developmental plasticity might depend on similar mechanisms as those in adult learning. Furthermore, it implied that plasticity had a threshold that could be overcome by increasing postsynaptic depolarization. This, however, presented a problem: We could no longer be certain whether the facilitatory effects of cholinergic and noradrenergic projections were mediated by specific second-messenger cascades, which acted synergistically with the cascades triggered by NMDA receptor-mediated calcium entry, or whether they acted simply by enhancing depolarization of the postsynaptic neurons. The depolarizing action of acetylcholine was well established. We had demonstrated that it reduces inhibition, whereas others had shown that it blocks the M current, a potassium channel. We left it there for the moment, because both interpretations provided explanations for our observations, and returned to these questions only after in vitro preparations were established.

The involvement of the NMDA receptor also suggested that gating of synaptic plasticity might not solely depend on global “now print” signals but also could be achieved through resonance in specific feedback loops. Positive feedback would add to the depolarization of the dendrites and help the plasticity threshold be reached by removing the magnesium block, thereby facilitating plasticity. Previously, we had seen that inputs to cells do not change if the latter cannot respond to afferent drive, because their position in the columnar system does not allow them to respond (Rauschecker and Singer 1979). We also observed that the input from a rotated eye is ineffective. It appeared plausible, therefore, to assume that changes in synaptic efficacy can take only place if input constellations resonate with the response properties of the network upon which they impinge. Thus, input from the rotated eye, even though it matched the response properties of primary visual cortex, may have failed to induce plasticity because it did not match with upstream polymodal networks, and these consequently failed to provide feedback signals that may have been required to lift cells in primary visual cortex above plasticity threshold.

Experience-Dependent Plasticity of Intracortical Connections

Our electrophysiological studies on gating mechanisms were conducted parallel to structural investigations into the plasticity of (a) ocular dominance and orientation maps and of (b) the layout of tangential intracortical connections, thus combining deoxyglucose imaging in cortical flat mounts with axonal tracing (Löwel and Singer 1992). Given the evidence of a critical role for correlated activity in the selective consolidation and strengthening of developing connections, we wondered whether the development of the network of tangential connections might follow the same rules. If so, these connections should selectively link columns that are most likely coherently activated (i.e., columns whose feature preferences match the statistical contingencies of the environment). To test this hypothesis, we traced the intracortical connections with fluorescent beads and superimposed the projection patterns on columnar maps, which were determined using the deoxyglucose method and later with imaging of the intrinsic signal. The outcome was fascinating. In dark-reared kittens, the trajectories of the tangential connections were entirely uncorrelated with the feature maps and ocular dominance columns; however, in normally reared or strabismic kittens, they were highly selective and connected columns with related functional properties (Löwel and Singer 1992). Together with the data from the kittens reared in the rotating striped drum, this was the first demonstration that the statistical contingencies of the outer world get imprinted in the layout of the network of the tangential association connections that convey contextual information from regions outside the classical receptive fields. One must remember that at that time, concepts of predictive coding and Bayesian inference were not yet being discussed in neuroscience. Otherwise, we would have certainly embedded our findings within such a framework. Despite our knowledge of recurrency and feedback from anatomical evidence, we adhered to using feedforward-processing concepts as they were accepted at that stage.

The in vitro Excursion

Our in vivo experiments allowed us to formulate a set of rules to describe the relations between the polarity of synaptic gain changes and the timing and amplitude of pre- and postsynaptic activity (for a review, see Singer 1995). Our hypothesis was that experience-dependent developmental changes in synaptic transmission are based on the same mechanisms as the phenomena of long-term potentiation and depression (LTP and LTD). To test this hypothesis, we extended our methodological repertoire to slice preparations of the rat visual cortex and decided to investigate whether the rules identified in vivo could be confirmed with intracellular recordings. At the time, all we knew was that tetanic stimulation of presynaptic afferents, if long and strong enough, would induce LTP of the stimulated inputs (Bliss and Lømo 1973) and that high-frequency firing of postsynaptic cells, induced by postsynaptic injection of depolarizing current pulses, would depress nonstimulated inputs (Christofi et al. 1993).

On the basis of evidence from the in vivo experiments for an involvement of NMDA receptors in developmental plasticity, we surmised that the polarity of a synaptic gain change should depend on the level of postsynaptic depolarization and that there should be three regimes separated by two thresholds for modifications. With weak depolarization, there should be no change; with intermediate depolarization, active inputs should depress; and with strong depolarization, they should potentiate. Considering local depolarization as the critical variable accounted well for the various outcomes of deprivation, because it is dependent on the activity and efficiency of the stimulated afferents, on the state of other inputs that are near enough to contribute to the depolarization of the spines under consideration, as well as on the strength of inhibition. As a critical variable for the translation of electrical signals into molecular changes at the synapses, we assumed intracellular changes in calcium concentration, differentiating between calcium entering through activated-NMDA receptor channels and voltage-gated calcium channels. We assumed that an intermediate increase should lead to LTD and large surges, requiring NMDA receptor activation, to LTP. This formulation happened long before spike timing-dependent plasticity was discovered by Markram and Sakmann (Markram et al. 1997) and by Mu-ming Poo (Bi and Poo 1999). Back-propagating spikes, the release of calcium from the endoplasmatic reticulum, as well as direct links between metabotropic glutamate receptors and intracellular messenger cascades were out of reach at that time. In a series of experiments, we confirmed the critical role of NMDA receptors in LTP (Artola and Singer 1987), verified the two threshold mechanism (Artola et al. 1990), and identified calcium as the involved second messenger through calcium imaging and application of calcium scavengers (Bröcher et al. 1992; Hansel et al. 1997). We were also able to understand why acetylcholine and norepinephrine facilitated plasticity, as we found that it enhanced depolarizing responses. Finally, by stimulating different subsets of afferents, we confirmed the prediction derived from the in vivo rules: Contingently activated afferents interact synergistically to mutually support their potentiation, whereas asynchronous activation results in competition and heterosynaptic depression of the less efficient input. Thus, we achieved close correspondence between the in vivo and in vitro experiments, which suggested that the mechanisms mediating experience-dependent circuit changes closely resembled those that support LTP and LTD. We reformulated the rule that we had identified in vivo to now consider postsynaptic depolarization and calcium fluctuations as critical variables. This rule, dubbed by others as the ABS rule (Artola-Bröcher-Singer), explains at a mechanistic level the Bienenstock-Cooper-Munro rule (Bienenstock et al. 1982), which had been formulated on the basis of published data on the effects of visual deprivation.

When I think back to this time, I realize that it never occurred to us to write a comprehensive review of these slice experiments. It was a period in which LTP and LTD research in the hippocampus took off and attained great momentum. Increasingly, we became more a part of this research community, and identified less and less with visual neuroscience.

A Decisive Encounter

Before describing further work, a most influential encounter needs to be recalled, as it served to catalyze my contact with the Buddhist world, the Dalai Lama, and Matthieu Ricard.

Shortly after the move to Frankfurt, I was invited to attend a conference in Chile and became acquainted with Umberto Maturana and Francisco Varela who, among many others (e.g., Susanna Bloch, Bernardita Mendez, Marie-Eugenia Moneta, and Jaime Alvarez), had resisted the dictatorship of Pinochet, defending their science at great risk and peril. From them, I learned about the concept of autopoesis, which differed greatly from the behaviorist stance of considering the brain as a stimulus response machine. A pilgrimage on horseback was organized to Pablo Neruda’s house (Chile’s famous poet), which was located on the coast. I fell in love with this remote yet tormented enclave of European culture situated between the Andes and the infinity of the Pacific. Back home, I organized support for Alvarez’s lab in Santiago through the VolkswagenStiftung and shortly thereafter was able to welcome Varela and his family to Frankfurt.

Varela was interested in investigating top-down effects on sensory processing; the autopoesis concept bore a close resemblance to a concept that would be addressed today as predictive coding. This coincided with my interest in the enigmatic function of the massive cortico-thalamic feedback projection from layer VI of the visual cortex to the lateral geniculate body, the anatomy of which had been analyzed in detail by Ray Guillery. While still in Munich, I had investigated, with Michael Schmielau, the effects of inactivating cortex by cooling or applying transcortical DC currents on thalamic transmission. We found that responses of LGN cells to small light stimuli were attenuated by stimuli presented to the nondominant eye, except when these were placed on precisely corresponding retinal loci. In this case, interocular inhibition gave way to binocular facilitation, and this facilitation was blocked by cortical inactivation (Schmielau and Singer 1977). We concluded that cortico-fugal activity reduced interocular inhibition for those channels that conveyed signals that could be fused perceptually, leaving signals from noncorresponding loci exposed to interocular inhibition and rivalry. This suggested that signal transmission in the LGN should be facilitated that matched cortical-processing requirements. In the experiments with Varela, we set up specific cortical activation patterns through patterned stimulation of one eye and then presented conflicting or matching stimuli to the other eye to study the effects of match and mismatch in the LGN. In present-day terminology, we set up a prior, or an expectancy, in the cortex and then probed how this prior affected transmission of information that either corresponded or contradicted expectancy. We observed effects compatible with a facilitation of transmission of matching patterns, but the effects were weak (Varela and Singer 1987). I now suspect that response selection acts on variables other than discharge rate, and if I had the chance to reinvestigate this question, I would look for changes in synchrony.

Varela remained in Frankfurt for two years before leaving for the École Polytechnique in Paris and founding a Centre National de Recherche Scientifique (CNRS) research unit for neuronal dynamics at the Salpétrière. While in Paris, he established close contacts with Buddhist teachers and initiated, together with the Dalai Lama, small workshops to investigate epistemic questions from the viewpoints of Eastern contemplative schools and Western science. This academic adventure gave rise to the Mind and Life Institute,¹⁰ which was cofounded by Varela in 1987.

Varela died of a chronic disease in 2001, far too early. In his honor, colleagues organized a colloquium, and I had the privilege of being invited because of our long-lasting friendship and because Varela also had explored the field of oscillations and synchrony while in Paris. At this conference I met many active members of the Mind and Life Institute, including Matthieu Ricard,¹¹ and decided that I needed to learn more about what practitioners of meditation had discovered, from their first-person perspective, about the functions of the brain and its mental dimension. These encounters sparked a friendship that led us to engage in structured, taped discussions. Later transcribed and published in German (Singer and Ricard 2008), these dialogues form the basis for a more comprehensive book, Beyond the Self, which will appear in French, English, and German.

To gain first-hand experience with contemplative practice, I enrolled in a two-week Seshin retreat in the Black Forest. This experience consisted of sitting in front of a white wall, counting breaths, for eight hours per day. We were not allowed to talk or have eye contact throughout the whole retreat. It was a mind-boggling experience, and it clearly did something to my brain. After a few days, interocular rivalry slowed down so much when I was sitting that I could observe change in eye dominance, and when watching the ant hills on my lonely promenades, I found that I could use my dorsal and ventral stream simultaneously; that is, I saw both the global flow of motion as well as the tiny ants in intricate detail. Later I learned that expert meditators can deliberately induce such states of nonfocused attention.¹² After the retreat, I returned to my normal routine. My coworkers, who had not known of the retreat, told me months later how puzzled they were about my (admittedly transient) transformation into a patient and calm person.

More Decisions

After the move to Frankfurt, I thought that life would not challenge me with further bifurcations, but I was wrong. In subsequent years, I received three tempting offers to return to Munich: the first to succeed my former mentor, Lux, who retired in 1992 as the director of neurophysiology at the MPI for Psychiatry in Martinsried; the other two were to serve as president of the Max Planck Society.

My decision to not return to my former institute was reached out of solidarity for the institute in Frankfurt, along with the gut feeling that I should not tread in my own footsteps again. The decision to decline the presidency of the Max Planck Society was much more difficult. I felt a strong obligation to give back to the society that had supported me throughout my career, yet I was unable to sever my ties with research. You see, unlike other scientific societies, the presidency of the Max Planck Society is a full-time administrative position, one accompanied by the cessation of a person’s research career. The request, made for the sake of continuity, involved service for two terms (each lasting six years), which would have precluded a return to science. The first call came much too early and, for this reason, it was out of the question. However, the second call would have brought me close to retirement age, which at that time was 65.

I seriously considered accepting the second call and tried to work out a way to accept it. My only request was that a solution be found to permit me to stay involved with my research, by retaining, for example, a small lab. My rationale was twofold: I reasoned that my future interactions with politicians as well as my scientist colleagues would be much easier if I was still recognized as a scientist. I also felt that I needed to resolve various lines of enquiry before completing my scientific career. My request, however, could not be met by the society, as it would have necessitated a redefinition of the presidency with an accompanying change to its constitution. So, again, I declined.

A Serendipitous Finding and the Beginning of a New Research Line

Because we had observed both in vivo and in vitro that synaptic modifications could be induced rapidly and reversibly, we wondered whether we could trace these changes in vivo by recording from the same set of neurons while kittens underwent variable regimes of monocular deprivation and reverse occlusion. If feasible, this would allow us to determine the time constants of activity-dependent disconnection and reconnection of inputs to cortical cells as well as to find out whether cortical cells maintained their orientation preference while the thalamic afferents went through a cycle of suppression and recovery. We needed, however, a method that would allow us to record single-cell responses over several days in kittens at the peak of their critical period. I built the same microconnectors that I had used for the chronic EEG recordings during my thesis, but this time replaced the silver ball electrodes with Teflon-coated platinum-iridium microwires. These were inserted in the visual cortex, affixed with tissue glue, and then left floating in a well filled with silicon oil and covered by a layer of bone cement. In this way, we could record repeatedly, over many days, from awake, gently restrained kittens and map the changes in receptive field properties by presenting whole-field moving gratings to the two eyes. These experiments were performed with Laurence Mioche, a PhD student (Mioche and Singer 1988, 1989). We found that disconnection in the deprived eye is rapid and close to complete within eight hours; it did not matter whether monocular exposure was continuous or whether kittens were allowed to have brief naps between exposures. By contrast, recovery after reverse occlusion was slow: it took a few days, including a phase during which cells became entirely unresponsive to either eye. We also observed that after the cells had become reconnected to the initially deprived eye, they exhibited the same orientation preference as before, a finding that we later replicated with optical recordings of intrinsic signals (Gödecke et al. 1997). This suggested that once maps are formed, neurons inherit their selectivity from the embedding network and select appropriate inputs via a Hebbian mechanism.

These experiments led to a most serendipitous finding that changed my research for decades to come: One morning, in late 1985, after I plugged in the connector, no spikes were visible. Endeavoring to discover whether there was a problem with the connections or whether the wire tips were simply remote from cells, I switched off the high-pass filters to see whether field potentials were still being recorded, heard a purring noise, and saw largeamplitude, surprisingly regular oscillations on the scope in the range of 40 Hz. A quick check showed that these oscillations were neither related to the periodicity of the drifting grating that the kitten was staring at nor to the mains. They were induced by visual stimulation but must have been generated by the brain. In addition, they were synchronized across the different wires, some of which were several millimeters apart. I knew that similar oscillations had been described in the olfactory bulb of rabbits while they were sniffing (Freeman 1978). I took a Polaroid screen shot, wrote on it “the visual sniff,” and taped it on the rack, where it remained for several months. I replicated this finding on another monocularly deprived kitten that had spikes on the leads and observed that spiking activity was synchronized to these oscillations, the amplitude of the oscillations reflected ocular dominance, their amplitude was largest for orientations that corresponded to the preference of the cells recorded from the respective leads, and oscillations together with the associated bursts of firing were synchronized across leads that happened to be in columns with similar preferences. My first thought was that we could henceforth use this analogue signal—which later became popular as the local field potential (LFP)—instead of spikes to assess the activity of local groups of neurons because it reflected so well the filtered multiunit activity. This would make it possible to record simultaneously from as many sites as desired and thus circumvent the problem of having to fish around for neurons—the main challenge in these chronic experiments.

My second thought was that these synchronous oscillations might provide a solution to the “binding problem.” Over the years, I had had close contact with Christoph von der Malsburg and was aware of his work on the cocktail party effect. He had proposed that segmentation might be achieved by exploiting the temporal parsing of utterances of different speakers. At that time I was unaware of Milner’s suggestions, published a decade earlier (Milner 1974), that the binding problem could be solved by synchrony. According to my intuition, it was highly plausible, for several reasons, that the brain could use temporal contiguity to encode semantic relations. First, there was the trivial evidence that temporally contingent events in the outer world are bound together. This implies that synchronously arriving signals are bound. In our previous psychophysical experiments (Wilson and Singer 1981; Altmann et al. 1986), we had observed that simultaneously presented visual stimuli were interpreted as belonging together. Second, we had ample evidence from the developmental studies that correlated activity is used as signature for the identification and selective association of inputs that convey semantically related information. In these cases, correlations were induced by contingencies in the outer world, but I reasoned that the brain could use the same mechanism to encode internally generated relations. All that would be required would be to impose temporal structure on self-generated activity and to synchronize those responses bound for further processing. Because the observed oscillations imposed temporal structure on the spike trains and apparently could become synchronized over large distances, I became excited at having discovered an important principle. The readout of correlated firing did not appear to be a problem because we had seen, in all experiments on synaptic plasticity, how well cells differentiated between synchronous and temporally dispersed inputs, both for the transmission of signals as well as for the selective association of inputs through LTP and LTD. If synaptic plasticity followed the Hebbian principle—and all our evidence supported the notion that the polarity of synaptic modifications depended on the degree of correlations—then there seemed to be only two solutions: Either the brain uses temporal correlations among discharges as a signature of relatedness all the time (in which case it has to impose temporal structure on responses that are not timed by external stimuli) or it has to use an entirely different strategy for the detection, encoding, and storage of relations among signals that lack temporal structure. I much preferred the first hypothesis as the more parsimonious.

A few months after the discovery of the “visual sniff,” Charles Gray joined the lab in early 1986 as a postdoc, wishing to participate in plasticity experiments. He arrived from J. E. Skinner’s lab in Houston, TX, where he had studied the modulation of oscillatory activity in the rabbit olfactory bulb by efferent pathways and developed a few simple programs for time-series analysis, such as auto- and cross-correlations. I showed Gray the “visual sniff” and we decided to analyze this phenomenon in greater depth rather than concentrate on plasticity. In a sense, the sniff-related oscillations in the olfactory bulb had the same effect as our oscillations—both imposed a precise temporal structure on sustained responses to stimuli that were continuous.

Peter König, Andreas Engel, and Thomas Schillen joined the lab soon thereafter and all of us became increasingly fascinated by the rich phenomenology of these stimulus-induced oscillations. Particularly exciting was the fact that synchronization probability was not a fixed property of a given cell pair; it depended on stimulus configurations that corresponded to certain simple Gestalt criteria for perceptual grouping. It was clear that we were not looking at trivial synchrony caused by common input but instead were observing the result of dynamic network interactions. We all shared the feeling that we were onto something potentially very important, and we wanted to nail it down carefully before presenting our results in a high-impact publication. We submitted the first results on the gamma oscillations showing the tight correlation between LFPs and spike responses to the Proceedings of the National Academy of Sciences (PNAS) in early 2008 and engaged in an extremely time-consuming review process, as the reviewers did not share our enthusiasm. Still, we did not want to go public by publishing in a fast-track journal, so we persevered with the reviewers. The first public communication of our results came at the Second International Brain Research Organization (IBRO) Conference in Budapest in summer 1987. We did, however, present our findings at an in-house symposium in autumn 1986 to which colleagues from neighboring universities were invited, as was our institution’s practice.

Another Stolen Moment, Backlash, and Resultant Tenacity

One of the guests at this in-house symposium was a colleague from Marburg. As we learned later from one of his coworkers, this colleague decided on the spot to repeat our experiments but insisted that his plan be kept secret. Because he was using the Thomas multidrive to determine receptive fields in the visual cortex of cats with reverse correlation, he was able to rapidly obtain data from multisite recordings, and this data was similar to ours. At the next European Conference for Visual Perception (ECVP), he presented a poster that looked so similar to what we had presented at our in-house symposium that I believed, from a distance, it to be ours. I turned to Gray, who was attending as well, to ask why he had gone ahead without discussing the matter with the group. Equally surprised to see the poster, Gray replied, “Have a look, it is not ours.”

In addition to the poster, we learned that our colleague had contacted the editor of Biological Cybernetics to obtain fast publication of his results, which ended up being published in December 1988 without reference to the IBRO abstract (Eckhorn et al. 1988). Because of the extensive review process, our first publication came out in PNAS in March 1989 (Gray and Singer 1989), at about the same time as the second paper on the feature selectivity of intercolumnar spike synchronization that we had submitted to Nature and that was processed much faster (Gray et al. 1989).

To say that we felt betrayed by a colleague, whom we trusted, is to put it mildly. Although there was satisfaction to be had in knowing that our results were reproducible, the whole incident left us speechless. Whether the community was less sensitive to such ethical misconduct is difficult to posit at this stage. For our part, we refrained from going public with details, but witnessed how it took several years before the scientific community became aware of the sequence of events.

The discovery of these dynamic synchronization phenomena, summarized in a first review in 1993 (Singer 1993) has been the source of occasional sleep deprivation, even to this day. I vividly remember attending a social of the vision club at an SfN conference in San Diego, where an otherwise-dear colleague had projected a slide taken from the first publication in Nature—PowerPoint had yet to hit the scene—after marking “bullshit” on it with a red felt pen. Later, at another SfN conference in Washington, DC, I was invited to participate in a symposium that had been organized by skeptics to provide a platform for the articulation of counterarguments; here, the oscillations and the associated synchrony were typified as the “exhaust fumes” of the brain that completely lacked all function.

I cannot emphasize enough that further pursuit of our research on oscillations and synchrony would not have been possible had we not enjoyed the freedom granted by the Max Planck Society to follow research agendas that are controversial and far from mainstream. It is unlikely that we would have received the necessary support from extramural funding sources.

Until today, the pendulum of opinions keeps swinging. Although the basic phenomena—once considered artifacts or to be irreproducible—have now been replicated, even in the labs of our most skeptical colleagues, the interpretations of their significance for processing and memory still diverge considerably. One of the primary reasons is that it is very difficult to come up with causal evidence, because these dynamic phenomena are an emergent property of network interactions: they are highly dynamic, nonstationary, and difficult to manipulate in isolation without interfering with other variables (e.g., the discharge rate of neurons). This should not come as a surprise to anyone: The situation is hardly any different for other theories that are based mainly on correlative evidence. Apart from the trivial argument that spikes are necessary for computations and can convey rate-coded information, only a handful of studies at best have shown, in a causal way, that modulating discharge rates influence perception or action (e.g., see Salzman et al. 1992; Brecht et al. 2004).

As time went on, I slowly faded out the developmental studies and in vitro work, except when we saw a possibility to use these approaches to search for a putative role of timing relations and correlations (Leonards et al. 1996). My lab became known as a place where multisite recording techniques were applied to analyze temporal relations among the responses of distributed neurons in search of temporal coding strategies. This attracted students interested in dynamics and, after a while, the whole lab engaged in this new line of research. This phase is intimately related to the work of Andreas Engel, Peter König, Pascal Fries, Pieter Roelfsema, Andreas Kreiter, Winrich Freiwald, Matthias Munk, Danko Nikolic, and Sergio Neuenschwander, all of whom took care of electrophysiology; Thomas Schillen, Sonja Grün, Gordon Pipa, Raul Muresan, and Michael Wibral, with their focus on mathematical methods and models; and David Linden, Peter Uhlhaas, and Lucia Melloni with their studies on healthy human subjects and patients—as well as the students each had supervised. Novel methods were developed for the analysis of dynamic variables in parallel recordings of LFPs and spike trains; time-frequency plots were introduced; and we ventured forth to confirm the existence of the phenomena that we had discovered in kittens, cats, and awake monkeys using noninvasive methods: first EEG and then later magnetoencephalography (MEG) in human subjects. Highlights from this exiting phase include the following demonstrations:

Synchronization probability reflects Gestalt rules for perceptual binding (Gray et al. 1989; Castelo-Branco et al. 2000).

Perceptual phenomena not accountable by rate modulations, such as amblyopia (Roelfsema et al. 1994), binocular rivalry (Fries et al. 1997), and brightness contrast (Biederlack et al. 2006), correlate well with changes in synchrony.

Synchrony can be established over long distances between the hemispheres (Engel et al. 1991a), between areas 17 and 18, as well as between the suprasylvian cortex and the tectum (Engel et al. 1991b).

Synchrony among cortical areas enhances their impact on tectal neurons (Brecht et al. 1998).

Cats trained to perform a visual detection task synchronize oscillations between the visual, parietal, somatosensory, and motor cortex in anticipation of the task with zero phase lag in the beta-frequency range (Roelfsema et al. 1997).

Small changes in the synchronicity of dual stimuli applied to the tectum alter the trajectory of eye movements: synchronous activity was interpreted by downstream oculomotor centers to have been evoked from a single large object, whereas asynchronous responses were interpreted as evoked by two independent objects (Brecht et al. 2004).

Basic findings in cats are reproducible in area MT and IT in awakebehaving monkeys (Kreiter and Singer 1996).

Gamma oscillations and synchrony are exquisitely state dependent, reduce rate variability, and are modulated by attention and expectancy both in cat and monkey (Munk et al. 1996; Herculano-Houzel et al. 1999; Lima et al. 2011).

In slices, the switch between LTP and LTD depend on the precise phase relation between oscillatory pre- and postsynaptic responses (Wespatat et al. 2004).

Cognitive functions in human subjects, such as conscious processing, are associated with topographically specific modulations of power and coherence of gamma oscillations (Melloni et al. 2007).

Measures of power and coherence of oscillations reveal abnormalities in patients suffering from schizophrenia and autism spectrum disorder and correlate with the severity of the syndromes (Uhlhaas and Singer 2010).

Analysis of coherence revealed major rearrangements of functional networks in late adolescence, the period in life when numerous psychiatric diseases become clinically manifest (Uhlhaas et al. 2009).

All this evidence supports the notion that oscillatory patterning of neuronal responses, and the option to synchronize them, is exploited by the brain (a) to encode semantic relations through temporal contiguity, as required for distributed coding; (b) to enhance the impact of responses for response selection and propagation; and (c) to dynamically bind subsystems into cooperating functional networks.

The Reception of Temporal Codes

The first labs to take up the idea that synchrony could play a role in the association of neuron groups into functionally coherent ensembles or networks were those applying EEG and later MEG measurements (e.g., Tallon-Baudry in Lyon, Varela in Paris, Pfurtscheller in Salzburg, and Hari in Helsinki). The likely reason for this is that these measurements are genuinely multisite; they selectively capture activity that is synchronized and oscillatory. Electrophysiologists who applied multisite unit recordings and were interested in oscillations were working on the hippocampus (e.g., McNaughton et al. 1983; Wilson and McNaughton 1993) because of the conspicuous theta rhythm that was suspected to play a role both in coding through phase shifting of discharges (Bragin et al. 1995; Huxter et al. 2003) and in mediating synaptic plasticity by increasing cooperativity through synchronization. A natural interest in dynamics was shared by colleagues working in the auditory system because phase, frequency, and temporal codes are integral features of the stimulus domain. In addition, the documentation of the extreme precision with which the inferior olive neurons detect coincidence of inputs between the two ears for the location of sound sources and the precise timing relations between neurons that control birdsong rendered auditory physiologists much more sensitive to timing issues and temporal relations among neuronal responses than our colleagues in the field of vision. Commonalities were found with colleagues working on pattern generators in the motor system, such as Sten Grillner (Grillner et al. 1991) and Eve Marder (1988), or on dynamic coding in the olfactory system, such as Gilles Laurent (Wehr and Laurent 1996). Thus, although we continued to use the visual cortex as our prime model, we began to lose touch with the vision community as greater points of convergence were achieved with colleagues who studied other model systems. I regretted this development and still wonder why it happened.

The BOLD Phase

In 1995, Rainer Goebel joined us as a postdoc to pursue a specific interest in the binding by synchrony hypothesis. He had developed a simulated multilayer neuronal network that exploited this strategy, won a prestigious prize for scientific computing for this modeling work, and now wanted to get closer to data. His arrival coincided with the first demonstration of the BOLD signal by Belliveau (Belliveau et al. 1991). Hans Hacker, the head of the neuroradiology department on the medical campus in Frankfurt-Niederrad, had a 1.5 Tesla machine (one of the first in Germany) and had obtained visually evoked BOLD responses in collaboration with Francesco Di Salle and Fabrizio Esposito, from Italy. Our labs began to collaborate. Goebel soon realized that this field would require sophisticated software for postprocessing. Because of his ingenious programming abilities, he took on the challenge and developed the Brain Voyager—a program package, now in use worldwide, for which he and the department held the copyright license for many years. With this powerful tool at hand, we were able to look into the brains of humans and, in particular, patients. Even though the BOLD signal was way too slow to assess the dynamics that my lab was pursuing, we expanded this line of research for several reasons. First, Brain Voyager offered us a methodological advance over other groups, and Goebel and his coworkers (especially Lars Muckli, who succeeded Goebel after he left for Maastricht) were eager to exploit it. Second, the option to localize whole functional networks was tempting and could help us constrain conclusions derived from EEG and later MEG measurements. Third, it afforded us the opportunity to interact with clinicians and resume work with patients, work that I had abandoned after moving to Frankfurt.

Coordinated initially by Goebel and later Muckli, the fMRI projects soon became a highly visible branch of my lab’s activities, complementing in many ways the animal experiments. However, they were obviously not suited to directly address dynamics at the time scales that were of primary interest. Still, with the introduction of event-related fMRI, a substantial number of fascinating questions could be addressed related to the dynamic formation of functional networks, cross-modal integration, predictive coding, interhemispheric binding, and binocular rivalry. We implemented the technology required for fMRI studies in monkeys and used this option to analyze functions of prestriatal cortical areas.

Expanding Horizons

European Neuroscience

When I first entered neuroscience, Europe was a continent marked by cultural and linguistic boundaries. Scientific journals (e.g., Experimental Brain Research and Pflügers Archive) accepted papers in German and at European conferences talks often were given in a speaker’s native tongue. The first concerted effort toward integration happened in 1968, when the European Brain and Behavior Society (EBBS) was established by Konrad Akert and Larry Weiskrantz. I joined EBBS early on and served for many years as its secretary. Over time, EBBS attracted a growing number of disciplines, and many national neuroscience societies were founded. This created the need for a larger umbrella organization, and thus the European Neuroscience Association (ENA) was established to unite these groups. ENA had a hard time keeping pace with the newly founded SfN in the United States, which grew faster and at times attracted more European participants to its annual meeting than the ENA was able to do. To strengthen the ENA and increase visibility of European neuroscience, four members of the ENA executive council—Michel Cuenod, Per Andersen, Anders Björklund, and myself—met in Sils Maria, Switzerland in 1987 to establish the European Journal of Neuroscience (initially published by the Oxford University Press, under the editorial direction of Ray Guillery, followed by Michel Cuenod and Berry Everitt, before going over to Blackwell).

Even then, the desired integration was lacking. Thus, during my presidency of the ENA in 1994, plans were set in motion to dissolve the ENA and replace it with a federation of national organizations (Singer 1994; Abbott 1998). Formalized in 1998, the Federation of European Neuroscience Societies (FENS) established practices to unite the individual national societies. The decision was made to convene the main meeting every second year in July (to avoid conflicts with the annual SfN conference) and to provide ample room for annual meetings within the national societies. Since then, attendance at the FENS biannual meeting has increased steadily, and it has become an important platform for European neuroscientists.

