New neurons, shown here in the mouse, are born throughout life in a specific region of the brain’s hippocampus. This region, known as the dentate gyrus, is involved in pattern separation, the ability to discriminate between very similar memories.
Image credit: Winkle, et al. The Journal of Neuroscience, 2016.
Neurogenesis occurs throughout life in the hippocampus (blue), an area of the brain involved in learning and memory.
Aerobic exercise like running can improve cognitive function in people, and one of the ways it may do this is by enhancing neurogenesis. Studies in mice show exercise boosts neurogenesis in the dentate gyrus of the hippocampus and this leads to improved learning and memory.
Exercise boosts neurogenesis in the dentate gyrus of the hippocampus. The images above show newly-born neurons in the dentate gyri of a sedentary mouse (top) and a mouse that ran on a wheel (bottom), as viewed through different microscopes. The running mouse has more new neurons in the dentate gyrus compared to the sedentary mouse.
Lazarov et al. Trends in Neurosciences, 2010.
The brain’s limited capacity to regenerate triggered the belief that neurogenesis — the birth of new brain cells — ceased after embryonic development. In the latter half of the 20th century, scientists found new cells are born in the brain throughout life. Today this knowledge is helping scientists understand learning and memory.
When the skin is cut, it will repair itself. Broken bones heal just as strong. But damage to the brain and spinal cord tends to be permanent. This limited capacity to regenerate led to the long-held belief that the brains of humans and many other animals couldn’t grow new signaling cells, or neurons. Scientists concluded that the birth of new neurons, or neurogenesis, was limited to embryonic development.
Pioneering research by Joseph Altman in 1962 suggested otherwise. Altman injected adult rats with a radioactive molecule that incorporates into new strands of DNA and as such labels new cells with a small amount of radioactivity. When he examined the rats’ brains he found radioactive cells indicating new neurons had been born in the adult brain.
Throughout the 1960s, Altman studied adult rats, finding neurogenesis confined to a handful of areas in the brain — including the hippocampus, a seahorse-shaped structure within each brain hemisphere. Later research would reveal the hippocampus is vital for learning and memory. Specifically, he found newborn cells in a part of the hippocampus called the dentate gyrus. He also discovered neurogenesis in the layer of tissue lining the ventricles, the fluid-filled cavities in the brain.
Even so, the scientific community remained skeptical of the findings because the radioactive labeling didn’t target neurons specifically and the imaging technology of the day couldn’t differentiate neurons from other types of brain cells. In addition, conventional wisdom held that a set number of neurons in the brain wired up together to form circuits. How would it be possible to learn or remember if new neurons were constantly being added to these circuits?
In the 1980s, neurobiologist Fernando Nottebohm provided more conclusive evidence of neurogenesis. Using the same radioactive labeling, he found new cells were born in the brains of songbirds and, going one step further, he found the cells conducted electrical impulses, definitively proving they were neurons.
But despite a growing body of studies like these, it wasn’t until the development of more sophisticated tools in the 1990s that neurogenesis moved to the fore.
New Tools Offer a Clearer Picture of Neurogenesis
In the 1990s, the identification of stem cells in the adult mouse brain demonstrated that unspecialized, precursor cells divided to produce new neurons. New tools for labeling and imaging neurons further propelled the field of neurogenesis.
One of these tools employed a non-radioactive molecule called bromodeoxyuridine, or BrdU. Like its radioactive predecessor, BrdU incorporates into new strands of DNA during cell division. Scientists could view new cells harboring BrdU by bathing slices of brain tissue in a solution containing fluorescent markers and using a microscope that captures fluorescence. Improvements in confocal microscopy provided higher-resolution pictures of fluorescently-labeled cells in the brain. With these new tools, scientists proved two things: new cells were born in the brain and some of them were neurons.
In 1996, researchers found that while the rate of neurogenesis in the brain plummeted as rats aged, it was never abolished completely. And in 1998, a landmark study offered the first evidence of neurogenesis in the adult human brain.
A slew of other studies during this time demonstrated neurogenesis didn’t just vary with age – it could be modified by experience and environment. Stress diminished neurogenesis in tree shrews, while exercise and enriched environments boosted neurogenesis in rats.
In 2002 researchers at The Salk Institute in California visualized and recorded newborn neurons in living mice, something which hadn’t been possible before. The researchers watched as over a period of several months the new cells grew and began to look and behave like mature neurons, forming connections (synapses) and firing electrical impulses.
Neurogenesis was a fact, both in lab animals and people. It declined with age, but could be enhanced by cognitive enrichment and exercise. And it produced functional neurons. But an important question lingered: what role did neurogenesis play in cognition? In the following decade, answers emerged and with them, implications for aging and cognitive health.
Insights for the Aging Brain
Identifying neurogenesis in the adult human brain was a revelation. Still, its mere existence didn’t establish whether adult neurogenesis made a significant contribution to cognition and, if it did, could it be enhanced to benefit the aging brain?
Research offered important insight into neurogenesis, exercise, and learning in 2005 when scientists discovered running on a wheel boosted neurogenesis in older mice as compared to mice that were sedentary. What’s more, running mice performed just as well as younger mice on a spatial learning task.
A discovery in 2009 demonstrated why the brain needs neurogenesis in adulthood. Adult neurogenesis takes place only in two specific areas including a section of the hippocampus called the dentate gyrus – a region key to the ability to discriminate very similar memories like remembering where you parked your car today as opposed to yesterday. Researchers found blocking neurogenesis in mice impaired their ability to remember similar locations in a maze.
A groundbreaking study in 2013 documented the extent of neurogenesis across the human lifespan. Using carbon dating, the researchers estimated the age of hippocampal neurons in postmortem brain samples and constructed a model of hippocampal cell turnover over the lifespan. They determined that there is substantial neurogenesis in the human hippocampus suggesting newly-born neurons make a significant contribution to brain function.
It also suggested enhancing neurogenesis may stave off cognitive decline. Numerous studies indicate the benefits of exercise go beyond cardiovascular health to include preserving cognitive function and mitigating brain atrophy in aging. In addition to increased blood flow and production of growth factors in the brain, neurogenesis may be one way by which exercise exerts its neuroprotective effects.
More than 50 years in the making, the story of neurogenesis began with Joseph Altman’s small study in 1962. With new tools and technologies at their disposal, a new generation of scientists are revealing truths about neurogenesis and the aging brain. With continued support from public and private institutions, scientists will continue to build on these discoveries and identify potential strategies to prevent cognitive decline in aging.
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