Social Conflicts

Throughout my career, I have attempted to meet the ethical and philosophical implications of neuroscience, and its role in society head-on through active engagement with students, the public, the media, and colleagues from the other areas of science (in particular, the humanities). As a scientist, I believe this obligation is mine, as Helmut Schmidt emphasized in his address to the general assembly of the Max Planck Society in 1977:

In a democratic society, lucidity and transparency in science and research is a moral obligation—one needed to propel society forward. It is not the moral obligation of the 60 million citizens to retrieve such knowledge, but rather the moral obligation of the scientist and researcher to bring knowledge to citizens.

Numerous public lectures have exposed the challenges and pleasure of discussing state-of-the-art brain research with laypeople. My activities and best of intentions, however, landed me almost immediately in trouble with animal rights activists, who targeted me pars pro toto, not the least because of the involvement of kittens (and later monkeys) in my research.

Through various discussions with my critics, I realized how little the public actually understood about the reality of research; in particular, how indispensable animal experiments were to basic research. In an attempt to rectify this, I intensified my public activities and penned a cover-page article for the feuilleton (arts and literary) section of the Frankfurter Allgemeine Zeitung, one of the most-read, serious daily newspapers in Germany. My activities did not accomplish their intended goal, but they did strike key neuralgic nodes in some, for my private life was suddenly subjected to heightened dimensions of aggression. A smear campaign was ignited that, to this day, has waxed and waned to varying degrees, marked by a repertoire of public mobbing, personal menaces, nightly telephone stalking, graffiti, and the like. At times, I have required police protection, postal packages have needed to be opened at the police office, routes to work constantly altered, and escort has been required at public events. Once I brought legal charges against a group of activists whom I could identify, but the state attorney advised me to retract the case out of fear that the ensuing publicity would stir up even more trouble.

My former student, Andreas Kreiter, suffered far more than this: Animal rights activists succeeded in blocking ethical approval of his work by government authorities. This forced Andreas to defend his right to conduct science through legal means and necessitated numerous court proceedings. His fight did a great service to all of science, one that cannot be acknowledged or emphasized nearly enough, and he has won every legal battle. But instead of bringing about a resolution, this has served only to expose him even further, exacting a heavy price on Kreiter and his family.

Germany lags behind other countries, especially the United Kingdom and the United States, with regard to public outreach activities in the defense of basic research. I sincerely hope that this will change, now that the major science organizations have decided to take concerted action to counter the excesses of radical antivivisectionists. In spite of my personal experience, and those of my colleagues, however, I remain convinced that rational arguments and transparency are effective and offer the following to lend weight to such optimism.

A few years ago I was invited to give a public talk in Stuttgart, and because a protest had been announced, I was escorted to the hall by police. Rather than entering through the backstage door, as advised by the police, I insisted on using the main entrance and took the opportunity to speak to the few dozen protesters who had gathered in front, inviting them to attend the lecture. They readily agreed and accompanied me inside, as did the police. Before giving my talk, I held a vote among the audience to determine whether science should be the first topic of discussion followed by ethics, or the other way round. The majority opted for science first, and so I began. Once my talk was over, a most lively discussion on ethics ensued, lasting until around midnight. My role during this portion was to moderate the discussion between the protesters and the rest of the audience. At the end of the evening, a woman came up to the stage to express how impressed she was by the evening’s discussion. A few months later, I learned that this woman had passed away and that she had donated a few million euros to the MPI of Brain Research in Frankfurt, which was then turned over to the Max Planck Society. The lawyer who handled her will told me that she initially had given this sum to an animal rights group, but had changed her mind, and will, after attending that public talk in Stuttgart.

Another source of conflict has been, and still is, the naturalistic or reductionist approach taken by the neurosciences to explain the origin and nature of mental phenomena. In 2003, during a keynote lecture to an International Congress of Philosophy in Essen, Germany, I presented commonly accepted concepts on the organization of the brain and spoke about distributed processing, nonlocal representations, and self-organization. At the end, I posed questions related to the difficulties involved in identifying an “observer” or “decider” in the brain as well as in defining a singular convergence center as the seat of the intentional “Self.” I used evolutionary arguments to support the notion that neuronal processes are highly conserved and that the known laws of nature seem to suffice to account not only for the functions of simple but also of highly evolved nervous systems. Then, I left it up to the audience to discern what this all meant for concepts of top-down causation, free will, and ontological dualism.

Although what followed was entirely unexpected, it did reveal how deeply my worldview and self-understanding was influenced by my immersion in the neuroscience community, and how much this deviated from that of the audience. With few exceptions, these were analytical philosophers of the mind with Anglo-Saxon backgrounds, I discovered that the majority of philosophers in the lecture hall were either explicit or clandestine ontological dualists. They perceived my keynote lecture to be a frontal attack on human dignity, and most of my arguments were discarded as category error—a killer argument with which I would be confronted time and again over the ensuing years. A journalist from the Frankfurter Allgemeine Zeitung was in the audience and subsequently initiated a series of front-page articles in the feuilleton, wherein contributors were invited to disqualify my views. I was portrayed as an 18th-century homme machine mechanic, an epigone of La Mettrie. Some of the writers accused me of preparing the grounds for anarchy and the collapse of our legal system, sacrificing the precious achievements of enlightened humanism or, if they were of a particular religious persuasion, of violating basic religious tenets. The arguments were simple: no free will → no responsibility → no guilt → no sanctions → anarchy. A conservative fraction of the federal parliament even queried the Vatican, demanding to know how a scientist who propagated such heretical views could possibly be a member of the Pontifical Academy of Sciences.

Once again I reached out, attempting to explain that a naturalistic view of brain functions is compatible with responsibility, attribution of authorship, sanction of norm violations, and educational programs that utilize reward and punishment to change behavioral dispositions. Countless conferences and public debates were organized around the topic, and it has taken years to resolve the bulk of these misunderstandings. A positive aspect of this controversy was that it nurtured interest in a deeper understanding of the consequences of neurobiological insights for conceptions of humanity and the legal system. Seen in retrospect, some of the conflicts could have been avoided had clearer definitions been used to describe the ontological status of neuronal mechanisms, the emergent cognitive functions, and the social realities that came into existence through cultural evolution. Phenomena such as free will, intentionality, responsibility, guilt, justice, and fairness are perceived as realities, but they cannot be deduced from the cognitive functions of individual brains. Unlike the primary sensations, these phenomena exist only after cognitive agents begin to exchange their experiences and integrate the observations of the respective other in their own self-model. This emergence of new qualities still can be accounted for without having to take a dualistic stance, but this requires, for its analysis, an extension of the methods that we apply for the analysis of the functions of individual brains. As the social neurosciences begin to pursue this extended strategy, social realities may, with all likelihood, become amenable to naturalistic interpretations. This time, however, the explananda are phenomena that the humanities have been exploring for centuries. Thus, there is hope that any present distrustfulness will give way to cooperation.

Because most of these fascinating issues arose through interactions with German colleagues in the humanities, philosophy, and jurisprudence, they were conducted primarily in German. Thus, most of these lively debates passed unrecognized outside German-speaking countries. I am aware of similar discourse in other countries. Given the idealistic tradition of German philosophy and psychology, the debate was, and to some extent still is, particularly polarized in this country.

The Creation of New Institutes

The research pursued by my lab to analyze integrative functions of the brain necessitated state-of-the-art technology and this need set into motion a series of events that changed the scientific landscape of Frankfurt. Interested in investigating similar research questions in animals, healthy persons, and patients, we prepared a concept paper together with our colleagues from the clinical departments of psychiatry, neurology, and neuroradiology that outlined a multidisciplinary undertaking and approach. This concept was awarded a competitive grant from the German Ministry of Science and Technology and, together with substantial financial backing from the Max Planck Society, led to the establishment of an imaging center on the medical campus in Frankfurt-Niederrad. The Land of Hesse financed the construction of a dedicated building, and on May 7, 2004, the Brain Imaging Center¹³ opened, equipped with two 3T scanners and (shortly thereafter) a MEG machine. Two full professors, Ralph Deichmann and Michael Wibral, were recruited to coordinate methodological advances in the MRI and the MEG units, respectively. Since its establishment, the Brain Imaging Center has provided advanced noninvasive imaging technology to a multitude of researchers and has developed an extensive multidisciplinary network in support of transinstitutional cooperation and scientific exchange.

The production of complex, high-dimensional data sets, however, increased the need for competency in theoretical disciplines. Although my lab had always included colleagues trained in these disciplines, they were somewhat lonely voyagers in a foreign environment—one dominated by experimentalists. Aware of similar needs in other biological disciplines, I submitted a proposal to the VolkswagenStiftung and, after international evaluation, received funding for an endowed chair in computational neuroscience at the Goethe University. As we moved forward to fill the chair, however, a most unusual problem arose: Neither the biological nor theoretical disciplines at the university were prepared to accommodate such a chair. The former argued that such a person would lack knowledge in biology, while the latter maintained that someone interested in biological problems would not be competent in math or physics. To get past this hurdle, I teamed up with Walter Greiner, a highly respected theoretical physicist at the university who was interested in strengthening theory in particle physics. Over time, and in multiple consultations with the president of the Goethe University, Rudolph Steinberg, and one of the vice presidents, Horst Stöcker, we developed a plan that envisioned an institute of theorists working on different animate and inanimate model systems, but sharing interests in complex systems with nonlinear dynamics.

Using the project proposal evaluated by the Volkswagen Foundation as a calling card, we initiated a fund-raising campaign. In October 2003, after about 5 million euros were secured, we founded the Frankfurt Institute for Advanced Studies (FIAS). This institute has a unique status: It is a nonprofit organization that is administratively attached to the university, and it runs an interdisciplinary graduate school. Because of the support of its many donors and supporters, the FIAS is thriving. It has its own dedicated building on the Riedberg campus,¹⁴ engages about 120 scientists from 28 countries, and interacts closely with the data-producing experimental institutes throughout Frankfurt. The theoreticians working in my department have a second desk at the FIAS and are able to interact and share advanced theoretical and computational methods with their peers. The lonely voyagers are no longer alone.

Scientific Fairy Tales

On March 9, 2006, while at a Juan March conference in Madrid, I was sitting in a tapas bar celebrating my 63rd birthday when my cell phone rang. To my surprise, the caller was not Francine or my daughters, but rather Thomas Strüngmann, the twin brother of Andreas, who I knew from my mentoring days at Schloss Neubeuern. Thomas called to ask whether I would be interested in establishing a research institute on their behalf. Having recently sold their pharmaceutical company, Hexal, the two brothers were interested in giving back to science as a way of acknowledging the contributions that science had played in enabling their own success. For this purpose, they offered me 100 million euros.

Their generous offer, completely unexpected, set off myriad thoughts and caused me to return home quite perplexed. My first instinct was to secure an endowment for the FIAS, since at that time it was working with a capital fund of 30,000 euros. This, however, was not an option, because Andreas and Thomas Strüngmann wanted a new institute with a strong experimental base.

Exploring various possibilities, I began to calculate what it would take to establish an institute similar to mine at Max Planck. Soon it became obvious that an endowment of 100 million euros would not generate enough interest to run an institute with the critical mass required for excellence and international competitiveness. Without hesitation, Andreas and Thomas Strüngmann doubled the endowment, and now concrete steps were required.

I reasoned that such an institute could be successful—both in terms of science as well as in meeting the expectations of the donors—only if it were embedded within a research organization of high reputation, such as the Max Planck Society. Thus, I began deliberations with Barbara Bludau (secretary general of the Society) and Herbert Jäckle (MPI vice president responsible for institutes within the biomedical section). The goal was to establish this new institute under the umbrella of the Max Planck Society and to adopt its well-established instruments for governance, recruitment of directors, quality control, and definition of scientific priorities, but to finance all institutional running costs through the interest generated by the endowment. Unexplored territory was encountered on all levels: Legal issues had to be resolved, because Max Planck is supported by public money. Issues regarding autonomy needed to be discussed and clarified between the donors and Max Planck authorities. And once feasibility had been established, I needed to gain approval from the administrative and scientific boards of the Max Planck Society, as well as permission from its president, Peter Gruss, and Senate.

On more than one occasion, efforts were thrown back to square one, and often I doubted whether a solution could be found. Thanks, however, to the incredible engagement and goodwill on the part of all parties, success was achieved. Named after the donors’ father, the Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society (ESI) was established on September 12, 2008, with the status of a nonprofit organization with limited liability.

A competitive search process followed and, in 2009, Pascal Fries was nominated by the Senate of the Max Planck Society to be ESI’s first director. Once Fries accepted, I stepped down from my role as founding director. In 2011, after officially retiring from the MPI for Brain Research, I was named by ESI’s Board of Trustees as a Senior Fellow at ESI. At the same time the Max Planck Society granted me some support for an emeritus lab. This generous support offers me the opportunity to continue some of my research and to stay connected to the world of science.

Commensurate with the retirement of the directors from the old MPI for Brain Research in Frankfurt-Niederrad—Heinz Wässle, Heinrich Betz, and myself—the Max Planck Society decided to relocate the institute to the Riedberg campus to coincide with the appointment of new directors, Gilles Laurent and Erin Schuman. This move necessitated, however, a new building for the institute. Laurent and Schuman chose to begin their tenure in interim offices on the Riedberg to be close to the construction. Their decision opened up space in the old institute, thus enabling Fries and the newly recruited principal investigators of independent junior groups to begin work immediately.

Writing these lines from my office in Frankfurt-Niederrad, I look out over a massive construction site now under way to create new space for ESI. The construction of the ESI science complex is due to the efforts and support of Roland Koch, minister president of the state of Hesse (1999–2010). During the early stages of negotiations to establish ESI, locations in both Frankfurt and Munich were considered. Keen to secure ESI in Frankfurt, Roland Koch offered to help us refurbish the old MPI building if we founded ESI in Frankfurt. Expecting a few million euros for this purpose, the state of Hesse offered ESI 30 million euros to establish its working quarters, and we look forward to moving into the new complex in 2017.

This brief description of the Strüngmann brothers’ charisma and passion for science would be incomplete without mentioning yet another incredible and generous act. In 2004, the Dahlem Workshops—a unique and prestigious form of scientific discourse that was established in 1974 as a five-year project of the Stifterverband für die Deutsche Wissenschaft, with Silke Bernhard as its founding director—became mired in problems at the Freie Universität Berlin (which assumed its administration in 1990). I was familiar with Dahlem, having been invited as a young postdoc to one of its first neuroscience workshops in 1977, “Function and Formation of Neural Systems,” chaired by Gunther Stent. The experience was truly eye-opening: for an entire week, I discussed and debated with the most distinguished neuroscientists of that time and remember, with great fondness, my interactions with Eric Kandel, Gerald Westheimer, David Hubel, Torsten Wiesel, Pasko Rakic, and Pat Goldman. Ever since, I have been an aficionado of the Dahlem Workshops. In 1987, I organized one together with Pasko on the “Neurobiology of Neocortex” (Rakic and Singer 1988), and I was in the process of proposing another theme with Christoph Engel (on conscious versus subconscious decision making) when the crisis came to light.

Many efforts were attempted to secure this revered conference series. For my part, I approached the Berlin-Brandenburg Academy of Sciences, of which I am founding member, as well as the Max Planck Society, but neither was able to help. Thus, in 2006 (not long after the Madrid telephone call), I turned to Andreas and Thomas Strüngmann to see whether they would be interested in rescuing this jewel. They immediately agreed and so I approached Julia Lupp (successor to Silke Bernhard) to ask whether she was ready to move to Frankfurt. After a short latency, I received an overwhelming “yes.” Julia’s commitment to this forum cannot be esteemed high enough as the preparation of these special meetings, the editing of the proceedings, and in particular the guidance of the scientists during the study week require not only a deep understanding of the dynamics of scientific discourse but also a good deal of charismatic authority.

As an institutional harbor, I anchored the institute within the FIAS because of its special status, and because ESI did not yet exist. And on October 1, 2006, Julia began the work necessary to reestablish the philosophy and approach to scientific discourse that had been lost in Berlin. Named after the brothers’ father, the Ernst Strüngmann Forum¹⁵ took off like a phoenix rising from the ashes. Since then, it has embedded itself within the scientific community, earning the reputation as the place where intellectual dead ends are overcome, where new ways of conceptualizing issues are grasped, and where future collaborations are created. To cultivate communication among past participants in the neuroscience community, we hold an annual social at SfN. And once the new ESI complex has been completed, the Ernst Strüngmann Forum will join us in Frankfurt-Niederrad to continue its work.

The Accompanying Love Story

In fairy tales, we expect that protagonists will have to master challenges and overcome twists of fate along the way. Often, a love story weaves itself in and out as the plot develops. Thus, it will probably come as no surprise to learn that our fairy tales involve an episode of thwarted love and happy resolution, albeit on an extended timeframe. With gratitude, and humility, let me explain.

During the first year of my university studies in Munich, I often would return to my boarding school at Schloss Neubeuern during academic breaks to serve as a mentor to younger students. In one of my groups was a young boy by the name of Thomas Strüngmann, who must have been about 14 or 15 years old at the time. One day, Thomas confided to me that he was completely in love with a girl from his class. The girl’s mother, however, did not approve of this innocent liaison and was refusing all weekend invitations to the teenagers’ respective homes. Suffering desperately as a result, he turned to me for advice. On his behalf, I wrote a letter to his mother—longhand, of course, in the very best cursive, as would be expected—and met with her to speak about the matter. Through my intervention, she changed her mind and the problem reached a happy ending.

In all honesty, that day in the tapas bar, I would not have been able to recall this incident for it did not occupy a prominent place in my 63-year-old memory. For Thomas Strüngmann, however, it was a poignant experience—one that he related to me much later, after Madrid. He obviously had not forgotten.

Epilogue

Writing this has afforded me the opportunity to reflect comprehensively on my past, and I wish to thank wholeheartedly those who invited me to do so. It made me realize the irreversible passage of time as well as the curious role that hazards and fortuity have played in determining the decisive bifurcations in my life’s trajectory. The eminent support that I have received from my family, teachers, mentors, friends, and colleagues is humbling, for without it, most of what I am now able to report would never have happened.

There is this deep and undirected feeling of gratitude to still be around. It is natural to lose relatives and friends over the course of a long lifetime, but some of them departed far too early: Creutzfeldt was just about to harvest what he had sown, Sireteanu was in the midst of consolidating a chair at the Goethe University’s faculty of psychology when she left us, and Varela was up to something grand as he was taken away. All three left loving partners, children not yet autonomous, and students who were at the beginning of their careers.

This cursory account of my life would be ever so incomplete without acknowledging my family. Our two daughters, both fiercely determined to never get even close to their parents’ professions, failed miserably in this respect. Nathalie, who began her career introducing French contemporary composers to German radio listeners, accepted a chair for “experimental radio” at the Bauhaus University in Weimar and promoted me to the rank of grandfather, a role that I deeply cherish. Tania is now a director at the MPI for Human Cognitive and Brain Sciences in Leipzig. Since her institute is part of the humanities, we rarely meet at Max Planck section meetings but do, on occasion, get invited to the same conferences and enjoy it when colleagues discover that we know each other fairly well. The two girls—monozygotic twins, as we found out through DNA sequencing when they were 30—have always been, and still are, an inexhaustible source of wonderment and surprise. Above all is the overwhelming sense of gratitude that I owe to Francine: her cultivated attitude, caring insistence about the truly important issues, and way of embracing the totality of life ensure that I never forget that there is a life beyond science.

Creutzfeldt used to warn that one should “never let your department get too big.” Although neither of us quite succeeded, we did try to create a setting designed to spur young researchers on their way to independence. The value of a mentor is immeasurable, as is the return that one derives from working with young minds.

Since my initial foray into neuroscience, more than 45 years have passed. The finesse of our methods has increased dramatically over this time, as has our awareness of the mind-boggling complexity of the brain. The really big questions, however, have not changed, and in lucid moments, I feel further away from understanding them than I thought I was whenever a question seemed to be resolved. Fortunately, thanks to my association with ESI, I am able to continue the journey. I find it highly gratifying to work again with a small, devoted group of enthusiastic colleagues. The freedom to pursue knowledge, without the need to administer a large department or serve as managing director of a whole institute, is new. And I embrace this next stage with élan and renewed commitment.

Acknowledgment

I wish to thank wholeheartedly Julia Lupp for helping me to cope with the idiosyncrasies of the English language and Larry Squire and Tom Albright for their invitation to this gratifying adventure.

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Jeannerod M, Sakai K (1970) Occipital and geniculate potentials related to eye movements in the unanaesthetized cat. Brain Res. 19: 361–377

Kleinschmidt A, Bear MF, Singer W (1987) Blockade of ‘NMDA’ receptors disrupts experience-dependent plasticity of kitten striate cortex. Science 238: 355–358

Kossut M, Singer W (1991) The effect of short periods of monocular deprivation on excitatory transmission in the striate cortex of kittens: a current source density analysis. Exp. Brain Res. 85: 519–527

Kreiter AK, Singer W (1996) Stimulus-dependent synchronization of neuronal responses in the visual cortex of the awake macaque monkey. J. Neurosci. 16: 2381–2396

Leonards U, Singer W (1997) Selective temporal interactions between processing streams with differential sensitivity for colour and luminance contrast. Vision Res. 37: 1129–1140

Leonards U, Singer W, Fahle M (1996) The influence of temporal phase differences on texture segmentation. Vision Res. 36: 2689–2697

Lewandowski MH, Müller CM, Singer W (1993) Reticular facilitation of cat visual cortical responses is mediated by nicotinic and muscarinic cholinergic mechanisms. Exp. Brain Res. 96: 1–7

Lima B, Singer W, Neuenschwander S (2011) Gamma responses correlate with temporal expectation in monkey primary visual cortex. J. Neurosci. 31: 15919–15931

Löwel S, Singer W (1992) Selection of intrinsic horizontal connections in the visual cortex by correlated neuronal activity. Science 255: 209–212

Marder E (1988) Modulating a neuronal network. Nature 335: 296–297

Markram H, Lübke J, Frotscher M, Sakmann B (1997) Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275: 213–215

Max Planck Institute for Brain Research (2014) 100 years Minds in Motion. Max Planck Institute for Brain Research, Frankfurt am Main.

McNaughton BL, O’Keefe J, Barnes CA (1983) The stereotrode: A new technique for simultaneous isolation of several single units in the central nervous system from multiple unit records. J. Neurosci. Meth. 8: 391–397

Melloni L, Molina C, Pena M, Torres D, Singer W, Rodriguez E (2007) Synchronization of neural activity across cortical areas correlates with conscious perception. J. Neurosci. 27: 2858–2865

Milner PM (1974) A model for visual shape recognition. Psychol. Rev. 81: 521–535

Mioche L, Singer W (1988) Long-term recordings and receptive field measurements from single units of the visual cortex of awake unrestrained kittens. J. Neurosci. Meth. 26: 83–94

Mioche L, Singer W (1989) Chronic recordings from single sites of kitten striate cortex during experience-dependent modifications of receptive field properties. J. Neurophysiol. 62: 185–197

Mitzdorf U, Singer W (1978) Prominent excitatory pathways in the cat visual cortex (A17 and A18): A current source density analysis of electrically evoked potentials. Exp. Brain Res. 33: 371–394

Mitzdorf U, Singer W (1980) Monocular activation of visual cortex in normal and monocularly deprived cats: an analysis of evoked potentials. J. Physiol. (Lond.) 304: 203–220

Müller CM, Best J (1989) Ocular dominance plasticity in adult cat visual cortex after transplantation of cultured astrocytes. Nature 342: 427–430

Müller CM, Singer W (1989) Acetylcholine-induced inhibition in the cat visual cortex is mediated by a GABAergic mechanism. Brain Res. 487: 335–342

Munk MHJ, Roelfsema PR, König P, Engel AK, Singer W (1996) Role of reticular activation in the modulation of intracortical synchronization. Science 272: 271–274

Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307: 462–465

Pettigrew JD (1974) The effect of visual experience on the development of stimulus specificity by kitten cortical neurones. J. Physiol. (Lond.) 237: 49–74

Phillips WA, Singer W (1974) Function and interaction of on- and off-transients in vision. I. Psychophysics. Exp. Brain Res. 19: 493–506

Rakic P, Singer W (1988) Neurobiology of neocortex: report of the Dahlem Workshop on Neurobiology of Neocortex, Berlin, 1987. Chichester, New York, Wiley

Rauschecker JP, Singer W (1979) Changes in the circuitry of the kitten visual cortex are gated by postsynaptic activity. Nature 280: 58–60

Rauschecker JP, Singer W (1981) The effects of early visual experience on the cat’s visual cortex and their possible explanation by Hebb synapses. J. Physiol. (Lond.) 310: 215–239

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Roelfsema PR, König P, Engel AK, Sireteanu R, Singer W (1994) Reduced synchronization in the visual cortex of cats with strabismic amblyopia. Eur. J. Neurosci. 6: 1645–1655

Salzman CD, Murasugi CM, Britten KH, Newsome WT (1992) Microstimulation in visual area MT: Effects on direction discrimination performance. J. Neurosci. 12: 2331–2355

Schmielau F, Singer W (1977) The role of visual cortex for binocular interactions in the cat lateral geniculate nucleus. Brain Res. 120: 354–361

Singer W (1977) Control of thalamic transmission by cortico-fugal and ascending reticular pathways in the visual system. Physiol. Rev. 57: 386–420

Singer W (1993) Synchronisation of cortical activity and its putative role in information processing and learning. Ann. Rev. Physiol. 55: 349–374

Singer W (1994) Neuroscience in Europe: The European Neuroscience Association. Trends Neurosci. 17: 330–332

Singer W (1995) Development and plasticity of cortical processing architectures. Science 270: 758–764

Singer W, Bedworth N (1973) Inhibitory interaction between X and Y units in the cat lateral geniculate nucleus. Brain Res. 49: 291–307

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Singer W, Creutzfeldt OD (1970) Reciprocal lateral inhibition of on- and off-center neurons in the lateral geniculate body of the cat. Exp. Brain Res. 10: 311–330

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Sireteanu R, Fronius M, Singer W (1981) Binocular interaction in the peripheral visual field of humans with strabismic and anisometropic amblyopia. Vision Res. 21: 1065–1074

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Uhlhaas PJ, Singer W (2010) Abnormal neural oscillations and synchrony in schizophrenia. Nature Rev. Neurosci. 11: 100–113

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Von der Malsburg, C, Phillips, WA, Singer W (2010) Dynamic Coordination in the Brain. From Neurons to Mind. MIT Press & FIAS, Cambridge, MA & Frankfurt A. M.

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Wespatat V, Tennigkeit F, Singer W (2004) Phase sensitivity of synaptic modifications in oscillating cells of rat visual cortex. J. Neurosci. 24: 9067–9075

Wilson MA, McNaughton BL (1993) Dynamics of the hippocampal ensemble code for space. Science 261: 1055–1058

Wilson JTL, Singer W (1981) Simultaneous visual events show a long-range spatial interaction. Percept. Psychophys. 30: 107–113

¹Pisa was a center of excellence in systems neuroscience due to Morruzzi’s legacy. His impressive scientific offspring—Emilio Bizzi, Giacomo Rizzolatti, Lamberto Maffei, Piergiorgio Strata, and Giovanni Berluchi—have ably continued this tradition.

²Earned after one has obtained a PhD, the habilitation is the highest academic qualification a scholar can achieve in Germany. It is based on a thorough, external review of independent scholarship and qualifies a person to teach at a university and supervise PhD students.

³Seewiesen is where Konrad Lorenz observed his geese and von Holst and later Horst Mittelsteadt pioneered the reafference principle and the notion of corollary discharge.

⁴Founded by F. O. Schmitt in 1962, in conjunction with the American Academy of Arts and Sciences, the Neuroscience Study Program provided a focus, through its conferences and publications, for research in neurosciences throughout the world.

⁵The importance of this cannot be underestimated; however, I know of no counterpart in Anglo-Saxon countries to convey its gravity.

⁶The conference was held in the famous Schatzalp Hotel that had served as the setting for Thomas Mann’s novel Der Zauberberg (The Magic Mountain).

⁷It took us another decade to discover that amblyopia also was associated with changes in cortical dynamics and that it caused reduced synchronization among neurons (Roelfsema et al. 1994).

⁸School curricula differ drastically between states because of agreements put in place in the federation of Germany.

⁹See http://www.edinger-institut.kgu.de/.

¹⁰See https://www.mindandlife.org/.

¹¹Earlier, I had briefly met Matthieu Ricard in London at a small workshop on the relationship between science and contemplative practices, organized by my daughters Tania and Nathalie.

¹²In a little study performed much later on expert meditators, we were able to confirm that they had much better control of attention than the control group (van Leeuwen et al. 2012).

¹³See http://www.kgu.de/bic/.

¹⁴Located at the northern edge of Frankfurt, the Riedberg is home to a natural science campus that contains departments of the Goethe University, the Frankfurt Institute for Advanced Studies, the Max Planck Institute for Biophysics, the Max Planck Institute for Brain Research, and various independent research groups.

¹⁵See http://www.esforum.de/.

David C. Van Essen

BORN:

Glendale, California

September 14, 1945

EDUCATION:

California Institute of Technology (honors), Pasadena, CA, Chemistry, B.S. (1967)

Harvard Medical School, Boston, MA, Neurobiology, PhD (1971)

APPOINTMENTS:

Postdoctoral Fellow, Harvard University (1971)

Postdoctoral Fellow, University of Oslo (1973)

Postdoctoral Fellow, University College London (1975)

Assistant, Associate, Full Professor, California Institute of Technology (1976–1992)

Edison Professor of Neurobiology, Washington University in St. Louis (1992)

Alumni Endowed Professor of Neurobiology, Washington University in St. Louis (2012)

HONORS AND AWARDS (SELECTED):

Helen Hay Whitney Foundation Postdoctoral Fellow, 1973

Alfred P. Sloan Research Fellow, 1978

Best Professor teaching award, California Institute of Technology, 1989

Fellow, American Association for the Advancement of Science, 1994

Distinguished Service Teaching Award, Washington University Medical School, 1992, 2015

Krieg Cortical Discoverer Award (Cajal Club), 2002

Peter Raven Lifetime Achievement Award, St. Louis Academy of Science, 2007

Second Century Award, Washington University School of Medicine, 2015

Editor-in-Chief, Journal of Neuroscience, 1994–1998

Founding Chair, Organization for Human Brain Mapping, 1996–1997

Society for Neuroscience Secretary, 2002–2004; President, 2006–2007

President, Association of Medical School Neuroscience Department Chairs, 2006–2008

Senior Editor, eLife, 2015–present

David Van Essen has studied the structure, function, connectivity, and development of cerebral cortex in humans and nonhuman primates. He and his colleagues have developed powerful methods of computerized brain mapping, with a particular emphasis on surfacebased visualization and analysis of cerebral cortex. He has been a pioneer in neuroinformatics and data-sharing efforts for nearly two decades. His tension-based theory of morphogenesis accounts for how and why the cortex gets its folds. He has also contributed to our understanding of the functional and hierarchical organization of primate visual cortex. He is a principal investigator for the Human Connectome Project (HCP), an ambitious endeavor to map brain function and connectivity in healthy adults. The HCP is setting new standards for sharing rich and complex neuroimaging datasets with the scientific community.

David C. Van Essen

Preface

It has been my immense good fortune to be engaged in neuroscience research since the late 1960s, when the field was entering a period of explosive progress and growth. My personal neuroscientific journey has taken many twists and turns, by way of somewhat eclectic choices regarding research directions. I have enjoyed the excitement and challenges of delving into a broad spectrum of research arenas, including neuroanatomy, neurophysiology, neural development, computational neuroscience, brain evolution, neuroimaging, and neuroinformatics. My choices of experimental preparation have also spanned quite a range, from leeches and rats to monkeys, humans, and even some great apes. This autobiography aims to weave a coherent narrative, providing context and rationale for how my career evolved in ways that reflect the interactions between long-term visions and various opportunistic decisions. Scientifically, I consider myself first and foremost a cortical cartographer, and the lion’s share of this autobiography revolves around efforts to map the structure, function, connectivity, and development of the convoluted cerebral cortex. Counter to my early expectations, I have also devoted a major portion of my professional life to various service and administrative roles. Some of these activities are also woven into the narrative, as they provide a historical as well as personal perspective on how various neuroscience subfields have evolved, particularly in the realms of brain mapping and neuroinformatics.

Four disparate, but interrelated themes are integrated into this essay. One is to provide insights about the origins of important scientific ideas and approaches in which I have been engaged. For example: what are the backstories behind the development of cortical flatmaps, the concept of cortical hierarchies, and the hypothesis of tension-based morphogenesis? How did modern neuroinformatics get off the ground? How was the Human Connectome Project (HCP) conceived and launched? Another is to share vignettes regarding important individuals in my scientific life—mentors, colleagues, and scientific progeny. I have benefited greatly from wonderful mentors and have in turn had the opportunity to train many talented students, postdocs, and technical staff, as well as junior faculty I have helped recruit. Their aggregate accomplishments are truly impressive but can only be told in part. A third aspect entails a hefty dose of personal and family history. My personal adventures are tame in comparison to the often extraordinary and sometimes harrowing adventures told in various other autobiographies in this series. Nonetheless, family life has always been very important to me—despite the long hours in the lab—and represents a core part of this story. Finally, it has been interesting to reflect on how the future of neuroscience has been seen from various vantage points over the past five decades. Some predictions that I and others have made over the years have borne fruit and proved to be prescient. Many others—arguably the majority—have fallen well short of the mark, some awkwardly or even embarrassingly. Reflecting on the successes as well as failures of past predictions hopefully will provide a bit of entertainment, but might also help improve our batting average in the future.

Childhood

I was born in Glendale, California, in September 1945. My mother, Dorothy Burns, was a direct descendant of the Scottish poet Robert Burns. I’m proud of this lineage, but speculate that the Burns genes for poetic genius became degenerate and contributed to my incorrigible predilection for puns. My father, Roland, was of Dutch lineage, as his father emigrated from Holland and landed at Ellis Island in 1910. Both sides of the family migrated to the Midwest, then eventually to California, and my parents grew up mainly in southern California. For my first six years, we lived in the Los Angeles suburb of Tujunga, but I have only faint recollections of those early days. When I was six, our family moved to Fresno, in the San Joaquin valley, where my father began work as a radio technician, repairing radio equipment for the Highway Patrol and the Forestry Department.

My parents grew up during the Great Depression, and neither had the opportunity to complete a college degree (though my Dad eventually received his B.A. at the age of 50, after many years of night school). They had higher aspirations for their offspring, and they stressed the importance of education to me and my older sister, Carylon. I became hooked on science and technology from an early age, frequently peppering my father with questions about how things worked. I was fascinated by rockets, and when I was about eight, I put pencil to a large sheet of brown shelf paper and drew “detailed” plans for a rocket ship, including a cabin that would comfortably hold my family—grandparents included! This was in 1953—pre-Sputnik days—and my concept of payload capacities was naïve, to put it mildly. Like the rocket itself, my aspirations of becoming a rocket scientist never got off the ground, but my fascination with the space race and its sequelae have never abated.

Around the same time, I got involved in amateur (ham) radio. My father and our close family friend, Jerry Faas, were both hams, and they took me along to “hamfests” where people would show off their “rigs” and talk technical stuff. To get my own license, I learned Morse code, some basic electronics, and rules of the road for amateur radio. I passed my Novice exam at the tender age of eight and became the youngest ham radio licensee in California. Using a Heathkit radio set that I built, I was on the airwaves, but soon realized that conducting a conversation via Morse code at a paltry five words per minute was painfully slow! Permission to use voice communication required a Technician license, which demanded a deeper understanding of electronics than I could handle at the time.

In 1957, my father was promoted and transferred to the town of Visalia, an hour south of Fresno, where I spent the rest of my childhood. I got along well with my sister Carylon, seeing as how my worst complaint was suffering through Johnny Mathis (her favorite singer, but whose voice I still loathe) crooning while she washed and I dried the dishes. I forgave her later, after my love for classical music began literally while listening to a concert I had been dragged to because she was playing flute in an All-State Orchestra. (Decades later, we are still close.) I was a voracious reader, devouring adventure stories (Huck Finn was a favorite), science fiction (e.g., Isaac Asimov), and other genres. I also spent countless hours poring over our family encyclopedias—initially the Book of Knowledge, until my parents sprang for a full 24-volume set of the Encyclopedia Britannica. It was a far cry from our modern-day fingertip access to Google and Wikipedia as modes of knowledge exploration, which I don’t think were on the radar screen of even the most visionary sci-fi writers back then.

I spent lots of time outdoors, playing with the neighborhood kids, mowing lawns in the neighborhood in order to earn big bucks ($0.25/hour—that’s not a typo!), and trying with limited success to broaden the vocabulary of my pet raven (Hercules, or “Herky”). The late 1950s were when the Cold War was near its hottest, and I recall digging a primitive three-footdeep fallout shelter in our back yard. Highlights of our family activities and adventures included water skiing with our friends the Faases at Millerton Lake outside of Fresno (where my swimming proclivities became permanently spoiled by the warm water temperatures); tent camping in Yosemite before it was completely overrun by tourists; and large family get-togethers at “The Rockies,” a sprawling, ramshackle, utterly charming house in the high-desert that was built by my grandfather largely through accretion of scrap materials. My horizons broadened during the summer of 1960 when our family spent six weeks driving around the country, visiting most of the continental United States.

I was generally a well-behaved child, and my mother only occasionally had to put red pepper on my tongue for being sassy. However, I did have a short fuse, and once I lost my temper, it often took many hours before I could cool down and regain emotional balance. Fortunately, I eventually gained better control of my temper, but this occurred gradually, over decades. It makes one wonder whether such changes reflect the imposition of personal “will power,” the natural maturation of emotion-related brain circuits, or (most likely) the interaction between the two.

I was raised as a Methodist and was a regular attendee at Sunday school and church. In high school, I became president of our Methodist Youth Fellowship, yet I also began to question the existence of an allpowerful God who could be so tolerant of human suffering and evil. It was increasingly difficult to reconcile with my understanding of how the laws of physics applied to the real world. Our pastor couldn’t answer questions to my satisfaction, and I was torn by ambivalence and even guilt about my emerging disbelief in God.

In high school, I did a couple of science fair projects that received honorable mention, but I didn’t really gain a sense of what it was like to do scientific research. I loved math and was able to take a fast track when my algebra teacher let me work through a college math book in lieu of regular classwork. In 1961, I spent several weeks at UC Berkeley at a mathematics summer program. This enhanced my passion for math, but also made me realize that I was cut from a different cloth than those who are truly gifted in theoretical mathematics. Even though this was before the free speech movement, Berkeley was a hotbed of liberal and radical thinking. It was my first real exposure to a different political landscape than the very conservative perspective imbued by my parents. It was an eye-opening experience, but it took some years and a transcontinental move before the seeds of liberalism sprouted within my brain.

Caltech Undergraduate Days

In keeping with my passion for science, my first choice for college was Caltech, in Pasadena and near my southern California birthplace. I visited Caltech in 1962 and remember being enthralled by a talk to prospective students given by Richard Feynman, a theoretical physicist and prankster who was already a legend in his time. In the spring of 1963, I was thrilled to receive a letter of admission to Caltech plus a scholarship, which was vital given our family’s modest means.

Once at Caltech, I was further inspired by the brilliant, eclectic style of the Feynman physics textbook, so my initial plan was to major in physics. Although I got A grades in freshman physics, I soon decided that theoretical physics, like theoretical mathematics, was not a good fit for what my brain could handle. Instead, I gravitated toward chemistry and lined up a summer job after my freshman year with an organic chemist, Carl Niemann. As fate would have it, that spring Dr. Niemann died suddenly and prematurely of a heart attack. I had no specific interest in biology, but Jerome (Jerry) Vinograd, a wonderful (albeit chain-smoking) molecular biologist, agreed on short notice to take me under his wing. I worked in the Vinograd lab for two summers, using density gradient ultracentrifugation to study supercoiled DNA in bacteriophage and bacteria. I enjoyed this research, but did not find the work fully captivating.

During the second summer—after my sophomore year—I was browsing through the Caltech bookstore and chanced upon The Machinery of the Brain, a book by Dean Woolridge. It turned out to be the most transformative book I have ever read. I immediately resolved that I wanted to become a neuroscientist (though that term was not yet in vogue). It was too late to switch my academic major, but starting in my junior year I took all available neuroscience-related courses, including ones taught by Felix Strumwasser (a dynamic and engaging lecturer), Roger Sperry (a great neuroscientist, but regrettably not so inspiring a lecturer), and Max Delbruck (a brilliant physicist turned biophysicist).

As an undergraduate, I was of a studious bent (a nerd, to be blunt) but did manage to enjoy extracurricular activities, including sports. In high school I had never played on an athletic team, opting instead to play trumpet in our marching band. At Caltech, I decided to go out for the freshman basketball team. Caltech was not exactly a powerhouse athletic school—a perennial doormat was more apt, which was hardly surprising given its academic orientation and small student body (180 per class). I joined the Caltech “Beavers” freshman team and found myself on the third string of a team that had only 12 players (go ahead, do the math!). I played only sparingly, usually at the end of games that were hopelessly lost, but I vividly recall what it is to get a hot hand. Our frustrated coach once inserted me early in the game because my teammates were even more hapless than usual. I reeled off several shots that miraculously went in, and ended up scoring a dozen points, which exceeded my aggregate point total for the rest of the season.

In my sophomore year my roommate was John Hosher, who overtly hoped I would improve his own study habits (by osmosis), while on the flip side I was looking for help in cracking my overly nerdy “shell.” It worked for both of us, and I hooked up with a great group of friends (guys, because Caltech was not yet co-ed). Extracurricular activities at Tech revolved around the student “houses” (like fraternities but a bit more tame). I became active in inter-house athletic competition and gradually got better in sports such as volleyball and tennis. Intramural athletics also drove home the unpleasant reality of Los Angeles smog during the decade when it was at its worst. Pasadena is snuggled up against the San Gabriel mountains, which are really beautiful—when you can see them. Alas, in those days the noxious smog often completely obscured the nearby mountains. Even worse, the air was foul, and simply breathing deeply while exercising outdoors was painful.

This smoggy storyline segues into an opportunity that enlivened my summer of 1966. Caltech had a Junior Travel Fellowship program in which applicants could propose a self-initiated activity or project anywhere around the world. Motivated by my loathing of smog and inspired by the groundbreaking research of Caltech’s Arie Haagen-Smit on the origins and control of smog, I proposed a low-budget plan to travel around Europe to study pollution control efforts in various northern European countries. On becoming one of several awardees, I used my princely stipend of $1,000 to fly to Europe, buy a bicycle, and hit the road while overnighting in youth hostels. I bought the bike in Denmark (“flatland”) and discovered belatedly that my bike didn’t have a low enough gear ratio to handle the mountainous roads of Austria and southern Germany. Nonetheless, it was a great experience overall, as I learned a little bit about pollution and a lot more about getting on and around in the world. Biking along various scenic routes provided lots of time to ponder big issues in life. I came to a parting of the ways with religion as a belief system that worked for me. For a while I wondered whether it would suffice to profess being an agnostic, in the sense of not really knowing for sure whether or not God exists. I decided that atheism was a better expression of my core beliefs, in the sense of being willing to bet all of my marbles (including how I would raise children) against his/her existence. To me, the important fundamentals of human morality relate to setting and following high ethical standards, and experience shows that this can be decoupled from religion per se.

Back at Caltech for my senior year, I began research in Felix Strumwasser’s lab on a neurophysiology project that involved recording extracellularly from crayfish stretch receptors. My specific topic—how does extracellular potassium affect sensory responses to tail extension?—was less than profound. Nonetheless, the thrill of hearing neuronal spikes crackling away on a loudspeaker resonated deeply with my own neural circuits.

Boston and Harvard Neurobiology

In the fall of 1966, I began looking for graduate schools with training opportunities in neuroscience. Today there is a veritable smorgasbord of outstanding neuroscience graduate training programs to choose among, but the options were very limited back then. I sought advice from Seymour Benzer, who had just arrived at Caltech to begin his pioneering work on Drosophila neurogenetics. Seymour encouraged me to check out the Department of Neurobiology at Harvard, which had just been established under the leadership of Stephen Kuffler.

Not long after I submitted my application to Harvard, Dr. Kuffler’s secretary called to say that Dr. Kuffler would like to meet me at the LA airport, during a stopover while he was en route to Australia. At that meeting (at a bench in the public area), I found Steve to be gracious and friendly, with a charming Hungarian accent. This and a follow-up interview at Harvard the next month went well, and I was thrilled to join the first class of students admitted to the new department.

Soon after arriving in Boston, I met Jim Hudspeth and Eric Frank, the two other students in the department’s inaugural class. Jim, Eric, and I interacted closely on various fronts over the next few years. One of the most formative was a series of graduate reading courses taught by the five faculty Kuffler had recruited as founding members of the Department of Neurobiology: Ed Furshpan, David Potter, Ed Kravitz, David Hubel, and Torsten Wiesel. Those courses focused on reading classic studies, such as key papers of Hodgkin, Huxley, and Katz. Each weekly session would typically discuss only one or two papers, but we would go over them intensively and exhaustively. It was a great experience in learning how to critically read the literature, probing into what exactly was done, why it was done, and what interpretations and pitfalls to bear in mind. The great strength of these courses was their depth, as they focused on papers that have stood the test of time. The trade-off was that the courses were short on breadth, and I later came to recognize significant gaps in my neuroscience education. Of course, in today’s world, the situation is profoundly different in two fundamental ways. The current neuroscience literature contains vastly more publications, and this information can be accessed with blinding rapidity through online resources such as PubMed and Google Scholar rather than trudging to the library and scouring hefty books and journal volumes. But learning how to critically evaluate the literature hasn’t become easier and, in some respects, is perhaps even harder to do.

The Harvard Neurobiology Department offered a very collegial as well as stimulating intellectual environment. There was a common room where many of us ate lunch and talked about science, politics, and the like. It also served as a seminar room, in which a parade of outside speakers gave talks that were characterized by frequent interruptions and intense questioning, sometimes to the point that the speaker couldn’t get through even half of the planned material. Steve Kuffler was notorious for asking questions that superficially appeared naïve but more often than not keyed on a critically important issue. Faculty, postdocs, and students alike were actively engaged in questions and discussions, making it a great environment for fostering critical scientific thinking.

The number of students, postdocs, and junior faculty in the department grew each year. In the early days, I got to know Nick Spitzer, who was a grad student with Potter and Furshpan before the department had been launched, as well as Zach Hall, John Hildebrand, Paul Patterson, Darwin Berg, and Jack McMahan. Parties at David and Molly Potter’s house were highlights, as was the annual departmental Christmas party. The latter included irreverent skits by the grad students and culminated in the infamous Suit Joke told by the inimitable Ed Kravitz. Thanksgiving at the Kuffler house was a memorable occasion for anyone in the department who wasn’t able to be with family for the holiday. For many wonderful vignettes focused around Steve Kuffler, I recommend Jack McMahan’s book entitled Steve: Remembrances of Stephen W. Kuffler (1990) as a great read.

Life with Leeches

During our first year of grad school, Jim, Eric, and I collaborated on a neurophysiology project, working in the Kravitz lab to study identified neurons in lobster abdominal ganglia. This project strengthened my fascination with neurophysiology and my desire to study a “simple” nervous system for my thesis research. Around that time John Nicholls was recruited to the Neurobiology Department from Yale, and by good fortune, his research program meshed well with my interests. John had worked with Steve Kuffler a few years earlier (when Steve was in the Harvard Pharmacology Department), and they had studied the neurophysiology of glial cells in the segmental ganglia of the medicinal leech. At Yale, John continued with the leech nervous system but had decided to focus on sensory neurophysiology rather than glial cells. He and Denis Baylor published a beautiful study (Nicholls and Baylor, 1968) on individually identified sensory neurons, following up on classical neuroanatomical observations by the Swedish neuroanatomist Gustav Retzius (Retzius, 1891). This was right up my alley, and I approached John about joining the lab shortly after his arrival at Harvard. John welcomed me into his group, which initially included Dale Purves and Ann Stuart. My relationship with John was a study in contrasts, insofar as John’s effusive highs and lows (“isn’t that simply marvelous?” or “what a truly horrid seminar that was”) were counterbalanced by my more laconic and middle-ground style of tending to look at both sides of a given situation. John was a truly dedicated teacher and an excellent speaker and writer, and I gradually learned through his tutelage to improve my style of oral and written communication. John is famous for his wonderful but quirky sense of humor. To get a taste (well, a hefty dose) of it, I recommend his recent book, Pioneers of Neurobiology: My Brilliant Eccentric Heroes (Nicholls, 2014).

My thesis research in the Nicholls’s lab focused on signaling in primary sensory neurons, particularly a group of three touch-sensitive neurons on each side of each segmental ganglion. Their official names were “T” cells, but in lab parlance they were known (based on size and shape) as “plum” cells to distinguish them from “peach” (P, for pressure) and “pear” (N, for nociceptive) cells. John and Denis had previously reported that leech sensory neurons hyperpolarized dramatically after a burst (tetanus) of impulses, in part due to the activation of an electrogenic sodium pump (Baylor and Nicholls, 1969). I found evidence that this “post-tetanic hyperpolarization” increased sensory thresholds to tactile stimulation of the skin, thereby accounting for some (but not all) aspects of sensory adaptation. In addition, post-tetanic hyperpolarization appeared to contribute to a separate phenomenon, in which action potentials were blocked at branch points and failed to invade the cell body (as they normally did) and in some cases failed to propagate along some but not all axonal branches. This raised the intriguing possibility that branch point failure might contribute in some systematic way to information processing. A less interesting (but real) possibility was that branch point failure was largely an epiphenomenon, because it generally required stimulation that might lie outside the normal operating range in intact animals. Intermittent branch point failure has been reported in other systems both before and after I published my thesis research, but it does not appear to be a major component or feature in current models of neural information processing. I published my thesis work as a singleauthor paper—my first scientific publication—in the Journal of Physiology. I asked John to be a coauthor, given his major contributions to writing as well as design of experiments, but he refused on grounds that he hadn’t actually “done” any of the experiments—a not uncommon practice regarding authorship in those days. My only publication coauthored with John was a Scientific American review article on the leech nervous system (Nicholls and Van Essen, 1974).

While carrying out neurophysiological experiments on the leech, I also learned to use the exciting new stick-and-stain method of visualizing neuronal morphology using microelectrodes filled with the fluorescent dye, Procion Yellow. This method had just been developed by Tony Stretton and Ed Kravitz (Stretton and Kravitz, 1968), and it was exciting to see “Golgilike” visualization of individual, identified sensory neurons through a fluorescence microscope. While the Procion Yellow injections were largely tangential to the main scientific thrust of my thesis, they turned out to be hugely important for the direction my professional career would take. But before proceeding on that front, there are some important facets of nonacademic life to cover.

Life as a Grad Student

Shortly after arriving in Boston in 1967, I responded to a newspaper ad for a room to rent in a third-floor apartment on Francis Street, right next to the medical school. My prospective roommates were three other grad students (two Bobs and a Ted) who offered me a really tiny room, but the price was right: $18/month (again, no typo!). This turned out to be a great living arrangement for the next two years. The congeniality of our living situation was enhanced by our hiring a student from nearby Simmons College to cook dinner for the group on weekdays.

Our dinner conversations were highly animated, more often than not revolving around politics. In 1967–1968, debates about Vietnam were raging around the country, and our dining room was no exception; nor was our departmental lunchroom. As noted already, I had been raised in a very conservative family, both socially and politically. While at Caltech, I had moved past my family’s background as teetotalers and had come to enjoy beer and wine, but my political views remained very conservative. (For context, during the Vietnam era, Caltech was reputed to be the only college in the country whose student body was more conservative than the faculty!) In Boston, many an evening at our Francis Street apartment was devoted to vigorous political discussions. This, along with a lot of reading and introspection, profoundly reshaped my world view. Duly converted to the liberal cause, I drove up to New Hampshire to campaign door-to-door for Eugene McCarthy in the spring of 1968, as he audaciously challenged the sitting president, Lyndon B. Johnson, in the Democratic primaries. McCarthy didn’t win the New Hampshire primary, but his strong showing helped reshape the political landscape.

Besides science and politics, there was also time for fun. I played a lot of volleyball and learned to play squash. My roommate Bob Bolender (a grad student in the Anatomy Department) suggested we spend the 1967–1968 Christmas holidays away from the Boston winter. We resolved that Acapulco was an attractive venue in Mexico, but round-trip airfare was outside our budget. Instead, we arranged via a drive-away car company to return someone’s car (a gold Cadillac, no less!) from Boston to New Orleans. From there, we took a plane to Mexico City, saw some archaeological sites, then took a bus to Acapulco for a few days of R&R.

Early in the following summer (1968), I took an embryology summer course at Woods Hole, learning a lot about development but doubting at the time that this would loom in my scientific future. For the late summer, Bob had come up with another bright idea for adventure, this time inviting me to join several of his friends on a horsepacking venture in the Cascade mountains east of Seattle. I happily agreed, expecting it to be a lark, but without a glimmer of its long-term implications. One of Bob’s friends, Jim Gerlach, lived in the village of Twisp in the foothills of the Cascades. His other two friends in this adventure were Isabel Hunter (a junior in college at UC Riverside) and her mother Margaret, who had driven together up from southern California. During the horsepacking trip (with a lot of rain and with the whole group sharing a single large tent), Isabel and I became good friends, and our relationship soon turned into a transcontinental courtship. As this long-distance romance blossomed, Isabel flew back to see me over Thanksgiving and Christmas holidays. I then flew to California in March of 1969, and we drove Isabel’s little Volkswagen Beetle cross-country so we could be together while she finished her undergraduate coursework at Northeastern University. While naturally garrulous, Isabel managed to maintain extended quiet periods, in this instance while I studied for my qualifying exam as we drove along the highways and byways. We were engaged in April 1969, a mere eight months after having met in the Cascades.

When Isabel and I considered when and where to hold our wedding, we benefited from another fortuitous turn of events. It turned out that Steve Kuffler was planning to spend the summer at the Salk Institute in La Jolla, California, where he was a nonresident fellow. Steve invited John Nicholls to join him so they could collaborate on experiments and also work on a soon-to-be-famous textbook, From Neuron to Brain (1976). Steve and John in turn invited several colleagues, including me, to join this venture (which included trucking several full neurophysiology rigs transcontinentally for the summer). The summer was productive scientifically and also afforded a great opportunity to become better acquainted with these colleagues as well as others at the Salk Institute. On the personal front, it conveniently enabled Isabel and me to plan for a July wedding in Isabel’s home town of Fallbrook, not far from La Jolla. John and Steve attended the wedding—the first (and almost the only) time I saw John wearing a tie. The wedding was fun, and Isabel recalls that I was rather more nervous about an informal research presentation I was giving at the Salk the week before than about reciting my wedding vows. Isabel is as outgoing as I am reserved, and she embodies the adage of “A stranger is a friend she hasn’t yet met.” We recently celebrated our 46th anniversary, with two fine sons and four grandchildren as delightful progeny.

Drafty Days in Boston

In the fall of 1969, Isabel and I settled into a small apartment in Allston, between Boston and Cambridge. Isabel got a job at the Peter Bent Brigham Hospital, tissue typing for kidney transplants in the early days when there were no computers and blood draws were done without using gloves. One night in early December, we were awakened by a call from Mike Biglow, a close high school friend. Mike said, “Hi, David. Isn’t your birthday September 14th?” When I replied “Yes, but so what?” he responded, “Well, congratulations may not be in order, but you should know that you are number one in the draft lottery!” That was indeed the case, and my angst about it heightened soon thereafter when the Selective Service canceled my student deferment. Some months later, I passed my Army physical exam and being drafted into the Army was an imminent prospect.

My options were limited and not attractive. Option 1 was to let myself be drafted, which would entail serving for two years in the Army with a high probability of being sent to Vietnam. Option 2 was to promptly volunteer for the Navy or Air Force, which would entail serving for an additional year in exchange for a higher probability of avoiding the front-line infantry. Option 3 was to seek political asylum in Canada, which quite a few young men were electing to do around that time, but which would have entailed profound career and personal implications. Option 4 was to wangle a way into medical school, where student deferments were still possible. Jim Hudspeth managed to go this route, but that didn’t work out for me.

While pondering these options, Option 5 emerged through the intervention of Lady Luck. On a visit to Isabel’s brother’s house in Rhode Island one fine summer weekend in 1970, I played a pick-up game of touch football with a group that included Isabel’s beefy brothers. I discovered after the game that I had somehow “blown a gasket” in the sense of having a recurrence of an inguinal hernia that had been surgically repaired a decade earlier. My initial consternation (“Oh, no, not this added to my other woes!”) quickly turned to immense relief upon realizing that I could not be forced to have elective surgery before being officially drafted. Thus, while the injury was “below the belt,” my escape from being drafted was completely above board. I was now damaged goods, and my draft status was converted to an ineligible 2F status that allowed me to stay out of the Army. For the next three years, Isabel and I lived in a fourth-floor walkup, and she did all of the heavy lifting. Ironically, while I was medically absolved from carrying groceries and laundry up the stairs, I was still cleared to play tennis, ski, and keep physically fit.

Stick and Stain in the Brain

The previous scientific thread left off with a description of my Procion Yellow staining of leech neurons. While I loved studying the leech, I was having mixed feelings about whether I wanted to spend my career working exclusively on a “simple” model nervous system that on closer inspection was turning out to be pretty complex!

Down the hall from the Nicholls lab, Hubel and Wiesel were immersed in their pioneering studies of visual cortex in cats and monkeys. I had first encountered their work when I read The Machinery of the Brain in college. At Harvard, we read many of their papers in one of the graduate reading courses. It was fascinating to read in greater depth about the functional organization of visual cortex and to discuss these issues weekly with the masters themselves. I recall musing with other students at the time as to whether Hubel and Wiesel had skimmed up most of the cream of what was to be learned about visual cortex, leaving mostly “skim milk” for the rest of us to mop up. I didn’t really believe that was the case, but over time, I have converted to a complementary view in which the more we learn about any given part of the brain, the more we expose how much remains to be deciphered to achieve a truly in-depth understanding.

Aki Kaneko, a postdoc with the Hubel and Wiesel lab at that time, was making quite a splash by using Procion Yellow to elucidate structurefunction relationships of bipolar cells in the goldfish retina (Kaneko, 1970). An obvious extension would be to explore structure-function comparisons in the visual cortex, especially because there was a tantalizingly appealing hypothesis to explore. One of Hubel and Wiesel’s most famous hypotheses involved a “functional hierarchy,” in which lateral geniculate nucleus (LGN) axons converge on cells with “simple” receptive fields, while simple cells project to (and give rise to) nearby cells having “complex” receptive fields. A natural anatomical corollary of their physiologically inspired hypothesis is that simple cells would be concentrated in the input layer (layer 4) and should be stellate as described by classical anatomists for layer 4. Complex cells, by this hypothesis, would be pyramidal cells in superficial and deep layers.

To tackle this project, Hubel and Wiesel encouraged me to team up with Jim Kelly, who had expressed interest in the endeavor and was just finishing up his thesis research with Max Cowan at Washington University in St. Louis. Jim’s solid anatomical expertise complemented my experience in neurophysiology and in working with Procion Yellow. Jim and I hit it off in our initial interactions, and we joined forces in the fall of 1971.

Hubel and Wiesel provided us with the equipment we needed, but beyond that, they had a pretty laissez-faire approach to letting new postdocs launch their projects. Neither Jim nor I previously had done any mammalian neurophysiology, but we got generous help from Jim Hudspeth and Carla Shatz in getting our rig operational and learning the ropes. Then we flew by the seat of our pants in getting intracellular recordings and dye injections under way. It was a challenge to get stable intracellular recordings from a pulsating agar-coated brain, then to characterize receptive fields as simple or complex (not as easy as David and Torsten had made it seem in their papers!), and to impale cells in a way that would inject dye into the cell without clogging on the one hand or excessive leakage on the other. Beveling the electrodes worked to keep the electrodes sharp while letting current pulses eject the electrically charged dye. If someone had suggested that within a decade patch clamping and gigohm seals would enable spectacular filling of axons as well as dendrites, I for one would have been deeply skeptical—and completely wrong.

Our dye-injection results were consistent with the original hypothesis, insofar as simple cells tended to be stellate and complex cells were predominantly pyramidal, confirming our hopes (Van Essen and Kelly, 1973; Kelly and Van Essen, 1974). Jim and I (and others) were excited by these findings, and we were invited to give seminars at various places. In general, the results were well received. When giving a talk at Caltech, I recall getting some pushback regarding our conclusion that “the majority of simple cells are stellate” just because it was a numerical majority of the cells in our relatively small sample of cells (8 out of 13). The importance of doing proper statistical analyses and being careful not to overinterpret one’s experimental data belatedly began to sink in.

Neurobiology at Cold Spring Harbor

In 1971, Jim Watson, of double helix fame and then Director of Cold Spring Harbor Labs, decided to expand their famous summer courses from molecular biology and genetics into the realm of neurobiology. Watson invited Regis Kelly (at the time a senior postdoc with Zach Hall) to lead a threeweek lecture course in neurobiology. Reg in turn asked Jim Hudspeth, Eric Frank, and me to serve as teaching assistants. I jumped at the opportunity, knowing (from my earlier embryology course at Woods Hole) that summer courses of this type offer a unique learning environment. It was intellectually very stimulating to work with a great set of teaching faculty, plus “students” of all ages, including senior investigators switching fields, such as physicist George Zweig (of quark fame) and developmental biologist George Streisinger, as well as grad students and postdocs from around the world. Jim Watson’s interest in the course was evidenced by his showing up for most of the lectures, sitting in the back of the room, and more often than not leafing through the New York Times while paying some attention to the lecture. I recall being a bit put off by this behavior, but that was before I came to appreciate that multitasking is often a reasonable compromise when dealing with the finite number of hours in a day. The next summer was a repeat performance for me, while Jim Kelly joined as one of the teaching assistants. Sharing a crowded cottage with Jim and Carolyn Kelly and their two kids during a very rainy June was part of the memorable experience. Also, this was the summer of the Senate Watergate hearings; during lunch and at breaks we were often riveted to the television outside the cafeteria, following these historic events. In future years, Cold Spring Harbor continued to expand its neuroscience portfolio, and I was fortunate to have many additional opportunities to head to Long Island for courses and scientific meetings and to serve on their neuroscience advisory board.

When You Come to a Fork in the Road, Take It

In the early 1970s, I was in no hurry to “get a job” (i.e., to take a faculty position). Instead, my aspiration was to extend my postdoctoral training beyond the two years in the Hubel–Wiesel lab. I was particularly keen to spend some time in Europe, following the example set by a number of neuroscientists, such as Mike Dennis and Dale Purves, who had worked in Europe before returning to a faculty position in the United States.

As a grad student in the Nicholls lab, I had envisioned that my longterm research would be on an invertebrate preparation—not necessarily the leech, but one that would be amenable to detailed analysis at the level of individually identifiable neurons. I initially saw the postdoctoral project on visual cortex as an opportunistic digression rather than a permanent defection from the invertebrate scene. An appealing opportunity to return to a simpler system arose when I got to know Jan Jansen, who came from Oslo, Norway, for a sabbatical in the Nicholls lab in 1969–1970. Jan and I hit it off very well at a personal as well as a scientific level. During the winter, Jan and his family introduced Isabel and me to Norwegian-style cross-country skiing in the Harvard Forest on the outskirts of Boston. The following summer (1970), Jan and family joined the entourage making the trek to the Salk Institute. Isabel and I were able to join as well. (This involved yet another trip in someone else’s Cadillac, as Isabel and I headed west in Gunther Stent’s white Caddy, because he wanted it driven back to Berkeley after also having spent a sabbatical in the Nicholls lab.) Although Jan worked with Nicholls on leeches during his sabbatical year, his stated plan was to return to studies of sensory processing in the crayfish nervous system once back in Oslo. This appealed to me, and we made preliminary plans that I would spend two years in Oslo after completing my first postdoc under Hubel and Wiesel.

Once immersed in the visual cortex project, I began reconsidering my career trajectory. I became progressively more fascinated with visual cortex as a system potentially better matched to my long-term interests. Hubel and Wiesel at that time had mostly switched from the cat to studying primary visual cortex in the macaque. They identified many features in macaque V1 that were “crisper and cleaner” than in the cat, and there was also the fact that the macaque brain is evolutionarily much closer to the human brain. Sometime in 1972, Semir Zeki from University College London visited Harvard and gave a seminar on his physiological and anatomical explorations of macaque “prestriate” visual cortex. He presented anatomical evidence that area V1 was surrounded by more than just two concentrically organized areas (areas 18 and 19, or V2 and V3), and he presented preliminary neurophysiological data on functional specialization in some of these areas. I became intrigued by the prospect of diving into the relatively uncharted waters of higher visual cortex in nonhuman primates and was encouraged by Torsten and David to consider working with Zeki. I wrote to Semir to explore this possibility, and his response was enthusiastic. I then applied for and received a three-year fellowship from the Helen Hay Whitney Foundation. This was a wonderful fellowship, because it was completely flexible with regard to which labs I chose to work in during the three years of funding.

Given these developments, I became ambivalent as to whether I actually should proceed with a plan of two additional transitions in research orientation—that is, from cat visual cortex to crayfish, then from crayfish over to monkey visual cortex. Was this wise from a professional or career development perspective? Might I be shooting myself in the foot in terms of future job opportunities? I met with Torsten, and in essence asked him whether I was foolhardy, indecisive, audacious, or just plain crazy to jump back and forth from invertebrate to mammalian systems multiple times in my career. I asked accordingly whether I should revise my plan of working with Jan in Oslo for two years on invertebrates if I really planned to end up returning to the mammalian visual system. Torsten had been trained in Sweden as a psychiatrist, so he knew the real meaning of the term crazy. In his thoughtful but diffident manner, he encouraged me to stick with the game plan and pursue my postdoctoral plans with both Jansen and Zeki despite the divergent systems. It was a decision I have never regretted, as it kept my intellectual horizons very broad, in ways that affected later parts of this story. Whether this would be good advice for someone in our current scientific climate is an interesting question. I don’t have a simple answer, as scientific breadth and depth are both as important as ever. On the one hand, many experimental systems have become increasingly complex to master, and it is important not to bite off more than one can chew scientifically. On the other hand, many other neuroscientists (including esteemed contributors to this series) have been highly successful in pursuing multiple frontiers, either concurrently or in rapid succession. Moreover, there is something satisfying about stretching one’s intellectual perspectives. In the end, each scientist needs to make choices that fit one’s own career interests and ambitions. The imperative is to work on problems about which you are passionate and that offer opportunities to significantly advance our understanding.

Norway (1973–1975)

On a sweltering summer afternoon in 1973, Isabel and I headed to Boston’s Logan Airport to begin our three-year European adventure. We almost missed our flight, because I left my sports coat containing our passports and tickets behind at a farewell party hosted by Jim Kelly, and it was a mad scramble to get back to the airport, barely in time. After a few days in London visiting Dale and Shannon Purves, we flew to Oslo. Jan Jansen met us at the airport and took us out to dinner at a mountainside restaurant overlooking Oslo. Afterward, we went for a short hike in the nearby Nordmarka forest while it was late but still bright outside, followed by a brisk swim in a cool little lake. It was a great start to two years in Norway that were in many respects idyllic at both professional and personal levels, thanks to a special confluence of circumstances.

Scientifically, my two years in Jan’s lab were very productive, though we ended up working on completely different projects than the original plan (arranged back in Boston) to study crayfish neural circuitry. Our first departure from plan A was to initiate a new project on neural regeneration in the leech nervous system following peripheral nerve lesions (cuts or crushes). We found that reinnervation was strikingly specific for both sensory and motor axons, especially after a nerve crush, when the distal nerve stump was near at hand to guide returning axons. Then we decided to shift focus and study the reestablishment of neuromuscular connections in rats, in order to test whether synapses could be restored during a complete pharmacological blockade of synaptic transmission. We found that reinnervation of the rat diaphragm muscle proceeded normally even when acetylcholine receptors were completely blocked by sustained administration of alpha bungarotoxin (coupled with artificial respiration), demonstrating that synaptic transmission was not required for morphologically healthy synapses to be restored.

A third project, which turned out to be the most interesting and significant of my Oslo research, was a study of synapse elimination in newborn rat pups. In 1974, Michael Brown came to Jan’s lab for a sabbatical from his faculty position at Oxford. Michael and Jan decided to follow up on some intriguing observations by Redfern (1970), suggesting that newborn rat muscles have multiple synaptic inputs instead of the strictly single synapse per muscle fiber that is a highly distinctive feature of adult skeletal muscle. They quickly confirmed Redfern’s initial observations, and it became clear that there were many interesting follow-up experiments worth doing. Michael and Jan generously invited me to join the collaboration. The next few months were quite exciting, as we carried out a variety of experiments to systematically characterize the polyneuronal innervation and synapse elimination phenomena. We ruled out electrical coupling of muscle fibers and showed that motor units were many times larger (in terms of the fraction of muscle fibers innervated by individual motor axons) at birth than they were just a couple of weeks later. I found the writing of the paper on these results (Brown et al., 1976) to be the most interesting of the publications I had worked on up to that point, because of the intriguing developmental issue that arose. The reasons why muscles have this vast initial excess of synapses was (and still is) puzzling. But we were optimistic (correctly so) that this would prove to be an excellent model system for studying synaptic competition and pruning of excess synaptic inputs, as Jeff Lichtman and many others would later demonstrate.

Jan’s lab was small, but his lab and the nearby scientific environment were intellectually very stimulating. Eric Frank, my graduate student colleague at Harvard, had also decided to do a postdoc with Jan, which he began in 1972, a year ahead of me. Terje Lømo (codiscoverer of long-term potentiation [LTP], when working with Tim Bliss) was also working on neuromuscular development and plasticity in the same building. Our groups interacted very closely, and Terje became a good friend. Per Andersen, a pioneer of hippocampal slice physiology, was also an excellent neuroscientist and a good colleague at the university.

Most of our Norwegian colleagues and friends spoke excellent English, but Isabel and I had started learning Norwegian while still in Boston. We continued learning and practicing our host country’s language for many of our nonscientific interactions. Our life outside the lab mostly centered on outdoor activities—the Norwegian love for outdoors in all seasons was part of what had drawn us to Norway. Our apartment was on the outskirts of Oslo, right next to the Nordmarka forest that ringed the city. Eric Frank and his wife Jane lived in the apartment upstairs from us, and on weekends we often went out together, hiking in the summer/fall and cross-country skiing in the winter/spring.

Isabel became pregnant during our first year, but that didn’t slow her down much from our hiking and cross-country skiing ventures. Our first son, Scott, was born in August 1974, a day after Isabel had picked many kilos of strawberries at a nearby farm. A few days after Isabel and Scott came home from the hospital, Seymour Benzer came to Oslo to give a lecture. Jan and I had gotten to know Seymour from our summer at the Salk Institute in 1970. Seymour was a genuine food connoisseur, known for carrying a little black notebook crammed with information about restaurants and foods. Isabel and I volunteered to host a dinner party for Seymour at our apartment. (Jan at that time was living in a cottage that was too small and rustic to serve for the event.) Jan decided that the menu should highlight some fresh Norwegian crayfish, and he knew how and where to catch them. The night before the dinner party, Jan and I drove to a stream some ways out in the forest. Around midnight (once it finally got dark!), we put on rubber galoshes, waded down the middle of the stream, and used flashlights to make the crayfish “freeze” with their claws extended so as to make them easy picking. We grabbed many dozens of crayfish in a couple of hours, then headed home. The next night Isabel and I hosted the dinner party for Seymour, with strawberry shortcake accompanying the crayfish steamed with dill. I suspect the recipe made it into Seymour’s notebook, and perhaps mention of our nine-day-old son as well.

Many Norwegians had a family cottage (hytte) up in the mountains or along the seashore, where it was traditional to spend much of their holiday time. We were extremely fortunate that many of our colleagues and friends invited us up to their family hytte to share their special Norwegian experiences. The most rustic and our favorite was Jan’s hytte (Bakkevolden), which we visited several times. It was several hours northeast of Oslo and a short hike from the nearest road. There was no electricity, and water arrived only when someone lugged it up from a stream a short hike away. We had additional memorable experiences at the hyttes of Per Andersen and of several other friends we continued to visit during many return trips to Norway in subsequent years.

Our son Scott was a mellow little fellow, amiable from the outset. Two days a week, he stayed with me at the lab, staring at oscilloscopes while Isabel took a Norwegian course. Anyone walking into the lab might catch Jan and me doing an experiment at our rig, Jan with a pipe and his omnipresent dog underfoot, and me next to Scott in his pram. Isabel also learned the craft of pottery, working closely with a local Norwegian potter, Liv Keller, who has remained a close friend over the years.

London and My Start as a Cartographer

In the summer of 1975, Isabel, Scott, and I boarded a ship from Oslo to Newcastle, England. All of our belongings were crammed into our Volvo station wagon, and there was momentary angst as we watched a crane lower our car into the bowels of the ship while dangling from (what seemed to be) the most tenuous of cables. We drove to London and settled into an apartment in Finchley Central, north of the city. Living in England was a very different experience than Norway, both scientifically and socially. We made good friends with several of the neighbors and enjoyed playing in the local tennis club, but social interactions with my academic colleagues were infrequent. Here, I focus on the scientific aspects, as this became my entrée into a career as a cortical cartographer.

In Semir’s lab, the original plan was that we would study color processing in macaque area V4, following up on the findings he had presented in Boston but using a fancy new video graphics display he had just acquired. By then, he had published his earlier work and reported that all of the cells he encountered in V4 were color selective (Zeki, 1973). In the first few neurophysiology experiments in his lab, we found more of a mixture, in which many cells were color selective as expected, but many others appeared rather nonselective. However, it was unclear whether we were actually recording from area V4 as intended. This uncertainty persisted even after postmortem histological sectioning and reconstruction of electrode tracks. The heart of the problem was that the cortical convolutions were complex in the region we were exploring, as were the relationships that previously were reported between areal boundaries and the convolutions (Zeki, 1971).

After considerable discussion, I persuaded Semir to combine our neurophysiological recordings with an anatomical approach to delineating areal boundaries. Specifically, we surgically transected the corpus callosum prior to the neurophysiological recordings, then mapped the distribution of degenerating axonal terminations as a marker of the vertical midline between the left and right visual hemifields, which Zeki (1970) had previously shown to be a marker for boundaries between visuotopically organized areas.

Cortical Cartography, Part I

Around this time I became impatient and frustrated with the conventional approach of analyzing and displaying anatomical data using drawings of histological section contours taken at irregular intervals through the brain (typically accompanied by side-view sketches of the brain with lines showing the level at which sections were taken). This approach forced readers to conjure up a three-dimensional (3D) mental image of what the topology and spatial relationships were. I found it very difficult to evaluate data spread across multiple sections within a single hemisphere or to compare results across different brains.

In mulling over the problem, I harkened back to an important paper I had learned about from David Hubel several years earlier, during an informal discussion at one of the afternoon tea breaks Hubel and Wiesel routinely held in the common room next to their lab. In the context of discussing their own ongoing work on macaque area V1, Hubel mentioned a beautiful study published a decade earlier by Daniel and Whitteridge (1961), who dealt with the convoluted configuration of the macaque primary visual cortex (V1) by proposing a mathematical transformation of V1 and its visuotopic organization using a quasi-ellipsoidal flatmap representation. Daniel and Whitteridge also generated a physical “inverse transformation” in which they took a smooth sheet of plasticene (clay) as a model and folded it into the approximate shape of a real calcarine sulcus; then they physically sliced the convoluted model and thereby replicated the appearance of the calcarine sulcus in histological sections. I recall Hubel concluding that area V1 is (sort of) like a football that has been split in half (a half-football for each hemisphere), then deflated by crumpling to fit inside the skull. I was intrigued, but had no glimmer at the time how important this conversation would become as a personal and practical introduction to cortical cartography.

Recalling Hubel’s comments from the Harvard days, it struck me that a solution to our conundrum in London would be to make a map that would flatten out the convoluted monkey prestriate cortex, analogous to what Daniel and Whitteridge had done for area V1. Indeed, Hubel and Wiesel (1972) had already started down that path by generating straight-line contour maps in order to flatten out small portions of primary visual cortex from their histological data. I started down the same road, using pencil and tracing paper to straighten out the contours of histological sections through monkey prestriate cortex in the region Zeki and I were mapping. However, it soon became apparent that the straight-line approach was fundamentally inadequate, given the complex folding in the region we were studying, where the lunate sulcus and the inferior occipital sulcus run close to one another. Moreover, for a short while, it appeared that this mapping effort might be further confounded by virtue of an observation suggesting that there is a physical “tunnel” between two neighboring sulci (the lunate and inferior occipital sulci; Zeki, 1971, Fig. 8). If correct, it would imply that the macaque cortex is topologically equivalent to a donut! Zeki and I reexamined the histological sections in question and determined that there was actually no “intersulcal tunneling” after all. Reassured that all was well topology-wise, I returned to my efforts to manually flatten the cortex.

Toiling away in my windowless office at University College London, I struggled for weeks using pencil and tracing paper to manipulate the shapes of magnified section contour drawings. Extensive trial-and-error efforts grudgingly yielded primitive flatmaps that spanned limited regions of convoluted cortex and met two key criteria: (a) preservation of topological relationships (no crossing over of contours) and (b) avoiding severe areal distortion (i.e., excessive scrunching or stretching between contour lines). During this period, Semir and I often went to lunch together, and I would update him on the progress of this effort. I think it is fair to say that he was tolerant but less than fully on board with the need for this effort. In the end, we published one major paper from the combined neurophysiology, neuroanatomy, and flat-mapping efforts (Van Essen and Zeki, 1978). The paper introduced area V3A, the first of many visual areas that I had a role in identifying. The cartography story picked up again at Caltech, but first there are other topics to consider, including how I ended up on the Caltech faculty.

Landing Back at Caltech

Some of the events that eventually brought me back to my undergraduate alma mater occurred in the spring of 1973, before I headed off to Europe. Jim Kelly and I went on a joint road tour, giving talks at several institutions, including Wash U, Caltech, and UCSF, which had expressed interest in our research. It was a bit awkward, because Jim and I had worked closely together and wanted each to share equal credit for our joint effort, but our hosts didn’t want a tag-team seminar. We worked it out by alternating, with one of us giving a seminar on our common postdoctoral work and the other giving a talk on his thesis research. By the time I headed to Norway, there were no firm offers, but some informal good “vibes” made it seem that job prospects were encouraging.

Isabel, Scott, and I returned to the United States for several weeks in the summer of 1975, including a memorable Cold Spring Harbor symposium on the brain, followed by visits to the three institutions where job offers had emerged: Harvard, Stanford, and Caltech. The lure of Harvard was great, where I had spent six wonderful years and had the opportunity to interact closely with Hubel and Wiesel and other esteemed colleagues. Stanford was highly attractive, in part because of the Bay Area milieu, but also because John Nicholls had moved there and Max Cowan was about to become chair of the department. Caltech was attractive as well, even though I had never felt a specific hankering to return to my alma mater. What appealed to me most about Caltech was a new building devoted to neuroscience (Beckman Behavioral Biology Labs, made possible by a generous Caltech benefactor, Arnold Beckman), with great colleagues, such as Mark Konishi, Jack Pettigrew, and John Allman, plus Jim Hudspeth and Jim Kelly who were about to accept offers for faculty positions. In addition, when I expressed an interest in being able to set up a lab that would enable continuation of my split focus (primate visual cortex and neuromuscular development), Bob Sinsheimer, the Biology Division chair, didn’t hesitate to make a commitment to enable that opportunity. Finally, much as I respected my former mentors, my instincts told me that I might be better off to set off on my own path. In the fall of 1975, I agreed to return to my old stomping grounds at Caltech the following summer.

Caltech (1976–1992)

In the summer of 1976, my family (including baby Scott and pregnant Isabel) headed west to southern California, and I joined the Caltech faculty. On the home front, we soon found a house in Pasadena that would remain our abode for the next 16 years. In December 1976, Isabel delivered Brian, our second son. (Once again, childbirth was linked to a lab-related event, as we had hosted postseminar dessert for Darwin Berg the evening before Isabel went into labor.) Brian was as colicky as Scott was mellow. Their personalities remained very different, but they grew up as close friends and have become outstanding adults and parents.

Before delving into my research program at Caltech, it’s worth commenting on the neuroscience community in those early days. The Caltech neuroscience faculty continued to grow in the late 1970s and early 1980s with the recruitment of Jeremy Brockes, Mary Kennedy, Paul Patterson, David Anderson, and later many others. Weekly NeuroLunch and monthly NeuroDinner events helped build a strong sense of community. I especially enjoyed the local environment on the third floor, with close interactions of my lab with students and postdocs in the Konishi and Hudspeth labs. Unfortunately, things did not work out well for Jim Kelly (a complex and sad story). After he moved on, Howard Berg joined the faculty, and for a while, my lab was sandwiched between biophysicists doing pioneering work on hair cells (Hudspeth) and bacterial motors (Berg). On the teaching front, Jim Hudspeth and I began many years of teaching the introductory neurobiology course (Biology 150). It was the successor to the course that had inspired me when taught by Felix Strumwasser, Antonie Van Harreveld, and Cornelius Wiersma back in 1966. Our “Bi 150” course proved to be popular, and it was particularly enjoyable because we had bright and intellectually curious students, plus great graduate student teaching assistants year after year. Coming up with thought-provoking, out-of-the-box homework and exam questions was challenging but especially enjoyable. I also led a graduate reading course in developmental neurobiology, which helped broaden my developmental perspective in ways that in due course impacted my own research.

On the research front, my lab at Caltech launched into our two-pronged effort to concurrently study macaque visual cortex and mammalian neuromuscular development. The next four sections focus on themes related to visual cortex: neurophysiology, anatomy and connectivity, cortical cartography, and neural computation. Our efforts on neuromuscular synapse elimination and development are covered later, in conjunction with developmentally oriented research I continued at Wash U.

I was very fortunate to recruit two talented Caltech graduate students early on. John Maunsell worked on the anatomy and physiology of visual cortex. John Bixby did his thesis work on neuromuscular development but also made important contributions to our early studies of visual cortex. (I muffed an initial chance to recruit Bill Newsome as well, but later he joined the lab as a postdoc after doing his thesis with John Allman.) We set up a neurophysiology rig for acute monkey recordings, initially not much fancier than what Hubel and Wiesel or Zeki had in their labs. In an initial study, we used these conventional approaches to examine the “motion selective” area in the superior temporal sulcus (STS), which Zeki had originally described but not named (Zeki, 1974). In a review for Annual Review of Neuroscience (Van Essen, 1979), I had proposed that this be called area MT (the middle temporal area) in the macaque because of its likely homology (i.e., common evolutionary origin) with area MT that John Allman (my colleague downstairs) and Jon Kaas had reported in the owl monkey a few years earlier (Allman and Kaas, 1971). This proposal didn’t sit well with Zeki, who published a paper asserting (based on thin evidence, I felt) that a homology of this area in owl monkey and macaque was most unlikely, instead intimating that the macaque area should instead be called V5 (Zeki, 1980). The evidence in favor of a homology was further buttressed by a subsequent anatomical and physiological study with Maunsell and Bixby (Van Essen et al., 1981), in which we reported important similarities in myeloarchitecture and topographic organization for MT in the two species. To this day, the most intensively studied macaque extrastriate area is variously known as MT, V5, or the hybrid term “MT/V5,” depending largely on which camp and continent one is affiliated with!

My postdoctoral training in visual neurophysiology had emphasized qualitative rather than quantitative approaches to analyzing and reporting receptive field properties. This bias was most colorfully articulated by David Hubel, who famously declared that “if you need to do statistics on your data to know whether the results are significant, then the results are probably not very interesting.” However, my perspective changed once at Caltech. I became convinced that visual cortex was far too complex to be adequately understood by mainly subjective and qualitative assessments. While I felt strongly that the time was ripe to shift to quantitative computerized experiments, I personally had only limited experience with computers and programming. Fortunately, Jim Hudspeth and I teamed up and convinced our chairman, Bob Sinsheimer, to buy us a computer that we shared between our (adjoining) labs for many years. Once our shiny new PDP-11/34 arrived, it was necessary to code everything from scratch, but fortunately John Maunsell proved to be extremely facile in programming the requisite software for neurophysiology data acquisition and analysis.

We also needed customized hardware for generating visual stimuli that could be systematically varied in size, orientation, speed, direction, color, and disparity. We enlisted the efforts of a superb Caltech engineer, Herb Adams, who was amazingly gifted at designing and building customized equipment for highly specialized purposes, based on verbal instructions and no need for detailed blueprints. Herb had previously done wonders for Mark Konishi and Jack Pettigrew in building customized hardware for visual and auditory experiments in their labs. The auditory spatial localization device for the Konishi lab was respectfully known as “Herb’s Hoop.” The system he built for my lab didn’t get a name, but it did include a 1,200-watt projector (cooled by a large fan) to let enough light through our narrow-band color interference filters. Electronic control devices linking the optical projector to our computer were made by Mike Walsh, another excellent engineer. This system served the lab well for a decade, until we transitioned to video graphics displays for stimulus generation.

Duly armed with our computer-controlled visual stimulation system, John Maunsell carried out the first quantitative studies of receptive field properties in macaque MT. He confirmed the high incidence of direction selectivity and quantified the tuning for speed and binocular disparity in this area. This was a major part of his thesis, but it was only half the story, as there is an anatomical part to follow.

Several talented postdocs joined the lab in the early days, including Ted DeYoe, Bill Newsome, Andreas Burkhalter, and Dan Felleman. Most of the ongoing projects used anatomical and physiological methods in combination to characterize the location, functional properties, and connectivity of several areas, including V2, V3, VP, V4, and MT. Together with the two Johns (Maunsell and Bixby), we made complementary advances on several broad fronts that warrant further consideration: cartography (flatmaps), hierarchies, and processing streams.

Cortical Cartography, Part II: From Pencil and Tracing Paper to the Birth of Computerized Cartography

Cerebral cortex is a thin sheet of gray matter that is convoluted to varying degrees in different species. Convolutions allow a large surface area to be crammed into a compact cranial vault, much as one crumples a sheet of paper to fit it into a small box. The developmental question of how the cortex “gets its folds” comes later in this story. In this section, the focus is on the methodological advances needed to represent the cortical sheet, initially by purely manual methods, but eventually succumbing to computerized methods of reconstruction, inflation, and flattening.

Soon after arriving at Caltech I wrote a grant proposal emphasizing our plans to capitalize on the pencil-and-tracing-paper cortical flat-mapping method I had developed in London. I proposed it as a workhorse method for analyzing and displaying anatomical connectivity data as well as physiological recording sites in various extrastriate visual areas of the macaque. After submitting essentially the same grant concurrently to NIH and NSF (as was allowed in those days), feedback came first from NSF in the form of seven written reviews plus a summary statement. In general, the reviews were very positive, but the majority had one common criticism. Simply put, most reviewers strongly disliked my new flatmap approach; the critiques can be paraphrased as, “the flat maps the PI proposes to use for displaying his results are incomprehensible and detract from an otherwise fine proposal.” Had I followed the majority opinion, I would early on have abandoned the flat-mapping approach altogether. On the other hand, National Eye Institute (NEI) enthusiastically funded my grant, and many other colleagues were supportive of our mapping approach.

An important milestone was reached when we extended the original method to generate flatmaps of the entire cerebral hemisphere (Van Essen and Maunsell, 1980). A small cottage industry sprung up in the lab, reflecting the time-consuming demands of processing data from every monkey experiment in which recording sites and/or tracer injections were carried out (usually it was both). We systematized the process for localizing recording sites and the distribution of retrograde and anterograde tracers by viewing histological sections under the microscope and manually plotting the data onto photographic enlargements of each section. A large draftsman’s table served as the focal point for generating pencil-and-tracing-paper flatmaps from photographic enlargements of histological sections, and then transferring anatomical data from photographs onto the flatmaps with submillimeter accuracy. Over time, shelves in the lab became crowded with primary data (slide boxes), binders containing the enlarged photos, and sliding drawer cabinets filled with many large flatmaps in various stages of preparation.

We used these flatmaps not only to study extrastriate cortex, but also for analyses of area V1, including its topographic organization (Van Essen et al., 1984) and the complete pattern of ocular dominance stripes (LeVay et al., 1985). We even slipped transiently into the netherworld of the LGN to map the retinotopy of all its layers (Connolly and Van Essen, 1984).

Even though there was growing acceptance of cortical flatmaps as a method for analysis and visualization, our methodology was slow to catch on in other neurophysiology and neuroanatomy labs. The main problem was that flatmaps were laborious to generate and required expertise that was not easy to obtain without hands-on training. Gattass and Gross (1981) developed an alternate method using physical unfurling of 3D wireframe models, but this wasn’t particularly easier or more accurate. The Ungerleider and Desimone lab ended up using both of these methods (Ungerleider and Desimone, 1986a, 1986b).

It was crystal clear that the entire cortical reconstruction and analysis process was a job that needed to be handed over to computers. My initial encounter with this notion had come in the early 1970s, in a story that once again involves David Hubel. Not long after he had waxed eloquent in the Harvard common room about the clay model of primary visual cortex made by Daniel and Whitteridge, Hubel expressed an interest in using computers to generate 3D reconstructions of area V1 in the convoluted calcarine sulcus that he and Torsten were studying in the macaque. Since they hadn’t yet gotten a computer in their own lab, Hubel decided to spend several weeks working on the problem using a “high-power” computer Sydney Brenner made available in Cambridge, England. Soon after his return, I recall Hubel grumbling about how it was a much harder problem than he had envisioned. This turned out to be an understatement, to put it mildly! But my exposure to his experience had planted a seed, and I was keen to begin moving forward on this once I set up my lab at Caltech.

Obviously, the computers needed proper instructions (algorithms and code) in order to get the job done. This was far easier said than done, but little did I realize that it would take nearly two decades for such a seemingly simple concept to become a practical reality. The first part of the puzzle was to reconstruct a 3D model of the cortex based on information contained in a set of two-dimensional (2D) images obtained from histological slices. My first stab at the problem was in the late 1970s, when I teamed up with Gilbert McCann’s group at Caltech to reconstruct a chunk of macaque occipital cortex (see Van Essen, 2012, Fig. 1). However, surface generation and visualization were painfully slow, even though we were using stateof-the-art surface rendering software and the latest hardware (McCann’s PDP-10 computer). A decade later, my lab acquired a state-of-the-art Silicon Graphics Inc. (SGI) computer that had much better surface rendering capabilities (to the tune of $80,000, a whopping price at the time!). With considerable effort, my student George Carman and our programmer Dave Bilitch implemented a first-generation surface reconstruction program (called “anatomy”). The second part of the puzzle was to generate a flatmap of the cortex, given the information contained in a 3D model. Hence, in parallel, George tackled the cortical flattening problem. He implemented an algorithm based on simulated annealing that could indeed flatten area V1, but it was painfully slow and didn’t scale well with larger cortical expanses such as an entire hemisphere. We learned to appreciate the serious computational challenges of generating accurate surface reconstructions and flatmaps (Carman, 1990; Carman et al., 1995). Around the same time frame, other groups implemented alternative approaches to the cortical flattening problem (Schwartz et al., 1989; Wolfson and Schwartz, 1989; Dale and Sereno, 1993). This marked the beginning of a new era for the field, but my part in this story takes place mostly at Wash U and is covered later.

Hierarchies and Processing Streams

The story now reverts to the early 1980s. John Maunsell’s thesis research on physiologically characterizing MT receptive field properties was complemented by an analysis of cortico-cortical connectivity after injection of retrograde and anterograde tracers into MT. John’s results provided evidence for several newly identified visual areas as well as many previously unreported anatomical pathways. As he was trying to wrap this up and write his thesis, I recall challenging him to go beyond simply cataloging these new areas and pathways, but instead to strive for a broader synthesis. One Saturday morning I came into the lab, and John excitedly (especially for him!) asked me to come to his office. The night before, he had sketched out on his office chalkboard a schema for what turned out to be the first anatomically principled visual cortical hierarchy. He built upon observations by Rockland and Pandya (1979), that feedforward and feedback pathways have distinct laminar patterns of connectivity. Applying these pairwise relationships to known connectivity of MT and other areas resulted in an orderly hierarchy, based on 13 areas and six hierarchical levels, inferred from 36 pathways incorporated into this initial version.

At that time, many neuroscientists equated the notion of a neurobiological “hierarchy” with the unidirectional “serial hierarchy” proposed by Hubel and Wiesel for physiological cell types, in which (as described already) LGN axons made synapses onto cortical simple cells, which in turn converged onto complex cells, which in turn converged onto hypercomplex cells (Hubel and Wiesel, 1962, 1965). We decided to use the same term, but to generalize its usage to reflect an appropriately broader definition of a hierarchy as a system in which each component (cortical area) has a well-defined position (higher, lower, or equal) relative to the others. Our proposed anatomically based hierarchy embraced several key features, including (a) feedback as well as feedforward pathways, (b) multiple areas at a given hierarchical level, and (c) pathways that traverse more than one hierarchical level (Maunsell and Van Essen, 1983; Van Essen and Maunsell, 1983). In the meantime, some local pundits (notably including Bill Newsome) speculated that MT actually stood for Maunsell’s thesis.

John’s initial hierarchical scheme underwent substantial evolution and expansion over the subsequent decade. One important set of developments centered on the discovery of anatomically and functionally distinct modules within early visual areas (V1 and V2) and the hypothesis of parallel processing streams that a number of labs were exploring around that time. Livingstone and Hubel (1984) reported that V1 included an array of “blobs” having low orientation selectivity and high color selectivity (and somehow overlooked in earlier studies of orientation columns); these were surrounded by “interblobs” that were high in orientation selectivity and low in color selectivity. These modules in V1 showed specific patterns of connectivity with a coarser tripartite pattern of “stripes” in V2 (Livingstone and Hubel, 1984). Ted DeYoe and I used dual tracer injections, one into V4 and another into MT, to demonstrate that the V2 stripes are distinct from one another in their connectivity with areas V4 and MT and in their physiological characteristics (DeYoe and Van Essen, 1985); similar results were reported by Shipp and Zeki (1985). We later provided evidence for modularity at higher levels, within V4 and adjoining inferotemporal cortex (DeYoe et al., 1994).

These and other studies around that time linked the cortical processing streams to specialized subcortical channels, particularly the parvocellular (P), magnocellular (M), and koniocellular (K) cells in the retina and LGN. A seductive hypothesis (the one-stream, one-function point of view) was popularized, in which each processing stream was distinct from the others both functionally and anatomically, and was highly specialized for processing motion, form, and color respectively (Livingstone and Hubel, 1984; Shipp and Zeki, 1985). There was indeed experimental support for this hypothesis, especially if one looked at the data selectively. However, my lab emphasized from early on that cross-talk between processing streams also occurs and is fundamental to a deeper understanding of visual processing (Van Essen and Maunsell, 1983). We promoted an alternative perspective of “concurrent processing streams” (DeYoe and Van Essen, 1988) that gradually emerged as we incorporated a computational and psychophysically motivated perspective into our efforts, as discussed in the next section.

We continued to push forward on the cortical hierarchy front. I extended the analysis of visual cortex parcellation and connectivity in a chapter on visual cortex, part of a book series on Cerebral Cortex edited by Alan Peters and Ted Jones (Van Essen, 1985). The visual cortical hierarchy in that version had grown to 17 areas linked by 92 pathways. In 1990, I was invited to write a review on visual cortical organization for the journal Visual Neuroscience. I asked Dan Felleman to work with me on further updating the Maunsell and Van Essen (1983) and Van Essen (1985) versions of the hierarchy, given the many studies on cortical connectivity that had since been published. Plowing through the relevant literature turned out to be an arduous effort in which Dan and I each spent hundreds of hours in the library (what a quaint thought, nowadays!) and in our offices, trying to make sense of complex and often ambiguous figures or statements in hundreds of papers. As we began writing the review, we generated a revised visual hierarchy and parcellation that included 305 pathways among 32 areas that are largely visual in function. We also extended the parcellation to the entire cerebral cortex and the analysis to include a hierarchical scheme for somatosensory and motor cortex as well. It thus became clear that this was a story about cerebral cortex in general and not just visual cortex on its own. We ended up submitting our manuscript to the newly launched journal Cerebral Cortex (after apologizing to the Visual Neuroscience editor for jumping ship). It became not only the inaugural article of the new journal but also my most widely cited publication by far (more than 5,000 citations to date). The “Felleman and Van Essen” flatmap is imprinted on a T-shirt and was the centerpiece of a large 50th-birthday cake made by Isabel. The iconic subway-chart hierarchy is imprinted on a unique tie given to me by Erin Reid, which I wear on special occasions!

In subsequent years, I was occasionally asked whether I was planning to update the cortical hierarchy to incorporate another round of recently reported cortico-cortical pathways identified in the literature. My response was that I flat-out refused to consider an update to the monkey connectivity analysis by the same approach of poring over the literature to extract qualitative assessments of connection strength and areal boundaries. Instead, I was keen to shift our efforts in a direction that would enable more quantitative and precise assessments of the complexities of cortical circuitry. Key methodological advances that were needed included (a) automated surface reconstruction and flattening, (b) quantification of connection strengths to supplant the qualitative assessments or impressions from images, (c) improved intersubject registration, and (d) more accurate cortical parcellations. Over the next two decades, my lab would contribute to progress on each of these fronts, but it has been a long and unexpectedly challenging endeavor. It has also been highly rewarding, especially toward the end of the chapter. But next we switch back to neurophysiological themes, with a strong dose of computational and psychophysical perspectives included.

A Computational Perspective—Beyond Bars and Edges

The Hubel–Wiesel school of cortical function in which I was trained had promulgated the use of bars and edges as core visual stimuli used for visual neurophysiology. These had proven spectacularly successful for probing V1 and other early areas, and we got a lot of mileage exploiting them for many years and many studies of extrastriate visual areas in my lab. However, they were obviously inadequate for probing more complex aspects of form processing. Alternative types of visual stimuli were available in the early 1980s, but each had its limitations. One came from the spatio-temporal school, which used gratings of variable spatial and temporal frequency to characterize cells in ways that complemented what one could learn using bars and edges. While I had come to appreciate the strengths of the spatiotemporal frequency approach (overcoming a bias against it inherited from my mentors), conventional sinusoidal gratings lacked the flexibility to probe more complex spatial shapes. A third approach promulgated by Charlie Gross, Keiji Tanaka, and others was to use a potpourri of complex and sometimes ethologically relevant stimuli such as faces, squares, circles, and bottlebrushes. While these yielded intriguing observations, they weren’t appealing as a way for my lab to go forward, given that the stimuli and stimulus spaces were difficult to parameterize and explore systematically.

Over the two decades between the mid-1980s and the mid-2000s, many talented students and postdocs in my lab studied a diverse set of neurophysiological topics relating to visual form, motion, depth, color, and attentional processing. This section includes a historical background on how we came to explore these topics, and it aims to put them in a broader computationally and psychophysically oriented perspective. Many of the projects discussed here were done partly or entirely after our move to Wash U; thematic continuity has trumped a parsing into geographically chunked segments.

My association with computational and psychophysical approaches to vision has a number of diverse roots. Two of them involve long-term collaborations with senior investigators, Bela Julesz and Charlie Anderson (the latter story comes a bit later). These collaborations were supported by a grant I was fortunate to receive from the Office of Naval Research (ONR), which was very important in letting our research program branch out from the ongoing neuroanatomical and neurophysiological efforts supported by the NEI. Other influential factors included my extended participation in the southern California Helmholtz Club and in Caltech’s interdisciplinary Computation and Neural Systems (CNS) graduate program.

Bela Julesz (now deceased) was a psychophysicist whose home base was at Bell Labs in New Jersey. Our interactions started when he came to Caltech in the early 1980s as a Fairchild Distinguished Scholar to give a series of lectures on stereoscopic depth perception (he pioneered the use of random-dot stereograms) and on texture vision. Using visual stimuli that included large arrays of oriented texture elements, Bela had formulated a “texton theory,” hypothesizing that these texture elements represented fundamental elements of visual perception. I was not enamored of the texton theory, but Bela’s psychophysical observations were intriguing, and they provided a valuable entrée into more complex categories of stimuli for neurophysiological experiments. We struck up a collaboration to link psychophysics with the neurophysiology of texture processing. Starting in the mid-1980s, Bela came to Caltech annually for several months during the winter to teach and do research. Bela was a complex character, fond of telling jokes in his heavy Hungarian accent. He qualified as a “high-maintenance” collaborator insofar as his large ego needed regular stroking, but our collaboration thrived for the remainder of my time at Caltech. Bela and I jointly mentored a number of postdocs (Dov Sagi and others) who carried out psychophysical studies at Caltech. On the neurophysiological front, we began several psychophysically inspired projects, including examination of neural responses to texture contrast in area V1 (Knierim and Van Essen, 1992) and to moving texture patterns in area MT (Olavarria et al., 1992). These efforts were also important from a methodological perspective. It brought us into the realm of using computer-generated visual displays—thanks to a lot of effort from Ted DeYoe and our programmer, Dave Bilitch.

Jim Knierim’s project represented our first foray into alert macaque recordings, which would later become the dominant component of our neurophysiology research. It took a lot for Jim to learn the ropes, as there wasn’t a nearby lab doing alert macaque recordings. In retrospect, it might have been helpful if I had taken a sabbatical to learn more of the ins and outs in a lab that routinely did alert monkey training and neurophysiology. But I have always had many scientific and administrative balls in the air on the home institutional front and have never arranged for even a brief sabbatical—to Isabel’s disappointment, as I am occasionally reminded.

Another influential development was a decade-long participation in the Helmholtz Club, a gathering of vision neuroscientists in Southern California, held monthly for an afternoon and evening at UC Irvine, near the group’s geographic center. The Helmholtz Club was organized by Francis Crick and several others in 1982, a few years after Crick had come to the Salk Institute and turned his attention to neuroscience. One of Crick’s lasting contributions to neuroscience was to catalyze wide-ranging, intense discussions that brought together investigators with diverse neurobiological, psychophysical, and computational perspectives, as epitomized by the Helmholtz Club (see Aicardi, 2014, for an informative history).

On the Caltech computational front, an important early seed involved the recruitment of John Hopfield, a theoretical physicist from Princeton whose interests had turned to neuroscience. Murph Goldberger, the president of Caltech, had come from Princeton and felt that it would be a great idea to recruit Hopfield to Caltech. The biology faculty were initially lukewarm about having a theoretical neuroscientist in their midst, so it ended up that Hopfield was recruited to the Chemistry Division. Not long after his arrival in 1980, Hopfield and I met for an exploratory conversation in hopes we could find common intellectual ground for a more sustained dialogue. However, we didn’t speak a common language and couldn’t find much traction initially. This “impedance mismatch” would change markedly over the next several years. For starters, reading David Marr’s book, Vision (Marr, 1982) had a major impact on my thinking. In broad strokes, Marr articulated the importance of jointly considering three key aspects of vision: what are the computational tasks that need to be solved, the algorithms needed to accomplish the tasks, and the neural “hardware” that implements the algorithms? He also emphasized the highly inferential nature of vision as a process for generating percepts of a rich 3D world from a pair of 2D images. I considered Marr’s book very insightful, but it wasn’t immediately clear how we should adapt my lab’s experimental approaches to incorporate a more computational perspective.

Ted DeYoe and I had many discussions in which we strove to incorporate Marr’s conceptual framework with our perspective on the neuroanatomy and neurophysiology of cortical modules and processing streams. These discussions evolved into an article on “concurrent processing streams,” which we wrote for Trends in Neurosciences (DeYoe and Van Essen, 1988) and which occupies a special niche when I reflect on my various reviews and perspective articles. Ted and I argued that the relationship between low-level sensory cues and the higher-level attributes inferred by perceptual processes can be subdivided into a set of “Marr-style” computational strategies, such as structure from motion, shape from shading, and various other tasks. These strategies are presumably represented algorithmically by neural subsystems within an overall hierarchy that benefits from crosstalk and interactions among the anatomically identified processing streams. This didn’t by any means resolve the key questions, but I found it an appealing way to begin getting a better handle on observed anatomical and neurophysiological complexities.

In 1984, Caltech recruited Jim Bower to the neuroscience faculty as an experimental neuroscientist working on olfactory cortex. I got to know Jim extremely well, starting from early on because Isabel and I hosted his family (with two young kids) at our house for a couple of weeks once they arrived in Pasadena and were looking for housing. Also, Jim set up his lab right next to mine, in the space vacated when Jim Hudspeth moved to UC San Francisco. Jim (Bower) and I shared a growing interest in neural computation and had frequent conversations on that front.

Around that time, John Hopfield teamed up with Carver Mead (an engineer and pioneer in VLSI computer chips and “neuromorphic computation”) to teach a course on the Physics of Computation at Caltech. This morphed into a year-long triplet of courses when Richard Feynman joined the chorus the following year. The ensuing buzz around campus about the promise of interdisciplinary approaches to studying the brain motivated the Caltech administration in 1986 to endorse the creation of the Computation and Neural Systems (CNS) graduate option (training program; see https://en.wikipedia.org/wiki/Computation_and_Neural_Systems). This included the recruitment of Christof Koch, a talented postdoc of Tomaso Poggio at MIT. In an amusing déjà vu of Jim Bower’s arrival, Christof and his family (again with two young kids) also stayed with Isabel and me when they arrived in Pasadena and were looking for housing.

John Hopfield served as leader of the new CNS program, and I took on the role of option representative, which included administrative responsibilities in overseeing the graduate program. Christof and Jim were energetic, irrepressible, and charismatic characters, distinct from one another. Together they became a dynamic duo who helped energize and make the CNS program really take off in terms of recruiting talented graduate students keen to work at the interface of computation and neuroscience.

In 1988, Christof and Jim organized a computational neuroscience course at Woods Hole (which is still going strong after 28 years, with fresh leaders every five years!). I enjoyed giving lectures in this course for the first couple of years. It was another great opportunity to bring my family to the east coast (where we had friends and relatives), live in a cottage near the beach, and be immersed in an intensive summer course experience (oh, yes, and to thrive on the famous peppermint ice cream at a little shop called Jimmy’s!).

Back on the Caltech front and a few years earlier, I struck up a collaboration with Charlie Anderson, a physicist and engineer from RCA Labs, near Princeton. It started in 1984, when Charlie did a sabbatical in John Hopfield’s lab. Charlie had been working on machine vision using insights gained from human psychophysics. He and his RCA colleagues had implemented sophisticated image-processing algorithms to efficiently extract useful information from natural visual scenes. Charlie stopped by my office one day to introduce himself and to ask if we could talk about vision. We struck up a conversation that turned into a collaboration extending over more than two decades. It turned out we had a natural complementarity, insofar as Charlie’s expertise in physics and engineering and interest in neuroscience meshed with my expertise in the latter and interest in the former. There was still a communications barrier, especially initially. Charlie thinks deeply at a high level of abstraction; one of his favorite aphorisms extends the vintage “a picture is worth a thousand words” to “an equation is worth a thousand pictures!” My forte is in the neurobiological nuts and bolts, and though I love and respect equations as well as words, I am more comfortable with the latter. At a personal level, we found it amusing to realize that Charlie had gotten his BS from Caltech and his PhD from Harvard both exactly 10 years before me. A strong friendship also grew, not only between Charlie and me but also between our spouses, Pat and Isabel.

From the outset, Charlie was a strong proponent of the view that the nervous system as a whole is extremely well engineered. This can be appreciated most readily in peripheral sensory structures (e.g., eyes and ears) where detection (sensitivity) and discrimination approach what the laws of physics will allow. Inside the skull, Charlie argued that the brain is not just a “bag of tricks” as advocated by some (Ramachandran, 1985). Instead, it must use very sophisticated information processing strategies that reflect evolutionarily driven good engineering, even though the underlying computational principles are more challenging to decipher. These ideas resonated with me, and over the years, we found common intellectual ground in talking about the engineering as well as the neurobiology of the visual system at many levels, from the retina, through V1, and to higher-level visual processing.

One of Charlie’s provocative early ideas was based on the notion that dynamic routing of information, regulated by specialized control circuitry, must be fundamental to the workings of the brain, including the visual system. He proposed a novel computational construct, which he called “shifter circuits,” that he initially proposed could mediate the phenomenon of directed visual attention. These ideas initially struck me as somewhat implausible in terms of how they might be wired in real neural circuits. But the more we discussed this, the more I was persuaded that there must be something to it. The feedforward anatomical connectivity of visual cortex, with its progressive convergence at successive hierarchical levels, simply can’t explain many of the profoundly dynamic aspects of visual perception.

Once Charlie returned to RCA labs in Princeton after his sabbatical year, we continued our collaboration long distance, and I stayed with Charlie and Pat a couple of times while I was on the east coast. We published our first paper together in Proceedings of the National Academy of Sciences (PNAS; Anderson and Van Essen, 1987) proposing three distinct ways in which shifter circuits might operate at different levels to (a) stabilize depth perception despite empirical evidence of inherent “instabilities” in alignment of the two eyes, (b) compensate for motion blur (why do we have sharp percepts of moving objects despite spatio-temporal blurring as they streak across the retina?), and (c) mediate directed visual attention (how do we focus our visual attention on a tiny fraction of the information contained in visual images, while adjusting the location and spatial scale at which attention is directed from moment to moment?).

In 1987, Charlie and Pat moved to Pasadena, so that Charlie could work primarily at the Jet Propulsion Lab (implementing a multiresolution imaging system for the Mars Rover) but also have a part-time faculty appointment at Caltech to continue our collaboration once again at close range. Many of our early perspectives were summarized in a book chapter (Van Essen and Anderson, 1990) that provides a more in-depth analysis of several fundamental aspects of visual system organization, function, and dynamics, from retinal representations through higher visual processing. Bruno Olshausen joined the lab as a CNS grad student jointly mentored by Charlie and me. Bruno expanded on Charlie’s computational model of shifter circuits for visual attention (Olshausen et al., 1993, 1995). We also proposed useful ballpark estimates relating to key information bottlenecks in the visual system (Van Essen et al., 1991; see also Anderson et al., 2005): (a) at the front end, the optic nerve conveys only about 2% of the spatial information available in retinal images; and (b) at high levels, directed visual attention at any one moment accesses much less than 1% of the information transmitted via the optic nerves—it effectively “sees” a ∼30 × 30 array of “sampling elements” that shift dynamically in location and spatial scale.

Ed Connor joined the lab in 1989 as a postdoc (starting at Caltech, then moving to Wash U) to carry out neurophysiological tests of the shifter circuit hypothesis. Ed demonstrated dramatic attentional effects in V4, much larger than typical attentional modulatory effects reported before or since (Connor et al., 1997). This is important in view of the numbers just cited regarding the narrowness of the “attentional bottleneck.” The effects Ed reported supported the shifter circuit model in broad strokes, though there were complexities that weren’t easy to reconcile with a simple version of the model. Chris Eliasmith’s group has recently extended Bruno’s shifter circuit attentional model with a more neurobiologically plausible spiking neuron model (Bobier et al., 2014) that includes population coding and the neural engineering framework discussed later (Eliasmith and Anderson, 2003). However, much of the “attention” of the visual attention field has mainly “shifted” in other directions relating more to phenomena such as temporal synchrony and interactions across frequency bands (e.g., Baldauf and Desimone, 2014; Landau et al., 2015). These are important phenomena, but the jury is still out regarding which approach will provide deeper explanatory power for directed visual attention.

In 1990, I was invited to talk at a Cold Spring Harbor Symposium on the brain. As it happened, my talk was scheduled for the late evening, at the end of an exhilarating but exhausting day of excellent presentations. I was trepidatious about giving the talk, as I feared that my words might be drowned by loud snoring from a very sleepy audience—especially because I had crafted a jam-packed overview, filled with lots of facts as well as perspectives. But the feedback I received was very positive, and I was pleased that an editor from Science who attended the meeting promptly followed up with an invitation to write a review article recapitulating the thrust of that presentation (Van Essen et al., 1992).

In 1987, Jack Gallant joined my lab at Caltech, having done visual psychophysics research as a graduate student but wanting to learn singleunit monkey neurophysiology. Inspired by a combination of psychophysical observations and computational considerations, Jack designed a family of “non-Cartesian” gratings and showed that many cells in area V4 responded better to rings, spirals, radial, or “hyperbolic” patterns than to conventional (Cartesian) sinusoidal gratings. This made for a colorful cover article in Science (Gallant et al., 1993), but more importantly provided insights relevant to how complex patterns and surface shapes are processed and perceived. These experiments were done in anesthetized monkeys, and Jack wanted to learn to train and record from alert monkeys. Soon after our move to Wash U (described below), Jack was inspired to head in a novel direction by examining neural responses during “free-viewing” (Gallant et al., 1998), an approach that he and others have followed up in subsequent years. On a personal note, Jack is the most irreverent (and at times acerbic) of those who I have mentored, and it made for many a lively conversation during his time in the lab.

After we moved to Wash U, Dan Marcus joined the lab in the mid-1990s and carried out an interesting project on how scene segmentation occurs in early visual areas. He showed that figures defined by featural contrast located well outside the classical receptive field elicited stronger responses than a simpler background stimulus and that this enhancement occurs in V1 as well as V2 but does not require visual attention (Marcus and Van Essen, 2002). While Dan showed talent and potential for neurophysiological research, his intellectual interests shifted, and he decided to switch fields after getting his PhD. He took a position in Randy Buckner’s neuroimaging lab in the Psychology Department at Wash U. Dan designed and implemented a database to handle human neuroimaging data acquired by Randy’s group and by other neuroimaging labs at Wash U and elsewhere. When Randy moved to Boston in 2005, Dan was persuaded to stay in St. Louis, join the Radiology Department faculty, and set up an independent neuroinformatics endeavor. While I was pleased with Dan’s decision for several reasons, I had no clue at the time how important his remaining at Wash U would become once the HCP came on the horizon.

Another project that I took a strong personal interest in was carried out by my student Xinmiao Peng. She found that many neurons in V1 and V2 respond to uniform illumination, but with a peak response to intermediate (gray) luminance rather than to the brightest (white) or darkest (black) stimuli (Peng and Van Essen, 2005). This ran counter to the conventional wisdom that V1 cells respond primarily to stimuli with spatial and/or color contrast within their receptive field. However, I had actually predicted the existence of “gray-preferring” cells on grounds that they would be computationally useful as a way to explicitly encode different shades of surface luminance. The inspiration for this prediction came from our efforts to implement algorithms for cortical segmentation, which occurred prior to Xinmiao’s arrival but are covered in a later section.

The last of the visual neurophysiologists in my lab was Aki Anzai, a postdoc who studied form processing in area V2. The highlight of his project was the identification of cells in V2 having receptive field subregions that differed in their orientation selectivity (Anzai et al., 2007), consistent with earlier work by Jay Hegdé in my lab (Hegdé and Van Essen, 2003). Such cells are reminiscent of the “higher order hypercomplex” cells that Hubel and Wiesel (1965) had identified in cat extrastriate cortex more than 40 years earlier. I found it amusing and a tad ironic that the final visual neurophysiology project in my lab would resonate so strongly with work done by my postdoctoral mentors from decades past.

By the mid-2000s, I found that progressively more of my time and interests were devoted to the brain mapping and neuroinformatics efforts discussed below. Hence, I decided to phase out our visual neurophysiology and neuroanatomy lab and not to renew the NEI grant that had generously supported our research for three decades.

Before discussing our relocation to Wash U in St. Louis, a few additional comments about family life in Pasadena and California are in order. Pasadena was overall a good place to raise a family, though it was quite disappointing to find that the quality of the public school system had sunk far lower than what Isabel and I had experienced in our childhood, when California schools were ranked top in the nation. (We mainly blame the infamous statewide Proposition 13 that gutted school funding.) Isabel and I persevered in keeping our kids in public school, but she spent countless hours shuttling Scott and Brian to educational and other extracurricular activities that enriched their academic experience. Other highlights of family life included annual vacations in the Sierra Nevada Mountains. Our favorite spot was Lake Edison—a beautiful secluded lake that sadly is currently hardly more than a puddle owing to a severe drought. We started with tent camping when the kids were very young but soon graduated to annual backpacking adventures. On one trip, we were lucky to survive because our Volvo’s brakes nearly went out as we descended a steep downhill stretch near our destination. In a fleeting fast forward several decades, it was great fun to revisit the Lake Edison region recently with two of our grandkids (Jonathan and Anna) in tow (along with Brian and his wife LeAnn), at ages three and five, even earlier than when we had started with Brian and Scott.

The Transition to Washington University

Prelude

Several independent developments paved the way for my ending up at Wash U. The two most significant were my (unexpected) increasing engagement in administrative roles, plus a growing interest in human neuroimaging.

When I joined the Caltech faculty, I aspired to follow in the footsteps of my mentors by maintaining a strong hands-on engagement in experiments. I was able to put in full shifts on round-the-clock anesthetized monkey neurophysiology recordings that sometime lasted up to a full week. I also enjoyed being a scientific good citizen, such as serving on graduate admissions committees, but I was happy initially to steer clear of major administrative responsibilities. That changed unexpectedly in 1982 when I was asked by chairman Lee Hood to take up the role of Executive Officer for neurobiology, helping represent neurobiology faculty within the Division of Biology—a position that Jim Hudspeth had capably filled before deciding to step down. I accepted this responsibility with some hesitation and trepidation, and I certainly did not suspect it would prove to be a proverbial slippery slope that would carry me much farther down the road of many leadership roles (including the aforementioned role of CNS option representative, but many more to come).

Human neuroimaging. In about 1984, Mark Konishi organized a small conference at Caltech on cutting-edge systems neuroscience. One of the invited speakers was Marc Raichle from Wash U, who spoke about positron emission tomography (PET) imaging and showed early PET images of human visual cortex being activated by visual stimulation. John Allman and I immediately struck up conversations with Mark about using PET to map visuotopic organization in humans. This turned into a broader collaboration that also involved Peter Fox and Fran Miezen (Fox et al., 1986, 1987). It also planted a seed that not only fostered my interest in human neuroimaging, but also helped steer me toward Wash U some years later.

As a brief sidebar, another unsuccessful effort to predict the future involved musings about fMRI in the late 1980s, after MRI-based methods for imaging human brain structure had become commonplace. It was natural to wonder whether some kind of MRI-based signal might somehow be used to image brain function. I recall a lunchtime conversation brainstorming on this issue at the Caltech faculty club with John Allman and Jack Richards (a father of nuclear magnetic resonance spectroscopy, which was a forerunner to MRI). However, our imaginations were too limited, as we keyed on phosphorus as the only potentially “useful” activity-dependent element (because it is in ATP), and we figured there just wasn’t enough phosphorus around to provide decent spatial resolution. We missed the boat completely by not considering the fact that blood oxyhemoglobin and deoxyhemoglobin have different magnetic properties that might influence the vastly more numerous hydrogen atoms in water. Years later, I reviewed the first study that used fMRI to map human visual cortex (Belliveau et al., 1991). It became a cover article for Science, but while I was enthusiastic about the study, I didn’t appreciate how it represented the tip of a large and rapidly growing fMRI iceberg.

Regarding Wash U, I had been aware that Gerry Fischbach had stepped down in 1990 as chair of the Anatomy and Neurobiology Department and that a search was under way for his successor. I knew that Lou Reichardt had turned down an offer of this position, and I subsequently heard my name mentioned in casual conversations as someone who might be considered for the position. I honestly gave it hardly a second thought until one day in the summer of 1991 when I received a call from Phil Stahl. Phil (who later became a good friend) introduced himself as a member of the search committee at Wash U and asked whether I would be interested in being considered for the chairmanship of the Anatomy and Neurobiology Department. I knew the department well, as it was Jim Kelly’s old stomping grounds, and I had visited and given talks there several times over the years. Also, I knew several of the faculty at Wash U, including my former postdoc Andreas Burkhalter as well as the acting chair, Nigel Daw. I told Phil that I would consider it even though I felt well ensconced at Caltech and wasn’t looking to move anywhere. I arranged to interview at Wash U right after the SfN meeting in New Orleans. As Isabel drove me to the airport for this trip, I recall saying it was rather unlikely that this would turn out to be an appealing opportunity. I was wrong. Partway through my interviews at Wash U, and literally while pausing for a moment on the bridge (over Euclid Avenue) that separated the preclinical and clinical portions of the medical campus, I had an internal phase transition. I suddenly not only realized that this was a great opportunity but that I really (gut to brain!!) wanted the position! I called the dean, Bill Peck, that evening to apprise him of my outlook. It took months for the search committee to make up its mind, but in late January 1992, Dean Peck called to say that Wash U would extend a formal offer. Isabel, Brian, and I visited in February, negotiated the specifics of the recruitment package, and looked at houses and school options for Brian. I accepted the offer officially in mid-March, circumventing a protracted negotiation process. Within a month we made an offer on a house that we really liked, where we have lived for the past two decades.

Two factors loomed large in reaching a decision to accept the offer at Wash U. One was the appeal of helping strengthen a department that had a long tradition of excellence but had recently lost many excellent faculty. The second was a keen desire to expand my brain-mapping efforts into human neuroimaging in addition to the monkey-centric efforts we had pursued up to that point. Caltech at that time had no MRI facility and no human neuroimaging research, whereas Wash U had a strong neuroimaging program led by Marc Raichle and others, including Steve Petersen who I had known at Caltech.

We were keen to start in the fall of 1992, so that our younger son Brian could begin his junior year of high school in St. Louis. (Our older son Scott remained in Pasadena, as he had just finished his freshman year at Caltech.) To get my lab ready in time required fast-tracking a complex renovation effort. Lucille Miller, our departmental business manager, worked wonders to make this happen in record-breaking time. Lucille had very capably served the department (and with great devotion and loyalty) since Max Cowan hired her in the early 1970s, but this was the first of many times when I benefited from her administrative magic.

Research Centered at Wash U (1992—)

Fortunately, my entire group of postdocs and students at Caltech agreed to join in the eastward migration to St. Louis, thus allowing my lab to maintain momentum on ongoing projects, with only a short hiatus imposed by the move. Our visual neurophysiology efforts at Wash U were already described above. The next few sections cover the diverse topics of neural engineering (brief but important), neural development (including the part that started at Caltech), and our ongoing multifaceted efforts in cortical cartography and atlases.

Neural Engineering

One of my concerns when I decided to leave Caltech was that it would be difficult to maintain a long-distance collaboration with Charlie Anderson, given that his primary position was as an engineer at JPL. To my pleasant surprise, Charlie was enthusiastic about moving to St. Louis and transitioning to a full-time faculty position in the Department of Anatomy and Neurobiology. This became possible through sustained support from the McDonnell Center for Higher Brain Function.

Charlie’s office was next to mine until he retired in 2008. We talked frequently and co-mentored a number of students and postdocs, including Subrata Rakshit and Brandon Westover. Over the next several years, Charlie had deep conversations with other Wash U colleagues, including John Clark and Steve Highstein, and we (mostly Charlie) formulated a “systems engineering” approach that combines signal processing, motor control, and statistical inference. This provided a robust foundation for a theory of neural computation and a practical strategy for tackling specific computational problems. To support this project, we were fortunate to receive funding from the Mathers Foundation, a small private foundation based in New York. James Handelman, the foundation’s scientific officer, was a colorful character who found personal enjoyment in supporting unconventional projects that included outside-the-box thinking, such as Charlie’s theories.

As these ideas were gaining momentum, we were joined by Chris Eliasmith, a graduate student in the Philosophy, Neuroscience, and Psychology Program who had an unusual background that included interests in engineering, philosophy, and neuroscience. Chris was already a talented writer as well as a deep thinker. Chris and Charlie teamed up to write a seminal book Neural Engineering (Eliasmith and Anderson, 2003) that articulated an innovative general strategy for attacking problems in neural computation from a combined engineering and neurobiological perspective. It includes a framework (the Neural Engineering Framework, or NEF) that builds on and formalizes various approaches to population coding pioneered by Apostolos Georgopoulos, Bill Newsome, Tony Movshon, Mike Shadlen, and others. The NEF focuses on how neural systems compute and represent real-valued analog variables. This includes a robust mathematical framework for estimating how neuronal ensembles both encode and decode information at various levels, from sensory inputs, through higherlevel “cognitive” abstract representations, to motor outputs that control behavior. Chris moved on to a faculty position at the University of Waterloo and has subsequently carried the flag through his modeling efforts there (e.g., Eliasmith et al., 2012).

Cortical Cartography, Part III: Caret, SumsDB, and Surface-Based Atlases

Our cartography efforts accelerated after the move to Wash U in 1992. A key starting point was when I recruited Heather Drury, who in the ensuing decade designed and implemented what became Caret (Computerized Anatomical Reconstruction and Editing Toolkit) software. In collaboration with Charlie Anderson, we developed a multiresolution approach to cortical flattening that was computationally efficient (Drury et al., 1996). In collaboration with Mike Miller in the Electrical Engineering Department, we developed methods for surface registration (Van Essen et al., 1998; see below). In 2001, Heather moved on, but I was fortunate to recruit John Harwell and Donna Dierker; their contributions over the subsequent decade allowed Caret to progress along many fronts (until we shifted to Connectome Workbench, a new platform discussed later). Over the years, Caret became a workhorse tool in our lab and for thousands of other investigators for (a) surface reconstruction, visualization, and shape manipulation; (b) atlases and surface-based registration (SBR); (c) mapping parcellations and functional data onto atlas surfaces; and (d) interspecies comparisons between macaque and human cortex.

My grad student Jim Lewis was an early beneficiary of Caret’s capability for reconstructing and flattening surfaces generated from postmortem histological sections and mapping experimental data onto the cortical surface. Jim used these tools to carry out a heroic set of analyses on the organization and connectivity of macaque parietal cortex (Lewis and Van Essen, 2000a, 2000b). This entailed parcellating the entire cerebral cortex using multiple architectonic stains and plotting the distribution of retrogradely labeled neurons following tracer injections into different cortical areas. This was along the lines of the approach pioneered by Joel Price, a good friend and colleague in our department who made seminal contributions to our understanding of orbitofrontal cortex (e.g., Carmichael and Price, 1994; Ongür et al., 2003). We were able to push the methodological envelope farther, by quantitatively mapping the distribution of retrogradely labeled neurons across the cortical sheet (Van Essen et al., 2001), thereby getting our foot in the door for the type of quantitative neuroanatomy I had long envisioned would be the wave of the future.

As it turned out, Jim was the last in the line of neuroanatomists in my lab who would carry out anatomical tracer-based experiments. It had become increasingly difficult to recruit students and postdocs and to obtain funding for “classical” neuroanatomy or even its modern computerized successors. I harkened back to conversations more than a decade earlier in which my neuroanatomical colleagues bemoaned the impending “death of neuroanatomy.” Most vivid was a conversation on this topic with Leslie Ungerleider and Bob Desimone at the Caltech faculty club (Athenaeum). As I recall, my argument at the time was that neuroanatomy was simply much too important and fundamental, so it somehow would “find a way” to survive. But little did I realize how a host of stunning methodological advances would enable neuroanatomy to undergo a truly extraordinary resurgence, to the point where many erstwhile “pure” molecular and cellular neuroscientists have become dedicated neuroanatomical enthusiasts. (David Anderson at Caltech provides one of the most vivid examples on my radar screen.) In any event, my own involvement with quantitative tracer-based neuroanatomy entered a quiet phase, but it would reemerge about a decade later when I began a collaboration with Henry Kennedy’s lab (see below).

MRI-based surface reconstructions. In the 1990s, it became routine to obtain high-quality structural MR images using conventional T1-weighted scans. This motivated many successful efforts to implement segmentation algorithms that capture the shape of cortical convolutions in individual subjects (e.g., Dale and Sereno, 1993; Teo et al., 1997; MacDonald et al., 2000; Kriegeskorte and Goebel, 2001; Fischl et al., 2001; Han et al., 2004). Our contribution to this effort involved the SureFit (Surface Reconstruction by Filtering and Intensity Transformations) cortical segmentation algorithm. The basic idea underlying SureFit emerged from discussions I had with Charlie and Heather. The idea was to formulate image-processing algorithms that emulate the strategies used by the human visual system when we accurately (and usually effortlessly) determine what is or isn’t cortical gray matter when inspecting a set of MRI slices. We came up with what I considered to be a clever set of strategies that in principle would be suited for a broad range of image segmentations applications (e.g., electron microscopic as well as MRI data). We decided (mostly at my urging) to patent the concept and the general method. We were successful in getting a patent, though it turned out to be quite an effort. Like most patents, the net result financially was a resounding zero in terms of commercial viability, but in any event, I take pride in this small feather in my cap. More important, Heather was able to implement SureFit initially into a free-standing application (Van Essen et al., 2001) that Donna Dierker later incorporated into Caret. It was widely used for a while, but never became totally automated. This became a serious limitation relative to competing methods such as the FreeSurfer method pioneered by Anders Dale, Marty Sereno, and Bruce Fischl (Fischl et al., 1999a, 1999b).

A distinctive feature of SureFit is that it generates segmentation and surfaces running along the cortical midthickness. This gives a representation of cortical surface area that is roughly proportional to the associated volume of cortical gray matter. Our emphasis on midthickness surface contrasts with other segmentation algorithms, including FreeSurfer, which generate surfaces running along the pial and/or white-matter boundaries. Fortunately, the midthickness surface can easily be obtained by averaging FreeSurfer white and pial surfaces once they are imported into Caret. It remains puzzling why a conceptually advantageous and simpleto-implement method hasn’t been more routinely adopted, but I suspect it mainly reflects inertia, which is all too common even among scientists.

Beyond segmentation per se, the effort to implement SureFit yielded insights regarding information-processing strategies that work on real-world data, but I believe also have broader generality. One is to avoid premature “decisions” by throwing away information too hastily. Whenever experimental data (imaging or otherwise) is thresholded, subject to binarization, or smoothed spatially or temporally, then information is lost that might have been helpful. If a little bit of signal is buried in a lot of noise, there may be clever ways of extracting it if it hasn’t yet been discarded. Hence, such steps should be postponed unless or until they are really necessary. Another is to capitalize on transformations of data that make it more useful, on its own or when combined with other sources. For example, SureFit used a simple “intensity transformation” that made gray matter bright instead of gray (as it is in a T1-weighted scan). This was the step that generalized to Xinmiao Peng’s characterization of “gray-preferring” cells in visual cortex described above.

Surface-based atlases. A major component of our brain-mapping efforts for the past two decades involves the generation, utilization, and sharing of surface-based atlases of cerebral and cerebellar cortex in multiple primate species—and even in rodents. The overarching perspective has been that atlases serve as an anatomical substrate for specifying where you are in the brain (by spatial location and in relation to functionally relevant areas, or parcels), and for comparing results across individuals and across studies. The importance of this idea has been generally appreciated in neuroimaging since the Talairach atlas was introduced as a book-based representation of stereotaxic coordinates and also of Brodmann cytoarchitectonic areas (Talairach and Tournoux, 1988). Also, Fox et al. (1985) promoted the use of stereotaxic coordinates for reporting activations in human PET imaging. Once MRI was on the scene, volume-based digital atlases were introduced, for example, the widely used MNI152 population-average atlas (Mazziotta et al., 1995). For cerebral cortex, I knew that surface-based atlases had much to offer, to enable mapping of data and subsequent analyses in ways that respect the topology of the cortical sheet. Some of these ideas were articulated in a “Solutions Are in the Surfaces” article in PNAS (Van Essen et al., 1998). We started down the computerized atlas road for macaque cortex using a histologically reconstructed individual surface (the “79–0” right hemisphere; Van Essen et al., 1998) and for human cortex using the Visible Man postmortem brain slices (Van Essen and Drury, 1997). Once high-quality MRI scans became available, we switched to the F99 atlas for the macaque and the Colin individual-subject atlas for humans (Van Essen, 2002a, 2002b). Among their advantages were the ability to represent subcortical data in volume slices as well as cortical data on surfaces.

Using a single subject as an atlas isn’t a big problem for the macaque, because the folding patterns are relatively stereotyped. It’s a major issue for human cortex, owing to the high degree of individual variability (Van Essen, 2004, 2005). Any individual human brain chosen as an atlas has intrinsic biases associated with the idiosyncrasies of its particular folding pattern.

As we emphasized early on (Van Essen et al., 1998), SBR is a critical part of the toolkit for multiple applications: (a) to register individual hemispheres to an atlas while respecting the topology of the convoluted cortical sheet, thereby preserving the spatial fidelity of data from each individual; (b) to enable generation of population average atlases that would circumvent the biases of any individual subject; and (c) to enable interspecies registration that would open the door for exploring evolutionary expansion and homologies. As mentioned, we teamed up for a while with Mike Miller’s group in Electrical Engineering, as he had mathematical expertise that complemented my lab’s expertise in neuroanatomy and developing software tools. Our initial method was able to deform one cortical flatmap to another. However, this served mainly as a proof of concept and did not become a workhorse tool because it was difficult to arrange the cuts needed for flat-mapping to be in corresponding locations in an individual and an atlas. It was clear that SBR would be better done using spherical maps as source and target, as shown convincingly by Bruce Fischl and colleagues with their FreeSurfer software platform (Fischl et al., 1999b). While I was impressed by the FreeSurfer method, it wasn’t directly translatable to some of the key needs associated with our lab’s surface-based atlases. Once Mike Miller moved on to Johns Hopkins, we pushed forward on our own. John Harwell and I implemented a landmark-based SBR method (Van Essen et al., 2005). I then used this approach to generate a human population-average landmark- and surface-based (PALS) atlas (Van Essen, 2005) that was our primary atlas target for many years. It was eventually supplanted by the Conte69 atlas that did capitalize on FreeSurfer’s SBR (Van Essen et al., 2012b).

Parcellations. Another role for surface-based atlases is to enable relating various types of data (neuroanatomical, neurophysiological, and neuroimaging) to cortical parcellations generated from other studies. For the macaque, we had relied for years on the Felleman and Van Essen 1991 (FVE91) parcellation, even though other competing parcellations provided alternative (and potentially more accurate) options. Once we had our hands on tools for SBR, we registered Jim Lewis’s parcellations (and connectivity data) to a macaque atlas (Van Essen et al., 2001) and began an extended effort to bring other macaque parcellations under a common atlas umbrella (Van Essen, 2004; Van Essen et al., 2012a). For human cortex, fewer parcellations had been accurately mapped to cortical surfaces, but we later (Van Essen et al., 2012b) mapped many of them to an atlas surface that summarized the current state of the art. Our general conclusion at that time was that there was a long way to go before achieving a consensus parcellation in either species. To presage what will come later, the human cortex has finally leapfrogged that of the macaque in terms of having a comprehensive multimodal parcellation.

We were also able to generate surface-based atlases of the intensively studied mouse and rat cortex (Van Essen, 2002a; Van Essen et al., 2005), initially using histologically based atlas reconstructions (Paxinos et al., 2000; Paxinos and Franklin, 2012). These were followed by MRI-based segmentations and surface-based atlases for both species. More recently, it has been very gratifying to see “ground truth” parcellations of mouse cortex emerge from the lab of my former postdoc, Andreas Burkhalter (Wang and Burkhalter, 2007; Wang et al., 2012) and also from the Allen Institute for Brain Science—though these have yet to be mapped to a surface-based atlas.

SumsDB. In anticipation that progressively more data would be mapped to our emerging family of surface-based atlases, I was also extremely keen to find better ways to share the data with the neuroscience community in a systematic but flexible way. In a nutshell, this called for a database that would be hospitable not only to data on surface and volume-based atlases but also on individual subjects. James Dickson joined the lab and worked with Heather and me to implement SumsDB (Surface Management System database; Dickson et al., 2001). This database was further refined by Ping Gu and has been populated by many diverse types of data, including more than 60,000 stereotaxic coordinate locations associated with nearly 2,000 studies, extracted from the literature and curated by Erin Reid in my lab. SumsDB is still widely used, but the uptake by the community in submitting their own data has unfortunately been less than I had envisioned. One lesson is that the process must be very user friendly for both submitting and accessing data in order to promote broad usage. To jump ahead for a moment, we are taking this to heart in our current efforts to implement a new database, BALSA (the Brain Analysis Library of Surface-based Atlases) by John Smith in my lab (http://balsa.wustl.edu).

Primate evolution and interspecies comparisons. Once we had surfacebased atlases available for macaque and human cerebral cortex, it was of interest to see how they could inform our understanding of cortical evolution. Humans and macaques diverged about 20–25 million years ago (http://anthro.palomar.edu/primate/prim_8.htm) from a small, lissencephalic common ancestral primate (Allman, 1977). Our atlases confirmed that human cortex has 10-fold more surface area than a macaque (a 13-inch pizza versus a medium-sized cookie for each hemisphere; Van Essen et al., 2005). It was also known qualitatively that cortical expansion in the human lineage has been highly nonuniform, with greater expansion in regions implicated in higher cognitive functions, but it was difficult to pin this down with solid numbers. Using a set of candidate homologies based on various studies, we coaxed the landmark-based SBR method described above into successfully deforming the macaque cortex into registration with human cortex (Orban et al., 2004) and using this deformation to estimate that evolutionary expansion is around 30-fold in some portions of lateral temporal, parietal, and prefrontal cortex (Van Essen and Dierker, 2007) but as little as twofold in early sensory regions.

Because the great apes occupy a special niche as our closest living relatives, I was excited to access a single chimpanzee’s MRI scans that enabled generation of a cortical surface reconstruction (Van Essen, 2006). More recently, Matt Glasser and I have been able to access a population of chimpanzee MR scans and to generate a population average atlas that includes myelin maps (Glasser et al., 2013b). Hence, even without access to fMRI or other modalities, the stage is set for evaluating interesting candidate homologies and systematically exploring differential cortical expansion across multiple primate species.

The cerebellum. While cerebral neocortex has dominated my scientific agenda, I have a special fascination with the cerebellum and also something of a “love-hate” relationship with it. I love the cerebellum for its beautiful organization at both a cellular level and at the macroscopic level of its accordion-like regular folds, compared to the more disorderly crumpling of the cerebral neocortex. The “hate” part (not really!) is because the cerebellar cortex has stubbornly resisted surface-based analyses to a frustrating degree. Its resistance to segmentation and surface reconstruction reflects the fact that it is very thin (about one-third that of typical neocortex) and has very little white matter underneath its graceful lobules and lamellae. Once I got access to high-resolution MRI scans for human, macaque, and rodents some years ago, I was keen to put SureFit through its paces in order to obtain the first cerebellar surface reconstructions. Alas, the initial segmentations were downright crummy. I persevered, spending hundreds of hours manually editing these segmentations (especially the human Colin cerebellum). Once reasonably faithful surface reconstructions were obtained, it was another arduous task to flatten the cerebellum, because it is essentially a very long and skinny sheet with internal irregularities that were resistant to “well-behaved” flattening. Finally, they yielded, and I was very pleased to report on human, macaque, rat, and mouse cerebellar surfaces (Van Essen, 2002b) and to make them part of our freely available atlas suite available via SumsDB. Recently, Marty Sereno has generated a higher-quality human cerebellar segmentation using a postmortem MRI scan; it shows about twice the surface area of the Colin cerebellum that I segmented. However, it is inadequate for many purposes to have just an atlas cerebellar surface based on a single individual. If anyone finds a way to robustly and automatically generate cerebellar segmentations and surface reconstructions from highquality in vivo structural MRI scans (e.g., the HCP data discussed below), it will open up a fascinating arena of exploration of a still-mysterious major brain structure.

Neural Development

My involvement in neural development extends over four decades and involves three broad directions: synapse elimination, cortical development, and a theory of tension-based morphogenesis. Our efforts on synapse elimination were carried out entirely at Caltech, but the discussion was postponed until this section in the interests of thematic continuity.

My fascination with neuromuscular synapse elimination started serendipitously in Norway, then continued for many years in the capable hands of a succession of Caltech graduate students—John Bixby, Herman Gordon, Ed Callaway, Karina Schimmerling-Cramer, and Jim Soha. Our initial work in Oslo had used rats, but John and I decided to introduce rabbits as a model system that proved to have several advantages, including larger size at birth (Bixby and Van Essen, 1979). Herman Gordon followed up on this by analyzing the maturation of fast-contracting versus slow-contracting muscle fiber types within the rabbit soleus muscle. He showed that motor neurons innervate the different fiber types with high specificity even during the period of extensive multiple innervation (Gordon and Van Essen, 1985). Ed Callaway carried out what to me is the most intriguing of our neuromuscular projects, using selective inactivation of axons by inserting tiny tetrodotoxin-laden silocone plugs into one of the two segmental spinal nerves supplying the soleus muscle. The results demonstrated a clear advantage of inactive synapses when competing against active ones (Callaway et al., 1988, 1989). This “anti-Hebbian” synaptic competition seemed initially very counterintuitive, as we had long been attuned to singing the Hebbian mantra of “neurons that fire together wire together.” However, the results actually made a lot of sense functionally when considering the motor unit size principle, which states that smaller motor units are recruited more readily during reflex behaviors, and thus are presumably more active overall (Henneman et al., 1965). This would be a natural outcome if synapses from less active neurons are at a competitive advantage. Anti-Hebbian synaptic plasticity has been reported in other contexts and systems (e.g., cerebellar spike-timing-dependent plasticity; Roberts and Leen, 2010), but whether this is mechanistically related to what Ed and I reported remains to be determined.

When I launched parallel research projects on visual cortex and neuromuscular development at Caltech, I had hoped that there might be an eventual convergence or cross-talk, perhaps in the realm of studying synaptic plasticity in visual cortex. However, I admit to not having a focused vision or game plan for taking our research in such a direction. In the end, a felicitous convergence arose from a project on the development of cortical connections, which Tom Coogan started when he arrived as a postdoc at Caltech.

Tom had gotten his PhD with Andreas Burkhalter at Wash U studying hierarchical organization of rat visual cortex, but he was interested in the development of cortical connections. He was delighted by the opportunity to return to St. Louis and Wash U. We decided to explore the development of macaque cortico-cortical connectivity using as a tracer a lipophilic dye (“diI”) that slowly diffused along axons when placed as focal deposits in postmortem brains. Among the various interesting observations was the finding that bidirectional connections between V1 and V2 are established during the period of prenatal development when cortical folding starts to occur (Coogan and Van Essen, 1996). That key observation leads directly into the next story.

An “Aha” Moment

Discovery is at the heart of why science is fun as well as exciting, but it plays out in many ways. Often discoveries come slowly, emerging only after a hardfought battle to acquire, analyze, and interpret data of one sort or another. Occasionally there are true “aha!” or “light-bulb” moments. My absolute favorite light-bulb scientific moment of my own career came in 1996. I was sitting on our living room couch musing about anatomical connectivity patterns in visual cortex. I started by considering several facts that I had not previously conjoined: (a) areas V1 and V2 are powerfully interconnected by visuotopically organized projections; (b) in the macaque, cortical folding brings V1 and V2 opposite one another, making the distance between topographically corresponding locations relatively short; and (c) as Tom and I had just shown, interareal connections are established right around the time that cortical folding begins. It suddenly dawned on me that there might be a causal relationship. If axons happened to generate mechanical tension as they establish interareal connections, then regions that are strongly connected might be pulled closer together by virtue of a coordinated action of millions of tiny “fishing lines” being reeled in by the neuronal cell bodies (“fishermen”) benefiting from intercellular adhesion by synaptic contacts at the distant end. By this hypothesis, a gyrus would form in between the strongly connected regions (a winner), whereas a sulcus would represent the outcome of a losing battle in which weakly interconnected regions would become separated by a longer distance within white matter.

I quickly became excited (and obsessed) with this idea, because it was appealingly simple, yet had potentially broad explanatory power. If this idea could explain what was happening between V1 and V2, surely it might be relevant to the rest of cerebral cortex. Two further issues sprang to mind:(a) Was there any evidence that axons actually do generate mechanical tension? (b) Who else had proposed this idea and (gulp) published it previously, since it now seemed very obvious. For all I knew it might have been proposed by one of the great neuroanatomists or developmental biologists anytime between the present and the preceding century.

I had informative conversations with several colleagues at Wash U, including Josh Sanes, Jeff Lichtman, and Paul Bridgman, who helped shape my early thinking and point to relevant literature. I had vaguely recalled an earlier study by Dennis Bray inferring that neurites in tissue culture indeed generate tension. Then I learned about beautiful studies by Steve Heidemann and colleagues at Michigan State, showing that chick sensory neurons actually do generate a hefty amount of tension—plenty to drive morphogenesis (Lamoureux et al., 1989, 1992). The Heidemann lab later reported that explanted chick forebrain neurons generate much less tension than the spinal sensory neurons (Chada et al., 1997). I might have taken this as the death knell of tension-based cortical folding, but I decided there are any number of reasons why cortical neurons in a dish might not “feel like” generating much tension under particular experimental circumstances. For a broader context I devoured the wonderful book On Growth and Form by D’Arcy Thompson (1921). He thought deeply about how competing forces of tension and pressure shape all things biological. Had he been interested in the brain, I strongly suspect he would have proposed tension-based morphogenesis himself.

A strongly appealing aspect of tension-based morphogenesis is that wiring length minimization in a sense comes along, free for the ride. If every axon and dendrite is pulling, then the tendency is for wires to become shorter, and they will tend to be shortest of all when many axons are pulling together. “Compact wiring” is profoundly important in electronics (computer chip makers invest billions of dollars in this). Others (e.g., Mitchison, 1991) had proposed that neuronal components are placed so as to minimize wiring length, for example, in terms of position within a 2D cortical sheet (Cherniak, 1995).

With a lot of help from my friends, I wrote a manuscript on the tensionbased morphogenesis hypothesis and eagerly submitted it to Science. In relatively short order, I received an editorial rejection from the editors—they did not even see fit to send it for review. Infuriated, I contacted a senior editor and pleaded my case, but got absolutely nowhere. I have received my share of manuscript rejections, both before and after this episode. In general, I have tried to be philosophical and roll with the punches in such situations, but this one really got my goat. Chastened but not defeated, I revised the manuscript and submitted it to Nature, where it fared much better after a constructive round of reviews. It has become a widely cited publication, and to this day it routinely elicits interest if not outright fascination when I mention tensionbased cortical folding in talks and seminars, even if only briefly.

As appealing as tension-based morphogenesis was and is, I have studiously avoided the temptation to assume that it is true just because I and others like the idea and want it to be true. There are a few studies providing strong evidence that this is unlikely to be the full story, insofar as differential proliferation may contribute to primary gyral formation in some regions (Reillo et al., 2011). What I find notable, but also ironic and frustrating, is the number of studies that have reported the demise of tension-based morphogenesis based on evidence or logic that I personally find tenuous or shaky (Xu et al., 2010; Nie et al., 2012; Bayly et al., 2013). This is not the place to delve into the details. What I can say (and indeed have often said) is that if a sealed envelope containing the “definitive” answer were placed in front of me, I would unhesitatingly wager large sums that tensionbased morphogenesis is a dominant contributor to cerebral cortical folding. Moreover, it can account for other phenomena in neural development. For example, why is the cortex a sheet-like tissue, even in lissencephalic brains, whereas subcortical nuclei tend to be irregular blobs? My straightforward explanation is that the cortex is dominated by cellular structures with a radial bias (apical dendrites of pyramidal cells plus radial glial processes), and tension along such processes would tend to keep the cortex thin even as it expands in volume and therefore surface area; in contrast, subcortical neurons tend to have more isotropic dendrites, and therefore expand more uniformly in all directions. Mechanical tension can also explain why the retina has a fovea (in species where it does), and some (but probably not all) aspects of the radically different nature of how the cerebellum gets its folds.

Human cortical maturation. My involvement with human cortical development began in 2005 when a first-year medical student, Mai-Lan Ho, approached me about doing a summer project related to human cortical development. I had not previously worked in this arena, but I told her that there might be an opportunity because I had recently encountered a paper by Bob McKinstry, Jeff Neil, and colleagues (McKinstry et al., 2002) in which they showed high-quality in vivo structural MRI scans of neonatal human brains. Since Bob and Jeff were both at Wash U, I arranged to meet with them and explore a possible collaboration. They were enthusiastic, and they also apprised me that they would soon be joined by another pediatric neuroimager, Terrie Inder, who had just been recruited from Australia to join the Wash U Pediatrics Department to lead an effort in neuroimaging of preterm infants. Terrie, Jeff, and I hit it off both scientifically and personally. We began a collaboration that continued until 2013 when Terrie and Jeff were recruited to Boston. It was my first direct involvement in a clinically relevant project, as premature birth is associated with a host of later developmental disorders. I still recall Terrie giving me a personal tour through the Neonatal Intensive Care Unit (NICU) at Children’s Hospital. Isabel and I became good friends with Terrie and Jeff (who were together at the time and were married a few years later) and recall many enjoyable social events at their house.

Jason Hill was the first graduate student Terrie, Jeff, and I jointly comentored. Jason worked with an engineering student, Andy Knutsen, to implement a semi-automated cortical segmentation algorithm (LIGASE) that worked reasonably well on perinatal brains despite the dramatic age differences in tissue contrast as seen in T1-weighted and T2-weighted scans. Jason then used this to characterize cortical morphometry (folding patterns) in neonatal as well as preterm infants. The finding I found most intriguing is that neonatal cortex is on average one-third the surface area as in adults, but the expansion occurs nonuniformly, with regions we associate with higher cognitive functions (lateral temporal, parietal, and prefrontal cortex) expanding about twice as much as early sensory and motor regions (Hill et al., 2010). This ties in nicely with other aspects of cortical nonuniformity, including evolutionary expansion (see above), myelin content (Glasser et al., 2013), and dendritic arbor size (Elston and DeFelipe, 2002).

Leadership Activities

With the notable exception of my desire to take the chairmanship position at Wash U, I have in general not sought out leadership positions that have come my way. If I have my druthers on any given day, I would rather work on matters of science than administration. Nonetheless, over the years, numerous opportunities or requests have been proferred. I have often said yes, if I think (a) my efforts will make a difference for the better and (b) I can preserve enough time in the day to remain heavily and directly involved in ongoing research projects in the lab. As events have played out, the outcomes have generally been positive on balance—that is, I can look back and say that I’m glad I did it (and usually glad when it’s over!). The next few subsections provide a personal perspective on some of these leadership activities. Near the end, I will offer a brief perspective on some of the lessons learned.

It was a privilege to serve as chair (officially called the head) of the Anatomy and Neurobiology Department at Wash U for 20 years—almost half as long as the 42 years served by Robert Terry, the founding chair of the Anatomy Department. Max Cowan (chair from 1968 to 1980) brought the department into the modern neuroscience era, recruiting a number of outstanding neuroanatomists. Gerry Fischbach (chair from 1981 to 1990) recruited many cellular and molecular neuroscientists. From a faculty recruitment perspective, my objective was to strengthen the department broadly, including systems, cellular, molecular, and developmental neuroscience. This was one of the more rewarding facets of the position. We started with recruitments in cellular, molecular, and developmental neuroscience. This was in part to send a clear message to the department of my intent to maintain its breadth. It also reflected a practical constraint, which was that I wanted to recruit systems neuroscientists working on nonhuman primates, but this wasn’t logistically feasible until completion of a specialized primate facility in the new East McDonnell building that was part of my recruitment package.

Retention of key faculty was a more challenging aspect of the job. We were successful in many cases (including two rounds with Josh Sanes and Jeff Lichtman) but certainly not all cases over the years. Losing stars like Sanes and Lichtman to Harvard and Rachel Wong to the University of Washington despite intensive retention efforts was among the most disheartening aspects of the job. Nonetheless, this is part of the competitive nature of academia, and it even had its eventual upsides insofar as we were subsequently successful in recruiting fresh junior faculty who have been highly successful (e.g., Tim Holy, Valeria Cavalli, Paul Shaw, Camillo PadoaSchioppa, and others). The Executive Faculty system at Wash U also entails numerous responsibilities for the Medical School and the university more broadly. These were often challenging and generally rewarding. However, at the end of two decades and countless committees, I was delighted to hand over the reins to my successor, Azad Bonni, and to wish him the best in keeping the department on a forward trajectory. My loyal administrative assistant, Susan Danker, has remained on board, helping me with countless organizational matters and making my life more efficient and enjoyable since she began working with me in 1992.

I was also interested in promoting interactions across disciplines and between the medical school and Danforth (Hilltop) campuses. This included service on numerous search committees, including the chairs of psychology (Roddy Roediger), biomedical engineering (Frank Yin), and biology (Ralph Quatrano). Energizing the psychology and biomedical engineering programs in turn helped in the later launching of the interdisciplinary Cognitive, Computational, and Systems Neuroscience graduate pathway that continues to prosper. Another unique opportunity was to serve on the search committee for the Wash U chancellor, after Bill Danforth (one of my heroes and a true gentleman and farsighted leader) decided to step down in 1995. For one of the initial interviews, four of us were flown on a private jet (available to one of the trustees) to meet with a candidate in Boston. I was impressed by the clarity of thinking and speaking by this candidate, Mark Wrighton, who was offered the position and has served with distinction for nearly two decades at the time of this writing.

The Wash U neuroscience community has benefited enormously from the two endowments specific to neuroscience and devoted to their programmatic enhancement. The story of how the McDonnell Center for Higher Brain Function (now the McDonnell Center for Systems Neuroscience) came into existence in 1980 is fascinating and also instructive about the myriad interactions between scientists, donors (James S. McDonnell), and institutional leaders. Robert Grubb’s history of the Wash U Neurosurgery Department includes a very entertaining rendition of this story (Grubb, 2011). I enjoyed serving as director of this Center for more than a decade, working closely with Dennis Choi, and later Chuck Zorumski, who were directors of the McDonnell Center for Cellular and Molecular Neuroscience, established in 1983 and initially directed by Gerry Fischbach.

Neuroinformatics, the Human Brain Project, INCF, and NIF

Between 1989 and 1991, I served on a Committee on a National Neural Circuitry Database organized by the Institute of Medicine and chaired by Joe Martin (then at UCSF). The committee’s report articulated a vision for neuroinformatics (though it may not have used the term) that had a far-reaching impact. It laid the groundwork for the original Human Brain Project (HBP), a decade-long effort launched in 1993 to promote brain mapping and the nascent field of neuroinformatics. (It is not to be confused with the current European Human Brain Project, which is completely different in scale, style, and geographic center.) Led by visionaries Steve Koslow and Mike Huerta, the original HBP didn’t have a budget, but it was nonetheless able to fund many grants by soliciting support from various federal agencies, including NIH, NSF, Department of Energy, and Department of Defense (Huerta et al., 1993). I received an HBP grant (now in its 21st year) that was critical for expanding and sustaining my lab’s brain-mapping efforts. The HBP held annual meetings on the NIH campus that served to catalyze and coordinate efforts. While these meetings helped build a sense of community, a frustrating aspect for some of us was that we were mostly preaching to the converted and was not (yet) successful in strongly engaging the broader neuroscience community. That would change, but not quickly. In 2005, the HBP was phased out as a distinct program, having successfully served a catalytic role for more than a decade.

In the mid-1990s Steve Koslow also catalyzed an international effort via the Mega Science Forum to promote coordination of brain mapping, informatics, and databasing. In serving on this committee for a couple of years, one of my recollections is that way too much time was spent repeatedly debating whether to use a broad definition of neuroinformatics (which encompassed computational neuroscience) as favored by the Europeans, or a narrower definition (which emphasized just the databasing aspects) as favored by some of the U.S. representatives. In the end, the broader definition prevailed, which I felt was a more sensible outcome. The report of this committee led to the establishment of yet another committee(!), which eventually (in 2005) led to the establishment of the International Neuroinformatics Coordinating Facility (INCF). The INCF has its home base in Stockholm but has a broad international reach. I enjoyed serving on several of the INCF working groups, which aim to promote greater coordination and cooperation in the informatics domain.

Another neuroinformatics-related endeavor that emerged over the past decade is the Neuroscience Information Framework (NIF). NIF (https://neuinfo.org) is a web-based portal that provides rapid access to a large fraction of the amazingly diverse online resources associated with neuroscience. The NIF project was catalyzed by the Brain Information Group mentioned in the next section, which captured the attention of the NIH Blueprint for Neuroscience Research (http://neuroscienceblueprint.nih.gov). I was closely involved in the early days of getting the NIF project funded and under way, which had some touch-and-go moments. The many other neuroscientists, neuroinformaticians, and NIH leaders who helped in this endeavor are too numerous to list individually, but I think it is appropriate to identify Maryann Martone at UC San Diego as the project leader, who made particularly seminal contributions to the success of the NIF. There are some entertaining aspects to the NIF story, and hopefully a more complete history will emerge in due course.

Journal of Neuroscience and Society for Neuroscience

My extended period of involvement with various aspects of the SfN started innocently enough around 1990 when Dale Purves, then editor in chief of the Journal of Neuroscience, invited me to join the editorial board for the journal. Dale stepped down in 1993, and things did not go smoothly for his successor. One day in May 1994, I received a telephone call from Larry Squire (SfN president at the time) asking whether I would be willing to consider stepping up to the plate and serve as editor in chief for the journal. I told Larry that my platter was more than full, and I encouraged him to skip me and proceed to others on his short list. Larry apprised me that I was already the last person on his short list, and that if I declined, their committee would be back at square one! He also said it was urgent that I decide within just a few days. After deliberating and consulting with Isabel and a few others, including Jeff Lichtman, I decided to take the position. The transition took place very quickly. We implemented many changes to improve the timeliness and rigor of the review and decision process and to communicate to the neuroscience community a commitment to a fast and fair review process. Fortunately, submissions to the journal more than doubled in my four and a half years in this role, before I decided that one term was enough and gladly handed the reins over to my successor, Gordon Shepherd. However, it was not entirely smooth sailing. An effort that proved ahead of its time involved the launching of “Rapid Communications,” an all-electronic version of the journal that aimed to attract brief but highprofile articles. This did not catch fire with prospective authors, and “Rapid Communications” soon reverted to printed “Brief Communications.” Of course, printed journals are now largely historical relics—what a difference a couple of decades makes!

In 1999, I was elected to a four-year stint on the SfN Council. This was a very interesting experience, especially with the transition to the new executive director, Marty Saggese, who encouraged a thoughtful long-range planning process. A few years later (in 2002), I was elected SfN Secretary, which had traditionally been a pro forma job with no substantial duties other than serving on Council. However, the preceding Council had decided to give the secretary a “real job” by also chairing a newly established Committee on Committees. This committee’s task was to identify who would serve on and chair the many different SfN committees (a task previously handled by Council, sometimes with insufficient time to deliberate).

When Huda Akil became SfN president in 2003, she expressed a strong interest in neuroinformatics as a domain of growing importance to the neuroscience community. For her presidential initiative she set up an ad hoc Brain Information Group (BIG), which I was delighted to serve on. The report of the BIG committee led to establishment of a standing Neuroinformatics Committee for the SfN. It also helped catalyze the NIF project described in the preceding section. I think the Neuroinformatics Committee played a valuable role during its five-year existence, but it struggled to articulate a vision and a plan that consistently resonated with the SfN Council in subsequent years (despite concerted efforts from me and others).

In 2005, I became SfN president-elect, and in 2006 served as president. It was interesting and rewarding in many respects, as there was an opportunity to help shape many of the Society’s activities. For the “Dialogues in Neuroscience” public lecture series, I selected Jeff Hawkins of Palm Pilot fame, who had thought very seriously about the brain and computational neuroscience and had written a thought provoking book, On Intelligence (Hawkins, 2004). His presentation at the SfN meeting was well received, as were the four presidential lectures by distinguished investigators that I had invited in the areas of neuroinformatics and computational neuroscience. All was not hunky-dory, however, as Council decided over my objections to phase out the Neuroinformatics Committee. I was disappointed and felt that the decision lacked foresight. Nonetheless, it has turned out that neuroinformatics has continued to prosper as a subfield of growing importance and recognition. In 2007, I came to the end of a 14-year period in which I had more or less continuously been associated with a major SfN leadership role. It was a great ride overall, and I’m happy to be added to the ranks of SfN past presidents!

Organization for Human Brain Mapping

In the early 1990s, I attended annual BrainMap meetings in San Antonio that were organized by Peter Fox. The meeting grew in size as neuroimaging gained in popularity, but it was by invitation rather than an open meeting. At the 1994 meeting, there were conversations about a public human brain-mapping meeting, which Bernard Mazoyer had volunteered to organize in Paris the following June. I was invited to be a keynote speaker at the first meeting. This surprised me because I was a monkey cartographer and hadn’t yet delved directly into human brain mapping. Per Roland, one of the organizers, explained that they wanted at the outset to build a bridge to the community of nonhuman primate investigators rather than focusing exclusively on human neuroimaging. The meeting in Paris was a great success, with about 600 attendees. Jack Belliveau and colleagues stepped up and volunteered to host a meeting in Boston the following year. However, it was also evident that some organizational structure was needed in order to provide continuity and sustainability for having regular annual meetings. But how to bootstrap from nothing to something? At the next BrainMap meeting in San Antonio (December 1995), a group of us self-assembled into an ad hoc committee who tasked ourselves with drafting a set of proposed bylaws for a human brain-mapping entity. Most of the effort was straightforward, but a contentious issue arose regarding whether this should become an “organization” that would focus exclusively on organizing an annual meeting, or a “society” that might feel empowered to undertake a broader set of potential activities and responsibilities. The issue was put to a vote at a town hall meeting held at the Boston meeting. There were strong advocates on both sides. Our ad hoc committee had selected Alan Evans to chair this discussion, and I recall him wearing an army helmet in mock fright at the flack he might take as our committee sat on stage. In the end, the Society for Human Brain Mapping (SHBM; pronounced ShhhBoom) was voted down, and the more mundanely named Organization for Human Brain Mapping (OHBM) was officially launched.

At this town hall meeting, there was an election for a council that would steer the nascent organization. I was on the slate of candidates, and perhaps because I had been relatively vocal during the town hall discussion, I was elected to the first council. One of the action items at the first council meeting was to elect a chair. Two of the newly elected councilors were obvious candidates to become chair because each was an editor of a leading neuroimaging journal. Informal hallway conversations prior to the meeting made it clear that the council was strongly and approximately evenly divided. One of the new councilors, Bruce Rosen, suggested that the council identify a compromise candidate not associated with either “camp.” He asked me whether I would be willing to serve in such a role. Once again, with precious little time to ruminate, I agreed to take on this role, thereby becoming the founding chair of the OHBM council. It has been highly gratifying to see the OHBM prosper and become the leading “go-to” conference for a large portion of the neuroimaging community.

Allen Institute for Brain Science

I previously mentioned a couple of examples of philanthropic benefactors (Arnold Beckman, James McDonnell) whose generosity to neuroscience had an important, albeit indirect, impact on my career. In recent years I have had the privilege of serving on advisory boards for the Allen Institute for Brain Science, a private institute in Seattle funded through the generosity and vision of Paul Allen, the cofounder of Microsoft. The Allen Institute was launched in 2003 to tackle major problems in neuroscience that could be better handled by an industrial-scale operation than by conventionally funded neuroscience labs. The institute started with a mouse gene expression atlas and then expanded to include many other large-scale projects relating mostly to mouse and human brains. It has benefited from exceptionally strong leadership, including Allen Jones (a Wash U alum) and more recently, Christof Koch (whom I helped recruit to Caltech two decades earlier!). I joined the Human Brain Atlas Advisory Council in 2007 and the Scientific Advisory Board in 2010, becoming its chair in 2013. In exchange for providing (hopefully) useful high-level advice to the Allen Institute, board members get to learn about the latest progress in cuttingedge neuroscience and technology. For me, there has been a personal benefit as well, because multiple visits per year to Seattle have made it easier to visit family living in the area—initially Brian and family when he was a computer science graduate student at the University of Washington, and now Scott and family (wife Myra and grandkids Laurel and Max) since he took a job in the area.

Lessons Learned

Before proceeding to the final major story in this chapter, I will offer (at the behest of a colleague who read an earlier draft) reflections on approaches that may have helped in the success of various leadership activities. Here are a few. They are by no means novel, but perhaps they provide a useful perspective.

Listen! I think it’s extremely important for leaders to listen more than talk. And when listening, try to understand not only the words but also the subtext and the underlying intent of what others are trying to say.

Balance! Leadership is tested when dealing with differences of opinion. A good starting point is to strive for balance, seeing both sides of the debate, and looking for compromise solutions when that makes sense.

Go to the mat rarely. When tough problems arise and critical decisions need to be made, it is sometimes necessary to draw a line in the sand and/or make a stand on principle and against objections. I have intentionally avoided discussing most of the contentious and sometimes thorny problems faced over the years (though there have been enough to fill another chapter!). Overall, I feel it’s important to choose battles carefully, avoiding them when possible because they can be emotionally draining and enormous time sinks.

Keep an even keel. The hot temper I mentioned having as a child has mellowed for the most part, for which I am grateful. It is sometimes appropriate and useful to express anger, but in my experience, it is usually much better to keep emotions in check.

The Human Connectome Project

My role in the HCP emerged via a cascade of numerous serendipitous events. Given the uniqueness of my involvement, I will describe the early parts of this story at some length, to provide a personal perspective on a scientifically important endeavor. A key early event in redirecting part of my research effort was in May 2008, when I received an e-mail from a prospective student, Matt Glasser, who had been offered admission to the Wash U Medical Scientist Training Program (MD/PhD) program. Matt had extensive prior experience with neuroimaging of humans and nonhuman primates while a student and then a research assistant at Emory University, and he had clear notions regarding two projects he was interested in working on. One was a novel approach to estimating cortical myelin content using structural MRI scans, based on preliminary observations he had made at Emory. The other was to examine anatomical connectivity using diffusion imaging and tractography. I didn’t have direct experience in either of these realms, nor did I have imaging data to fuel either project. What I could offer was expertise in neuroanatomy and in the surface-based analyses that we both agreed was vital for both projects. I was also willing to go out on a limb, especially since I had been impressed when interviewing Matt earlier that winter. Matt accepted and began a rotation in my lab in the summer of 2008. He hit the ground running, as he had access to structural and diffusion imaging data from macaques, chimpanzees, and humans via a continuing collaboration with Todd Preuss and Jim Rilling at Emory. On the myelin-mapping front, Matt was able to generate promising myelin maps based on T1-weighted/T2-weighted ratio in all three species. On the tractography front, I saw one of my roles as playing devil’s advocate, challenging Matt to find compelling evidence for major pathways such as between V1 and V2, where ground truth was known. (The tractography versus tracer comparison has also finally come to fruition, but it took much longer and also engaged another MSTP student, Chad Donahue.)

Another important event got under way later that summer, when Walter Schneider from the University of Pittsburgh called and asked me to join an advisory board for a forthcoming Brain Competition 09. This was an event he had organized for several years running, with a different theme each year. For the 2009 competition, Walt had decided presciently to focus on mapping the human connectome. The advisory board was asked to provide guidance on data acquisition parameters that would be optimized to allow competitors to parcellate the cortex using structural connectivity (diffusion imaging plus tractography) and resting-state functional connectivity (rfMRI). My expertise was on cortical anatomy and parcellation, and when the teleconferences turned to neuroimaging data acquisition parameters, I found myself still in the early stages of a steep but invaluable learning curve on various nuts-and-bolts issues of MRI data acquisition. My role was in large part to emphasize the lack of ground truth and the critical issues involved in parcellation of human cortex. Walt was a true visionary in promoting this endeavor, but I also considered him wildly optimistic in terms of what the methods at the time would be able to deliver in terms of parcellating cortical areas and charting connectivity.

It took months for the advisory panel to settle on the data acquisition parameters and for Walt’s team to acquire and share the data. We eventually settled on ground rules for judging the competition and formally announced the competition the spring of 2009. In the meantime, Alex Cohen in Steve Petersen’s lab was developing a novel approach to cortical parcellation based on spatial transitions in functional connectivity. Alex was using our Caret software as part of his analysis, and I was part of this collaborative effort (Cohen et al., 2008) as well as a member of Alex’s thesis committee. As word got out about the forthcoming competition, Alex, Matt, and another MSTP student, Tim Laumann, decided to go in as a team (after we were assured by Walt that it was not a conflict of interest for students of advisory committee members to enter the competition). They got a head start in methods development based on Alex’s efforts as well as innovative approaches and ideas generated by Matt and Tim. They applied the novel multimodal parcellation method that emerged to the competition’s publicly released data set and submitted their analysis by the deadline before the June 2009 meeting of the OHBM. Alex, Matt, and Tim emerged as co-winners of the competition, but nobody involved was under the illusion that an even remotely accurate cortical parcellation had been achieved. It was an important lesson for everyone about the complexity of the challenge.

Meanwhile, an even more important and potentially exciting opportunity loomed on the horizon. It is a long saga that is still playing out. Here I focus mainly on the early stages of the process and from a personal standpoint. It started in early May 2009, when Mike Huerta (whom I knew well from neuroinformatics efforts described above) sent out a heads-up e-mail that I and many other neuroimagers received, indicating that NIH intended to launch the HCP by awarding a $30 million, five-year grant to study human brain connectivity in “up to several hundred” healthy young adults. I read the e-mail with modest interest but mentally tucked it away as something I was unlikely to get actively involved in. Later that month, in an informal conversation right after a meeting of Alex Cohen’s thesis committee, Marc Raichle mentioned this e-mail, as it had been sent to him and to the other two committee members, Steve Petersen and Brad Schlaggar. We discussed whether Wash U should consider throwing our collective hat in the ring. Mixed feelings were expressed, but we all agreed that this was worth further consideration. To initiate follow-up discussions, I agreed to convene a meeting of key local stakeholders. At the first meeting, someone suggested that it would be pretty cool to study brain connectivity in identical twins (to enable analyses of the heritability of brain circuits) and also noted that Andrew Heath in the Psychiatry Department had a long track record in studying twins in projects relating to addiction. With encouragement from Chuck Zorumski, chair of psychiatry, we approached Andrew, who was immediately enthusiastic even though he had not previously been involved in neuroimaging studies. Thus, the wheels started turning a bit faster.

It was obvious that a project of this scope would entail partnering with investigators at other institutions who could add strength in domains where Wash U was “underpowered” (e.g., MR physics, diffusion imaging, and magnetoencephalography, or MEG). I became the informal de facto point person representing Wash U as we entered a “courtship dance” with various potential partners. Two important conversations took place at the OHBM meeting in San Francisco. I met with Tim Behrens, whom I had gotten to know from our involvement in the Pittsburgh Brain Competition advisory group, and who had interacted a lot with Matt regarding tractography methodology (and also through his collaboration with Jim Rilling, Matt’s former research mentor at Emory). Tim was enthusiastic about a possible partnership, but his close colleague at Oxford, Steve Smith, was provisionally aligned with another nascent consortium. Also at the OHBM meeting, I was approached by David Feinberg, an MR physicist who had previously been at Wash U. David expressed interest in a possible partnership and encouraged me to consider others, including Kamil Ugurbil at the University of Minnesota (U Minn). I was impressed when I heard Kamil give a talk at the same OHBM meeting, but our first face-to-face meeting didn’t occur until later that summer.

In the meantime, we continued various exploratory conversations. For a while it appeared that a partnership with the team at Massachusetts General Hospital (MGH) might work out, but that didn’t happen for various reasons. Once the formal request for applications was announced in mid-July, we had a better idea of what would need to be pulled together—and quickly, because the due date was in November, just a few months down the road. We soon decided to explore the U Minn opportunity more seriously. In early August, I e-mailed Kamil, who was in Europe at the time, but we jointly rolled up sleeves immediately on his return. By mid-August, Kamil had visited Wash U and I had visited U Minn. A provisional partnership was established that was firmed up by mid-September. In the ensuing two months, a fast-and-furious effort carried us to the finish line. It included quickly pulling together preliminary data on many fronts (benefiting from the earlier efforts of Alex, Matt, and Tim with the Pittsburgh Brain Competition), coupled with intense discussions on how we would propose to acquire and analyze data from four MRI modalities plus MEG. Discussions were intense and sometimes chaotic, but the sense of enthusiasm and excitement allowed the multi-institutional consortium to focus and pull together when the chips were down. On a different front, we were also successful in obtaining major institutional commitments (totaling $4 million, or more than 10% of the amount to be awarded) from the dean of the Medical School, the Department of Radiology, and the McDonnell Center for Systems Neuroscience, which greatly strengthened our cause. The 90-page research proposal (360 pages all told) was submitted just before Thanksgiving in 2009. Just before the deadline, I discovered that the supposedly final text was a full two pages over the limit; I worked late into a Saturday night wordsmithing the document until it was under the limit! Altogether the proposal represented a monumental effort by many staff and investigators at many institutions. While they are too numerous to mention individually, I consider it especially important to commend Lucille Miller (who handled the budget) and Susan Danker (my administrative assistant), as key staff are too often unsung heroes in projects like this.

Then the wait began. In early March of 2010, we received reviews of our proposal and learned that we were in the running, but that a different proposal was in the lead. We wrote a detailed response to the criticisms and concerns expressed by the reviewers, then waited further. As it happened, several of the contenders were at a meeting on “Connectomics” organized by Sebastian Seung and held in Seoul, Korea, in late March, as the decision time was nearing. It made for a few awkward conversational moments. While en route back from this meeting, I landed in Dallas and read an e-mail from Mike Huerta asking me to give him a call. I had a close connection, so had to wait on pins and needles until I arrived in St. Louis to learn that our consortium would indeed receive the full award. (In addition, NIH made a separate grant to the MGH/UCLA consortium to enable them to build and use a customized scanner, highly specialized for diffusion imaging.)

There was great excitement over receiving the main HCP award. Isabel and I hosted a memorable party at our house to celebrate the good news. Then we quickly shifted our attention to the serious business of getting plans into motion so that the project would get off to a fast and good start. One of the first orders of business was to identify a project manager having the skill sets to help oversee and coordinate a bunch of academics, most of whom had never been involved in a project of this scope or technical demands. We recruited Sandy Curtiss, a PhD molecular biologist by training who had worked in industry for many years but who also had experience in academia and appreciated the cultural differences. I found it tremendously enjoyable working with Sandy; we have had lots of laughs plus a few tears as we jointly worked through an immense variety of issues large and small in order to keep the project on track. Susan Danker aided tremendously on the administrative side, as did Lucille Miller, Tami Evans, and several others in our departmental business office. We recruited Jennifer (Jenn) Elam as an outreach coordinator, and she has done yeoman’s work in building a very successful outreach effort.

On the scientific and technical fronts, well over 100 investigators, students, and staff have been heavily involved in the HCP effort over the past five years. We held an intensive two-day All-Hands Meetings at Wash U each fall and another equally intensive two-day Many-Hands Meeting at U Minn each spring. These were very useful for building up camaraderie and team spirit at the outset and sustaining momentum in the later years as we worked through a wide range of technical challenges. We collectively came to appreciate the complementary expertise of the different consortium sites. The Minnesota team (Kamil, Essa Yacoub, and many others) is especially strong on issues relating to MRI scanner hardware, pulse sequences, and initial stages of data processing. The group at the Oxford Centre for Functional MRI of the Brain, led by Steve Smith, Tim Behrens, and Mark Jenkinson, is especially strong in the area of data analysis for fMRI and diffusion imaging. Our other European colleagues provided key expertise in the analysis of MEG data. Finally, the Wash U group, including Deanna Barch, Mike Harms, Greg Burgess, and many others, provides expertise in neurobiological issues and task fMRI methods. Cindy Hernke capably led a team of research assistants who coaxed 1,200 subjects to be remarkably cooperative as they each lay very still in the scanner for four 1-hour scan sessions. Erin Reid has been the walking definition of how to carry out systematic quality control of structural imaging data on every one of these subjects.

Having invested two decades in various aspects of neuroinformatics, broadly writ, it has been especially rewarding to see neuroinformatics play a key role in the HCP success. This includes two broad aspects. Dan Marcus (my former graduate student turned neuroinformatician par excellence) spearheaded a large neuroinformatics group with whom I worked very closely. They have implemented the ConnectomeDB database, which has proven to be a user-friendly workhorse platform for sharing the immense amounts of multimodal HCP data—nearly a petabyte (1,000 terabytes) by the end of the project. Complementing ConnectomeDB is the Connectome Workbench visualization and analysis software spearheaded by John Harwell, Tim Coalson, Matt Glasser, and others in my lab. Workbench is proving to be a worthy successor to our older Caret platform, having kept what is most useful and having added countless cool additional features for analyzing multimodal structural, functional, and connectivity data.

Major parts of the scientific and technical aspects of HCP data acquisition and early stages of data analysis (including the “minimal preprocessing pipelines”) are described in a special issue of Neuroimage (Van Essen et al., 2013, plus seven other Wash U–Minn HCP articles cited therein). Many studies that make use of HCP data have been published (see http://www.humanconnectome.org), and there will be lots more in the coming years.

As I write this chapter, the Wash U–Minn HCP Consortium is wrapping up the five-year project, having successfully fulfilled its mission. As the main HCP winds down, NIH has decided to fund a number of other HCP-style endeavors that are just starting to get under way. Three “HCP Lifespan” projects will enable examination of brain circuits in healthy humans during maturation and aging. Another set of projects is under the umbrella of “Connectomes Related to Human Disease.” All of these projects will scan their participants using HCP-style advances in data acquisition, will process their data using HCP-style analysis pipelines, and will share their data on an expanded ConnectomeDB platform under the umbrella of the Connectome Coordination Facility that Dan Marcus and I will jointly lead. In short, there is life after the HCP, and it will be fascinating to see how the next stages of human connectomics unfold.

A few additional reflections on what has—and has not—been accomplished by the HCP seem in order.

The improvements in data acquisition and analysis achieved by the HCP include a few that represent major “quantum jumps.” One is the use of multiband pulse sequences that greatly increase not only the amount of data acquired but also its overall quality. Another is the introduction of the CIFTI (Connectivity Informatics Technology Initiative) data format and the concept of “grayordinates” that include gray matter from both cerebral cortex (surface vertices) and subcortical nuclei (voxels) in a common data format. Numerous other refinements are more incremental in nature but altogether add up to large improvements in aggregate (Glasser et al., 2013a, in preparation).

Patience required. Earlier parts of the cartography story described the slow time course not only of achieving key methodological improvements, but also additional lengthy periods waiting for the field to capitalize fully on these advances. Cortical flatmaps—and their partners in crime, cortical surface models—have gradually but inexorably become mainstream, insofar as they are widely accepted as valuable modes of analysis and display. However, it remains a reality that the majority of neuroimaging studies that would benefit from using cortical surface models either fail to use them altogether or use them suboptimally. I learned a lot of patience in the first several decades of cortical cartography, and the need for sustained patience has not dissipated. Ways to accelerate progress in widespread acceptance of improved methods, not just in implementing the improvements, is an important issue for the future.

Cartography and parcellation redux. Accurate cortical parcellation, while something of a holy grail for more than a century, has indeed proven enormously challenging, but the HCP data have proven to be a gold mine for progress on this front. It is highly gratifying that a new multimodal human cortical parcellation has recently emerged, which identifies 180 cortical areas in each hemisphere (Glasser et al., in preparation). Particularly striking is the fact that a large majority (∼90%) of cortical areas can now be robustly identified in a large majority (also ∼90%) of HCP subjects. This is a testament to the exceptionally high quality of the HCP multimodal data as well as the importance of continued methodological refinements. A host of interesting follow-up questions will loom as these data sets become freely available to the neuroscience community.

Be optimistic, yet critical of glasses half full and half empty. In talking and writing about connectomics over the past five years, I have split my “pitch” along two somewhat-disparate lines. On the one hand, there are excellent reasons to be enthusiastic and excited about the new methods and vast amounts of new, multimodal data to provide insights about brain structure, function, and connectivity, and their relationship to human behavior. On the other hand, there are major technical limitations to each modality, especially those relating to connectivity, that are seriously underappreciated in the neuroimaging and neuroscience community. Diffusion imaging and tractography have one set of major limitations; functional connectivity based on resting-state fMRI has another, very different set of limitations. We don’t have “ground truth” in humans, but comparisons with data from nonhuman primates suggest that the glass is half full and half empty (e.g., Van Essen et al., 2014, Donahue et al., in preparation). This is not the place to delve into the technical details, but it is incumbent at all levels to strike a balance that doesn’t oversell what can be done using current methodology.

Musings on the Mind

I close with a few more general remarks.

The advances over the past five decades in our understanding of the brain have been truly breathtaking. Yet I consider it equally fair to emphasize that neuroscience is still only scratching the surface in the effort to decipher many fundamental and profound mysteries of the mind.

In the realm of connectomics, the blogosphere is filled with chatter about how it may be possible “soon” (within decades) to map a complete human connectome across microscopic as well as macroscopic scales. Some respected scientists contribute to such speculation, but I consider it to be highly if not wildly optimistic. But I won’t try to rule it out entirely, because I’ve taken pains in this chapter to emphasize how unpredictable our predictions to date have proven to be.

I do anticipate it will be possible to map a complete micro/macroconnectome of fruit fly (Drosophila), and even that of a mouse, where physical scale and tissue preservation issues are far less challenging. But this brings us to an even larger question that looms. Knowing a complete connectome, like knowing the exact architecture of a powerful computer, doesn’t reveal exactly how or what information is processed and stored in that device in real time. And that’s an extremely tall order, as I tried to touch upon in the sections on computational neuroscience and neural engineering.

Can the human brain ever “fully” understand the human brain? I won’t say it’s impossible, but frankly, I doubt it. If we ask whether chimpanzees could ever understand their own brain, the answer would be a resounding negative. Yet while we are obviously a lot smarter than other great apes, I think there are serious limits to human intelligence, even when aided by increasingly sophisticated and powerful computers. So what gives our species the chutzpah to think we have or ever might cross that divide? Pitted against our efforts to guess the pace of progress is what I consider the far more serious issue of dealing with the pace of regress, given our power to sow the seeds for devastating our planet and civilization. Let us hope that progress in neuroscience and in other fields will enable us to better modulate our base instincts and keep the species and our planet alive and well.

On a very different note, death of course comes to us all, in very different life stages and modes of occurrence. My family seems to have genes that enable longevity. My father passed away peacefully at the age of 92 after a long and full life and aware that it had run its course. At the time of this writing, my mother is still going strong. My personal aspiration is not for longevity per se, but rather a fervent hope that fate delivers the opportunity to enjoy and remember life with family and friends until it is over.

Finally, I express my immense thanks to all who have helped directly and indirectly to contribute to a truly exciting and rewarding scientific joyride over many decades. Special thanks to Isabel, who has been extremely supportive and tolerant for lo these 46 years. To restate what we had imprinted on a T-shirt made for our 40th anniversary, “What a trip!”

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Index

Abbott, A. 469

Abbott, L. 100, 249, 250, 252

Abdollahi, R. O. 377

Abel, T. 199, 202, 203, 205

Abrams, T. 48, 187

Absug, B. 75

Achuthan, S. 251

Acker, C. D. 254

Adams, H. 508, 509

Adams. P. 23

Adelman, G. xi

Ades, H. W. 179

Adey, R. 189

Adrian, E. 337

Agnihotri, N. 201, 206, 207

Agranoff, B. 191

Aguayo, A. xii

Ahissar, M. 376

Ahlfors, S. 286

Ainsworth, M. 275

Aizawa, H. 359

Akert, K. 438, 443, 444, 468

Akil, H. 540

Alberini, C. 195

Albright, F. 80

Albright, T. xiii, xiv, 90, 478

Alexander, G. E. 407

Alford, S. 119

Allen, P. 541

Allen, W. 178

Allman, A. 155

Allman, J. 142, 152, 159, 506, 507, 508, 523, 530

Allport, A. 360

Altmann, L. 462

Altschuler, E. L. 336, 358

Alvarez, J. 458

Aly, G. 450

Alzheimer, A. 401, 402, 404, 409

Amatniak, E. 73

Andersen, P. 199, 468, 502

Andersen, R. 322

Anderson, C. 515, 517, 518, 519, 524

Anderson, D. 507, 526, 527

Angelaki, D. 100

Antonini, A. 351

Anzai, A. 521

Anzola, G. P. 360

Arbib, M. 355, 356, 357, 368

Arduini, A. 336, 337, 342, 343, 345, 346, 349, 360

Arduini, M. G. 343

Armstrong, D. F. 368

Arnal, L. H. 281

Arnstein, P. 6

Aron, A. 410

Aronson, D. G. 243

Arrow, K. 4

Arroyo, M. 409

Arschavsky, Y. 113

Artola, A. 452, 457, 458

Arvanitaki-Chalazonitis, A. 184

Ascher, P. 455

Åslund, N. 122

Assad, J. 87

Atwell, C. 91

Aurelio, W. G. 244

Avanzini, P. 380

Axel, R. 88, 194

Axelrod, J. 394

Bacskai, B. J. 195

Baddeley, A. 391

Bahar, A. 52, 53

Bailey, C. 195

Balaram, P. 153

Baldauf, D. 519

Baldwin, M. 152, 153, 154

Banks, M. 254, 263

Bar, E. 56

Barad, M. 199, 202

Barbas, H. 244

Barch, D. 547

Barco, A. 199

Bard, P. 179

Barger, G. 390

Barker, R. 408

Barlow, H. 156

Barthe, J-Y. 128

Bartlett 415

Bartsch, D. 195

Bassett, M. I. 96

Bastos, A. M. 275

Baumgarten, G. 452

Bayes, T. 456

Baylor, D. 74, 493

Bayly, P. V. 534

Bean, B. 88

Beang, N., xii 20, 29

Bear, M. 454

Beck, P. 147

Beckman, A. 506, 541

Bedworth, N. 453

Beethoven, L. van 173

Behn, C. D. 266, 267

Behrens, T. 545

Beital, R. 148

Belin, D. 412

Belliveau, J. W. 467, 523, 540

Belloni, G. B. 335, 342

Bellugi, U. 244

Belousov, B. P. 233

Benabid, A. 91

Ben-Barak, J. 47

Bender, D. B. 350

Benjamin, R. 140

Ben-Yakov, A. 56, 57

Benzer, S. 42, 43, 44, 45, 46, 51, 53, 60, 61, 314, 491, 503

Berg, D. 311, 492, 507

Berg, H. 507

Bergman, H. 128

Berkley, G. 168

Berle, M. 222

Berlucchi, G. 339, 340, 341, 344, 345, 346, 347, 359, 363, 433

Berlucchi, L. 339

Berlusconi, S. 374

Berman, D. E. 52

Bernard, C. 356

Bernhard, S. 475, 476

Berntsen, D. 61

Berridge, K. 398

Berthoz, A. 367

Berti, A,. 363 364

Bertoloni, G. 360

Best, J. 454

Bethe, A. 116

Betz, H. 449, 475

Bi, G-Q 457

Bibring, G. 186

Biederlack, J. 465

Bienenstock, E. L. 458

Biglow, M. 496

Bilitch, D. 511, 515

Birrell, J. M. 404

Bishop, P. 438, 442

Bisiach, E. 347, 363

Bixby, J. 507, 509, 532

Bizzi, E. 344, 433

Bjaalie, J. 130

Björklund, A. 468

Black, A. 347

Blakemore, C. 155, 445

Bleuler, E. 398, 441

Bliss, T. 199, 207, 457, 502

Blitzer, R. D. 207

Bloch, S. 458

Bloom, F. 17, 399

Bludau, B. 474

Bolam, P. 128

Bolender, R. 495

Bollinger, L. 96

Bonds, A. B. 149

Bongianni, F. 119

Bonini, L. 371, 375

Bonni, A. 537

Borgers, C. 259, 260, 261, 262, 274, 287

Boria, S. 373

Born, R. 87, 322

Bosch, H. 172

Bose, A. 251, 252

Bourtchouladze, R. 202

Bower, J. 517

Bowes, C. 150, 158

Boyden, E. 262, 270, 287

Braestrup, C. 396

Bragin, A. 467

Brailovsky, I. 289

Bray, D. 533

Brecht, M. 465, 466

Bremer, F. 337

Brenner, S. 511

Bridgman, M. 74

Bridgman, P. 533

Brigham, P. B. 496

Broadbent, D. 392, 399

Bröcher, S. 457, 458

Brockes, J. 507

Brodin, L. 118, 120, 121, 122

Brodmann, K. 145

Bronzin, L. 334, 337, 339, 340, 342, 347, 350, 351, 357

Brookhardt, J. 181

Brooks, D. C. 344

Brown, E. 266, 267, 268, 269, 273, 279, 286

Brown, G. 114, 115, 309, 310

Brown, J. 22

Brown, M. 502

Brown, R. 287

Brown, V. 400, 404

Broyles, J. L. 14

Brugge, J. 140

Brunelli, M. 193

Bruschweiler, N. 378

Buccino, G. 366, 367, 368, 380

Buchanan, J. 119

Buchtel, G. 349

Buck, L. 87, 88

Buckner, R. 520

Buhl, E. 128, 256, 257

Buisseret, P. 447

Bullier, J. 156

Bullmore, E. 280, 410, 415

Burden, S. 89

Bures, J. 51, 52

Burgess, G. 547

Burish, M. 154

Burke, R. 74

Burkhalter, A. 85, 509, 523, 530, 532

Burns, C. D. 189

Burns, D. 487

Burns, R. 487

Buschges, A. 128

Buschman, T. J. 276

Buser, P. 432

Bush, R. 4

Butera, R. J. 249

Buxbaum, J. 47

Buzsaki, G. 249, 256, 263, 272

Byers, D. 44, 45, 46, 314

Byrne, J. 188

Bystryn, D. 177, 179, 184, 186, 192, 208, 209, 210, 212

Cabelguen, J-M. 128

Cabot, J. B. 9, 10

Cador, M. 401, 409

Caggiano, V. 375

Cahill, G. 213

Cajal, R., xi 181, 188, 189

Cajal, S. 181, 188, 189

Calabrese, R. 250

Calford, M. B. 156

Califano, A. 95

Callas, M. 432

Callaway, E. 532

Camalier, C. 149

Camarda, M. 348, 349, 353, 354

Campo, N. del 413

Canavier, C. 251

Canetti, E. 169

Cangiano, L. 118

Cannon, J. 268, 280

Capantini, L. 122

Cardinal, R. 411

Carew, T. 187

Carli, G. 342

Carli, M. 400

Carlson, M. 94, 99, 158

Carlsson, A. 390

Carman, G. 511

Carmichael, S. T. 526

Carossa, H. 175

Carracedo, L. M. 277

Carter, R. 17

Caruana. F. 369

Casadio, A. 195, 196, 197

Casagrande, V. 145, 146, 152, 158

Cash, S. 286

Casile, A. 375

Caspers, S. 357

Castellucci, V. 188, 192

Castelo-Branco, M. 465

Catania, K. 147, 152, 159

Cattaneo, L. 366, 372, 373, 538

Cavaggioni, A. 343

Cavalli, V. 537

Cavanagh, P. 318

Cech, T. 213

Cedar, H. 192

Cerkevich, C. 154

Cervetto, B. 339

Cervetto, L. 338

Chada, S. 534

Chalazonitis, A. 84

Chalk, M. 262

Chamberlain, S. 413

Chang, Q. 93

Changeaux, J-P. 80, 128

Chen, A. 199

Cherniak, C. 534

Ching, S-N. 267, 268, 279

Chino, Y. 147

Choi, D. 84, 537

Chomsky, N. 244

Chopin, P. 213

Chory, J. 90

Chow, C. 253

Christianson, S-A. 36

Christofi, G. 457

Clapham, D. 87

Clarac, F. 128

Clark, J. 525

Clarke, H. F. 404, 413

Clinton, W. 93

Coalson, T. 547

Cohen, A. 117, 244, 245, 246, 544, 545

Cohen, D. H. 1–30, 2

Cohen, J. 80, 88, 89

Cohen, M. 82

Cohen, N. 2, 56, 57

Cohen, S. 18, 77

Cole, J. 94

Coleman, S. 268

Colgin, L. L. 275

Collins, C. 150

Collins, J. 244, 285

Colten, H. 94

Columbus, C. 223

Connor, E. 519

Conway, B. 323, 324

Coogan, T. 532, 533

Cook, D. 152

Cools, R. 407

Cooper, L. N. 458

Corazza, R. 343

Corballis, M. C. 368

Corbetta, M. 362

Corey, D. 87

Corfas, G. 49, 50, 51, 89

Cossoto, F. 432

Cossu, G. 372

Coulter, J. 23

Couteaux, R. 80

Cowan, M. 84, 448, 498, 506, 524, 536

Cowan, W. 259

Craighero, L. 362, 368, 375

Crain, S. 178, 180, 182

Cramon, Y. von 440

Creese, I. 393, 397, 399

Creutzfeldt, O. 355, 430, 431, 432, 433, 434, 435, 436, 438, 439, 443, 477, 478

Crick, F. 47, 391, 516

Crockett, M. J. 412

Crook, S. M. G. 254

Crow, J. 307

Crow, T. 401

Crunelli, V. 268

Csicsvari, J. 256

Cuenod, M. 443, 444, 468

Cullheim, S. 126

Culp, D. L., xii

Curtiss, S. 546

Cusick, C. 146, 148, 152

Cynader, M. 445

Dale, A. 511, 527

Dale, H. H. 390

Dale, N. 118

Dalley, J. 405, 410, 412

Danforth, R. 537

Danforth, W. 85

Daniel, P. M. 504, 505, 510

Danker, S. 537, 546

Dario, P. 128

Darnell, R. 97

Darwin, C., xi 138

Dascola, I. 360, 361

Dash, P. 195

Davidson, B. J. 360

Davis, R. 46

Daw, N. 523

De Renzi, E. 347

De Schutter, E. 128

DeFelipe, J. 536

Degenfeld-Schonburg, O. 427

Dehaene, S. 414

Deichmann, R. 472

Delbruck, M. 44, 61, 490

Deliagina, T. 123, 126

DeLong, M. 74, 91, 407

Dement, W. 443

Dennis, M. 499

Desimone, R. 92, 259, 261, 270, 286, 510, 520, 526

Desmedt, A. 52

Destexhe, A. 250

Dews, P. 80, 399

DeYoe, T. 509, 512, 513, 515, 516

Di Cesare, G. 378

Di Dio, C. 378

Di Pellegrino, G. 354, 355

Di Salle, F. 467

Diamond, I. 139, 140, 141, 153, 154, 155, 158, 351

Diamond, M. 155

Dias, E. C. 362

Dias, R. 403

Dichter, M. 78

Dickinson, A. 413

Dickson, J. 530

Dierker, D. 525, 530

Dobzhansky, T. 224

Dolabella, A. 452

Dollfuss, E. 170

Donahue, C. 543, 549

Dongen, P. van 121

Dostrovsky, I. 41, 42

Dostrovsky, J. 41

Doty, R. 340

Dräger, U. 436

Dreher, B. 156

Driver, J. 260

Drury, H. 525, 527, 528, 530

Dubinsky, J. 78, 81

Dubuc, R. 122, 128

Dudai, A-Z. 36

Dudai, B. 36

Dudai, O. 39

Dudai, R. 39

Dudai, Y. 35–61

Duff, T. 10, 12

Dunlap, K. 84

Dunnett, S. 401

Durkovic, R. 9, 10

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Eagle, D. 411, 412

Ebbensson, S. 155

Ebbinghaus, H. 194

Ebner, F. 146, 155

Eccles, J. 70, 128, 181, 182, 183, 339, 438

Eckhorn, R. 464

Edelman, G. 365

Edelson, M. 56, 58

Eden, U. 244, 279, 286

Edgerton, R. 113, 114

Eichenbaum, H. 244, 278, 286

Eickhoff, S. B. 357

Eigen, M. 439

Eisen, H. 84

Eisenberg, M. 52, 53, 54

Ekeberg, Ö. 120, 121, 128

El Manira, A. 119, 124, 126, 127, 128

Elam, J. 546

Elfvin, L. G. 126

Eliasmith, C. 519, 525

Eliot, L. S. 48

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Elmslie, K. S. 14

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Elston, G. N. 536

Emerson, R. 145

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Erlanger, J. 177

Ermentrout, B. 241, 242, 243, 245, 246, 247, 248, 252, 253, 254, 255, 257, 259, 260

Ersche, K. 412

Eshel, N. 56

Eskandar, E. 271, 287

Esposito, F. 467

Essen, A. van 522

Essen, B. van 507, 521, 522, 523, 542

Essen, C. van 487

Essen, D. 311, 485–550

Essen, J. van 522

Essen, L. van 522, 542

Essen, M. van 542

Essen, R. van 487

Essen, S. van 503, 506, 507, 521, 542

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Evans, T. 546

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Ewalt, J. 184

Ewins, A. 390

Faas, J. 487, 488

Fabbri-Destro, M. 358, 366, 373

Fadiga, L. 354, 355, 357, 358, 368, 380

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Fallah, M. 362

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Fang, P-C 147, 151, 157

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Fatt, P. 197

Favera, R. D. 94

Fazio, F. 357

Federman, D. 313

Feinberg, D. 545

Feldman, J. 118

Fell, H. 233

Felleman, D. 145, 149, 509, 513, 529

Fen, S. 398

Fenton, A. A. 54

Ferri, S. 377

Ferster, D. 316

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Fibiger, C. 401

Fineberg, N. 413

Finn, H. 488

Fioriti, L. 210

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Fischbach, J. 71

Fischbach, M. 72, 77, 81, 84

Fischbach, N. 72, 77, 84

Fischl, B. 527, 529

Fletcher, P. 410

Flexner, L. 191

Florence, S. 146

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Forbes, A. 188

Forssberg, H. 113, 117, 127

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Franca, J. 157

Francesconi, W. 452

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Frank, J. 502

Frank, K. 74, 76, 181, 182

Franklin, K. B. J. 529

Franzesi, G. T. 262

Fray, P. 398

Fredrickson, D. 194, 213

Freeman, W. 259, 461

Freiwald, W. 324, 325, 326, 465

Freud, S. 117, 138, 168, 169, 175, 176

Freund, H-J. 357, 366

Freygang, W. 74

Friedan, B. 308

Friedländer, S. 435

Friedman, N. P. 407

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Friston, K. 281

Fronius, M. 446

Fuchs, E. C. 256

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Furman, O. 57

Furshpan, E. 79, 184, 186, 492

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Fuxe, K. 126

Gabi, M. 150

Gaffan, D. 402

Gage, R. 90

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Gallese, V. 354, 355, 356, 367, 369, 371, 374

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Garcia, J. 51

Gardner, T. 244

Garraghty, P. 146, 148

Garvey, G. 95

Gaspar, P. 147, 156

Gasser, H. 177

Gastaut, H. 336, 358

Gastaut, Y. 336, 358

Gattass, R. 510

Gawriszewski, L. 360

Gazzaniga, M. 155, 340, 371, 430

Gelfand, I. M. 112

Geller, U. 346

Gelmini, M. 374

Gennari, F. 353

Gentilucci, M. 350, 352, 354

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Georgopoulos, A. 525

Gerard, R. 179

Gerlach, J. 495

Gerstner, W. 252

Geschwind, N. 310, 347

Gharbawie, O. 151

Ghirardi, M. 195

Ghitza, O. 286

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Gilbert, C. 316, 442

Gillan, C. M. 413

Gillies, M. 264

Gilman, A. 74

Giorello, G. 367

Giraud, A-L. 274, 281

Gispen, W. 47

Gitelman, D. R. 362

Gizzonio, V. 379

Glanzman, D. 195

Glasser, M. 531, 536, 543, 547, 548

Glickstein, M. 353

Gloveli, T. 264

Gödecke, I. 461

Goebel, R. 467, 468, 527

Goelet, P. 194

Goff, D. G. 11

Gold, A. P. 94

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Goldberg, I. 78

Goldberg, M. 28, 349

Goldberg, R. 274

Goldberg. I. 80

Goldberger, M. 516

Goldberger, R. 176

Goldin, D. 287

Goldman, A. 367

Goldman, P. 80, 475

Goldman-Rakic, P. 147, 407

Golgi, C. 442

Golomb, D. 262

Gombrich, E. 176, 323

Goodale, M. 363

Gordon, H. 532

Gould, H. 146, 147

Gould, S. J. 155

Grafstein, B., xii 74

Grafton, S. 357, 368, 371

Graham, B. 307

Granit, R. 111, 128

Grant, G. 126, 155

Grant, S. 199

Gray, C. 258, 463, 464, 465

Gray, J. 115, 116

Graybiel, A. 128, 278, 286

Graziano, M. 151

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Greenberg, M. 87

Greengard, L. 99

Greengard, P. 193, 197

Greenup, M. 94

Greiner, W. 473

Grillner, K. 130

Grillner, S. 109–131, 245, 247, 467

Gross, C. 347, 350, 514

Gross, C. G. 510

Grubb, R. 537

Grün, S. 465

Grünau, M. von 446, 449

Grundfest, H. 73, 176, 177, 178, 179, 180, 182, 192

Grupp, L. 348

Gruss, P. 474

Gu, P. 530

Gu, Q. 454

Guilleminault, C. 443

Guillery, R. 142, 143, 144, 154, 155, 458, 468

Guitton, M. J. 52

Gutierrez, C. 153

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Haagen-Smit, A. 490

Hacker, H. 467

Hackett, T. 147, 148, 152

Halbertsma, J. 117

Hall, R. 140, 141, 142, 153

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Hamalainen, M. 286

Hamburger, V. 85

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Handelman, J. 525

Hansel, C. 457

Hansel, D. 262

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Harkema, S. 114

Harlow, H. 139

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Harreveld, A. van 507

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Harris-Warrick, R. 312, 313

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Hartline, K. 183

Harwell, J. 525, 529, 547

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Hasson, U. 56, 57

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Heath, A. 544

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Hecaen, H. 347

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Hegdé, J. 521

Heidemann, S. 533, 534

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Heinemann, U. 433

Heisenberg, W. 426

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Henneman, E. 312, 532

Henry, G. 156

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Herman, R. 127

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Hildebrand, J. 22, 492

Hilgard, E. R. 184

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Himmel, E. 323

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Hitler, A. 170, 171, 172, 175

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Hobby, O. C. 90

Hochner, B. 195

Hochstein, S. 367

Hodges, J. 408

Hodgkin, A. L. 183, 253, 255, 492

Hofmann, P. 433

Hökfelt, T. 121, 126

Holst, E. von 115, 439

Holtzer, H. 75

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Honig, B. 95

Hood, L. 522

Hooper, S. 250

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Hopfield, J. 248, 516, 517–518

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Huntington, G. 401, 408

Husserl, E. 367

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Huxter, J. 467

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Ito, R. 410

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Jalalvand, E. 122

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Kalaska, J. 365

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Petersdorf, R. 73

Petersen, S. 524, 544

Petit, J-L. 367

Petrides, M. 397

Petrus, V. 334

Pettigrew, J. 156, 445, 506, 508

Pfurtscheller, G. 466

Phillips, R. 437, 438

Phillips, T. 401

Phillips Conroy, G. 85

Phillips Conroy, J. 85

Pierracini, C. 372

Pigarev, I. 350, 352

Pines, D. 48

Pinsker, H. 187

Pipa, G. 465

Pisa, M. 348

Pittenger, C. 199

Pittman-Polletta, B. 268, 272

Pitts, L. 10

Plailly, J. 369

Planck, M. 448, 451, 460, 464, 469, 470, 472, 473, 474, 475, 476, 477

Plenz, D. 271

Ploog, D. 433

Plum, F. 71, 73

Poe, E. A. 137, 138

Poeppel, E. 442

Poffenberger Jr., A. T. 345, 346

Poggio, G. L. 348

Poggio, T. 517

Polley, D. 287

Polyakova, I. G. 345

Pombal, M. 124

Pompeiano, O. 339

Pons, T. 146, 159

Poo, M-M. 447

Poppele, R. 342

Porter, J. 74, 92, 93

Posner, J. 71, 73

Posner, M. 348, 360, 362

Pospichal, M. 147

Potter, D. 79, 184, 186, 492

Potter, M. 492

Prager, K. 94

Precht, W. 449–450

Preuss, T. 146, 153, 158, 543

Pribram, K. 394

Price, J. 526

Prigogine, I. 230, 234

Pritchard, R. 347

Proshansky, E. 193

Purdon, P. 269, 286

Purpura, D. 177, 178

Purves, D., xii 85, 86, 493, 499, 501, 539

Purves, S. 501

Qi, H-X. 149

Quatrano, R. 537

Quine, W. V. O. 53

Quinn, W. 43, 44, 45, 46, 47, 313

Rabin, Y. 42

Raftery, M. 43

Rahman, S. 408

Raichle, M. 522, 524

Rajasethupathy, P. 210

Rakic, P. 475

Rakshit, S. 524

Rall, T. 192

Rall, W. 74, 75, 249

Ramachandran, V. S. 367, 518

Randall, D. C. 9

Rando, R. 80

Randrup, A. 394, 396

Raposo, C. 56

Rappoport. S. 74

Rauschecker, J. P. 445, 447, 455

Ravenna, C. 336

Raviola, E. 87

Rayport, S. 193

Redfern, P. A. 502

Reed, J. 149

Reed, W. 75

Reese, T. 74

Regher, W. 87

Reid, C. 87

Reid, E. 513, 530, 547

Reillo, I. 534

Rema, V. 155

Remmes, A. 23

Remple, M. S. 151

Rescorla, R. 188

Retzius, G. 493

Reynolds, J. 259, 261

Ricard, M. 459

Richards, J. 523

Richter, J. D. 209

Riggio, L. 360, 361

Riker, W. 72

Rilling, J. 543

Rinzel, J. 241, 249, 250, 252

Ritchie, T. 10, 11

Ritt, J. 253, 286

Rizzolatti, B. 347, 350

Rizzolatti, G. 331, 332–380, 414, 433

Rizzolatti, T. 334

Rizzuto, N. 336, 342

Robbins, E. 85, 390

Robbins, J. 415

Robbins, L. 85

Robbins, M. 415

Robbins, N. 74, 75

Robbins, R. 390

Robbins, T. W. 389–415

Roberts, A. 402, 403, 404

Roberts, P. D. 532

Robertson, B. 122, 124

Robinson, T. 398

Rocha-Miranda, C. E. 350

Rochat, M. 379

Rockland, K. S. 511

Rockoff, E. 150

Rodieck, R. 156

Roe, A. 152

Roediger, R. 537

Roelfsema, P. 446, 465, 466

Rogers, R. 410, 411

Roland, P. 126, 540

Rolando, P. 396

Role, L. 86

Rolls, D. 396

Roopun, A. 273, 275, 277

Rosa, M. 157

Rose, E. 94

Rose, J. 140

Rosen, B. 541

Rosenblum, K. 52

Rosenquist, A. 351

Rosenzweig, S. xiii

Rossignol, S. 113, 114, 115, 127, 128

Rotenberg, A. 201, 205, 207

Rothemund, Y. 159

Rothman, J. 95

Rotstein, H. 240, 264, 265

Rovainen, C. 117

Rowland, L. 192

Royet, J-P. 369

Rozzi, S. 358, 366

Rubin, D. C. 61

Rubin, L. 77

Rubin. G. 213

Rudenstein, N. 88

Rudomin, P. 442

Rupp, G. 94, 96

Sacks, O. 396

Sacktor, T. 54

Sadeh, N. 55, 56

Saggese, M. 539

Sagi, D. 515

Sahakian, B. 397, 398, 402, 404, 405, 408, 413, 415

Sahakian, W. 399

Sahgal, A. 393, 398

Saitoh, K. 122, 123

Sakai, K. 453

Sakata, H. 355, 356, 357

Sakharov, A. 289

Sakmann, B. 128, 433, 439, 441, 457

Salkoff, L. 85

Salzman, C. D. 465

Samson, F. xi

Sanderson, K. 143, 156

Sanes, J. 85, 316, 533, 536

Santaniello, S. 271

Sara, S. J. 53

Saraga, F. 265

Sarma, S. 271

Sarter, M. 405

Scammell, T. 267

Scandolara, C. 350, 352, 435

Schacher, S. 193, 194

Scheel-Kruger, J. 396

Scheich, H. 433

Scheller, R. 47, 48, 194

Schick, B. 169

Schiele, E. 168

Schildkraut, J. 311

Schillen, T. 463, 465

Schiller, P. 438

Schimmerling-Cramer, K. 532

Schlaggar, B. 544

Schmidt, H. 469

Schmidt-Nielson, K. 140

Schmielau, F. 458

Schmielau, M. 458

Schmitt, F. O., xi 442, 452

Schnall, A. 10

Schneider, W. 543, 544

Schnitzler, A. 168

Schoenberg, A. 168

Schotland, J. 119

Schrodinger, E. 239

Schroeder, C. 281

Schuetze, S. 82

Schultz, G. 26

Schultz, W. 401

Schulz, J. H. 431

Schuman, E. 197, 451, 475

Schuschnigg, K. von 170, 171

Schuster, C. 399

Schuster, J. B. 399

Schwaber, J. 10

Schwaber, M. K. 147

Schwartz, E. L. 511

Schwartz, J. 47, 48, 176, 187, 191, 192, 193, 194

Schwarz, J. 313

Scotus, J. D. 45

Scoville, W. 180

Seeger, P. 212

Seikmeier, P. 272

Seitun, A. 344

Sejnowski, T. 90

Sekuler, R. 287

Selverston, A. 128

Sen, K. 286

Serenevy, A. 263

Sereno, M. 511, 527, 531

Sesma, M. A. 146

Seung, S. 546

Seyss-Inquart, A. 171

Shadlen, M. 525

Shalala, D. 93

Shallice, T. 391, 406

Sharma, K. 76

Sharma, S. 76

Sharon, N. 39

Sharp, A. A. 252

Shatz, C. 498

Shaw, P. 537

Sheliga, B. 361

Shema, R. 52, 54

Shemesh, M. 56

Shepherd, G., xii 539

Sherman, A. 249

Sherman, M. 23

Sherrington, C. 113, 115

Shik, M. 111, 113

Shinn-Cunningham, B. 244, 286, 288

Shipp, S. 512, 513

Shub, M. 228, 292

Shupliakov, O. 121, 122

Si, K. 209, 210

Siegal, R. 83

Siegelbaum, S. 193, 194

Siegle, J. H. 260

Sigvardt, K. 118, 245, 246, 247

Silberberg, G. 126

Silman, I. 39, 40, 43

Silva, A. 199

Silverman, M. S. 320

Simons, J. 97, 99, 100

Simons, M. 97, 99

Simpson, E. 212

Singer, A. 262

Singer, F. 431, 432, 434, 435, 449, 473, 477, 552

Singer, H. 426

Singer, J. 426

Singer, K. 426

Singer, N. 436, 459, 477

Singer, P. 426

Singer, S. 426

Singer, T. 436, 459, 477

Singer, W. 259, 261, 425–478

Sinigaglia, C. 367, 368, 371

Sinsheimer, R. 506, 508

Sireteanu, R. 446, 449, 452, 477

Sivan, E. 279

Skinner, B. F. 180, 184, 399, 437

Skinner, F. 250, 265

Skinner, J. E. 463

Slatkin, L. 85

Sloan, A. P. xi

Sluyters, R. C. van 445

Smale, S. 228, 229

Small, S. 211

Smith, J. 530

Smith, L. 144

Smith, M. L. 408

Smith, S. 545

Smith, T. 76

Snyder, C. R. 360

Snyder, S. 393, 394, 399

Soha, J. 532

Somers, D. 250, 251

Sompolinsky, H. 249

Soto-Trevino, C. 250, 253

Sparaci, L. 378

Spease, G. 154

Spector, A. 92

Speemann, H. 85

Spencer, A. 73, 78, 181, 182, 185, 187, 192, 213

Spencer, K. 273, 287

Spencer, W. A. 8

Sperry, R. 339, 340, 430, 490

Spitzer, N. 492

Spitzer, R. 176

Sporns, O. 280

Sprague, D. 351

Sprague, J. 341, 342, 348, 350, 351

Squire, L. R., xii, xiii, xiv 57, 205, 478, 539

Srihasam, K. 326

Stahl, P. 523

Stalin, J. 113

Stegmüller, W. 429

Stein, G. 4

Stein, P. 127, 128

Steinbach, J. H. 85, 90

Steinberg, R. 473

Steindler, D. 143

Steiner, I. 116

Stent, G. 475, 500

Stephan, H. 450

Stephens, D. 405

Stephenson-Jones, M. 122, 124

Stepniewska, I. 146, 151, 152, 153

Stern, D. 377, 378, 379

Stevens, C. 73, 90

Stevenson, E. 95

Steward, O. 196, 197

Stickgold, R. 287

Stokoe, W. C. 368

Stolzenberg, G. 231, 232, 239, 244, 283

Stone, A. A. 61

Stone, J. 156

Storm, D. 199

Stouffer, S. 4

Straschill, M. 433

Strata, D. 339

Strata, F. 153, 155

Strata, P. 339, 433

Strauss, R. 427

Streisinger, G. 499

Stretton, T. 494

Strick, P. L. 407

Strogatz, S. 254

Struhl, G. 194

Strumwasser, F. 490, 491, 507

Strüngmann, A. 473, 474, 476

Strüngmann, T. 476, 477

Stuart, A. 311, 493

Stuart, D. 127

Stufflebeam, S. 272, 286

Stylianopoulou, F. 129

Suddendorf, T. 372

Sullenberger, D. M. xii

Sur, M. 145, 146, 152

Sutherland, E. W. 192

Sutherland, S. 393, 436

Swainson, R. 407, 408, 409

Swanson, L. xii

Swazey, J. xi

Switkes, E. 320

Symonds, L. 153

Szenthagothai, J. 438, 442

Taghert, P. 85

Takahata, T. 154

Talairach, J. 528

Talbott, J. 179

Tallon-Baudry, C. 466

Tamas, G. 257

Tanaka, K. 514

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Tanji, J. 359

Tank, D. 100, 248

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Taub, E. 19, 20

Tauc, L. 184, 185

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Tebaldi, R. 343

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Teilhard de Chardin, P. 429

Tempel, B. L. 314

Tennenbaum, J. 94

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Terman, D. 251, 271

Terry, R. 85, 536

Terzian, H. 335, 336, 342, 358

Teuber, H. L. 347

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Thier, P. 375

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Thompson, D. 534

Thompson, R. 182

Thorndyke, E. 184

Thorstensson, A. 118

Tiesinga, P. 262

Tinbergen, N. 183

Tjian, R. 213

Tonegawa, S. 199

Tootell, R. 320, 324

Tort, A. 265, 277, 278

Tosteson, D. 321

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Tradardi, V. 345

Traub, R. 254, 255, 256, 257, 258, 259, 260, 264, 273, 277

Trauner, D. 10

Tråvén, H. 120, 121

Tretter, F. 445

Trice, L. 154

Trotter, M. 85

Trussell, L. 87

Tsao, D. 323, 324, 325, 326

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Tsien, J. 53

Tsien, R. 84

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Turner, D. C. 413

Tye, N. 397

Tyler, K. xii

Ugurbil, K. 545, 547

Uhlhaas, P. 272, 273, 438, 465, 466

Ullman, S. 376

Umiltà, C. 346, 348, 360, 361, 365, 366

Ungerleider, L. 510, 526

Ungerstedt, U. 396

Uzzan, A. 47

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Vaina, L. 286

Vale, W. 90

Vanduffel, W. 324

Vanegas, H. 442

Varela, F. 458, 459, 466

Varmus, H. 90, 91, 93

Veirling-Claassen, N. 272

Verma, I. 90

Veroni, V. 379

Vierling-Claassen, D. 272

Vignolo, A. 347

Vijayan, S. 268, 269, 273

Vinay, L. 122, 128

Vincent, J. 326

Vinograd, J. 489

Vogt, O. 448

Vogt, S. 367

Volk, L. J. 55

Volkow, N. 412

Vreeswijk, C. van 252

Wadden, T. 121

Wagner, A. 188

Wald, G. 177

Wall, J. 10, 13, 146

Wallén, P. 113, 116, 117, 118, 119, 120, 126, 127

Walsh, M. 509

Walter, B. 168

Walters, T. 187

Wang, Q. 530

Wang, X. J. 249, 250, 252, 281

Wang. D. 119

Warburton, D. 394

Warren, W. F. 244

Warrington, E. 405

Wässle, H. 433, 449, 450, 451, 475

Watson, J. 391, 395, 498, 499

Waud, D. 80

Weber. A. 23, 26

Wehr, M. 467

Wei, F. 53

Weinberger, D. 408

Weisel, T. 79, 80

Weiskrantz, L. 392, 402, 438, 468

Weiss, P. 74

Weitz, C. 87, 88

Welker, W. 140, 141

Weller, R. 146, 147

Wendelstadt, J. von 427

Wenger, G. 399

Werfel, F. 169

Wespatat, V. 466

Westheimer, G. 475

Westover, B. 524

Whelan, R. 413

White, J. 244, 253, 254, 263

Whitelaw, R. B. 410

Whiten, A. 372

Whitney, H. H. 500

Whitteridge, D. 504, 505, 510

Whittington, M. 253, 254, 256, 257, 258, 259, 264, 273, 274, 275, 276, 279, 287

Wibral, M. 465, 472

Wickelgren, W. 5, 6, 7

Wicker, B. 369

Wied, D. de 46–47

Wiener, M. 356

Wiersma, C. 507

Wiesel, T. 143, 184, 186, 340, 438, 442, 445, 475, 492, 497, 498, 499, 500, 504, 505, 506, 508, 510, 512, 514, 521

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Wikström, M. 119

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Wilcox, S. E. 368

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Wilhelm, K. 448, 450

Wilkinson, L. 397

Williams, J. H. 372

Williams, T. 245, 246, 247

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Willner, B. 55

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Wilson, J. T. L. 438

Wilson, M. 29, 286

Wilson, M. A. 462, 467

Winder, D. 207, 208

Winfree, A. 251

Winstanley, A. C. 412

Wolfson, E. 511

Wong, D. 292

Wong, L. 292

Wong, P. 153

Wong, R. 536

Wong-Riley, M. 153, 316, 317

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Woolf, H. 71, 73

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Woolsey, C. 140, 141, 143, 144, 154, 179

Worden, F. xi

Wrighton, M. 537

Wu, C. 147, 157

Wurtz, R. 74, 349

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Xu, X. 152

Xue, Y-X. 55

Yacoub, E. 547

Yellen, G. 87

Yin, F. 537

Yinon, U. 448

Young, N. 150

Yovell, Y. 48

Yudkovsky, D. 37, 38

Zangger, P. 113, 116

Zangwill, O. 392, 393, 397, 415

Zeiss, C. 122

Zeitlin, R. 72, 73, 75, 76, 77, 79, 81, 85, 91, 94

Zeki, S. 142, 159, 500, 504, 505, 508, 512

Zemer, M. 56

Zhabotinsky, A. 233

Zhang, W. 119

Zieglgänsberger, W. 452

Zigmond, R. 80

Zilles, C. 154

Zilles, K. 357, 359, 366

Zimels, B. 172

Zimels, C. 169

Zimels, D. 170

Zimels, H. 170

Zimels, M. 170

Zohn, H. 168

Zorumski, C. 537, 545

Zuckerman, H. 209

Zuckmayer, C. 172, 175

Zvi, S. 47

Zweig, G. 499

Zweig, S. 168–169