Of Mice and Men: Exercise and the Brain

“Come, look at this”, said Professor Fred Gage, wheeling his chair around to click on his office computer, where a slide appeared. One squiggle of magenta on the screen was the enlarged picture of a mouse hippocampus (the part of the brain that plays in major role in learning and memory). On top of that was a sliver of dark blue – the dentate gyrus, a small region of the hippocampus. Extending out of that sliver were dozens of branches – mature neurons. And scattered around those branches were tiny bright green dots. They are baby neurons, proof that the adult brain can continue to grow new nerve cells as older ones attrition.

Fred Gage is professor of neuroscience at the Salk Institute in La Jolla, California, a premier medical and biological research institute. Those new brain cells, explained Gage, were produced in mice in a process called neurogenesis. Remarkably, they appeared after only an hour and a half of exercise on wheels in a cage. Gage says excitedly, “There’s no question – physical activity makes new brain cells proliferate.” He adds: “for the longest time, we thought that the brain was like a computer and if you threw in a new wire into that existing circuit, you would just screw it all up. Now we know that is not the case. The brain is an organ. It is tissue that is changing all the time and it is regulated by our environment. Our brains are altered by what we do.”

4 weeks-old newborn neurons (green) born in the dentate gyrus of the adult mouse hippocampus (nuclei of neurons and glial cells are shown in red), courtesy of Professor Sebastian Jessberger of the Brain Research Institute, University of Zurich.

Gage is not alone in arguing that exercise is good for the brain.  Another group of researchers led by Scott Small at Columbia University reached the same conclusion. In the spring of 2007, Small published an extraordinary study in the prestigious Proceedings in the National Academy of Sciences (PNAS). The study divided 46 mice into two groups. For two weeks, one group of mice was kept in cages with running wheels and the other without. Both groups of mice were injected with a dye (banned in human subjects) that clings onto new cells and allows scientists to see precisely where new brain cells form. After two weeks, the researchers scanned the mice to see what was happening to the blood flow in their brains. They also looked at slices of the mice brains under the microscope.

Small and his team found what they had expected. The mice that had run on their wheels had increased blood flow in their dentate gyrus, those tiny sections of the memory-critical hippocampus. Moreover, the increase was there long after the mice stopped exercising, which meant that the effects of exercise were not transient. And right in the middle of the dentate gyrus were the same green dots that Gage had observed in mice that exercised. There were twice as many green-dotted new brain cells in the exercising group as in the non-exercising group. For Small and his colleagues, these were exciting findings, a clear sign that exercise was not only a powerful producer of new neurons as Gage and others had suggested, but also seemed to “selectively target” the brain’s dentate gyrus, right in the middle of the brain’s memory machinery. This means that exercise may in fact help bolter the brain’s memory as we age.

Left: Fred Gage, President of the Salk Institute for Biological Studies and the Adler Professor in the Laboratory of Genetics at the Salk Institute. Right: Scott A. Small, Director of the Alzheimer’s Disease Research Center at Columbia University, where he is the Boris and Rose Katz Professor of Neurology. He is appointed in the Departments of Neurology, Radiology, and Psychiatry.

Still, these experiments were done on mice. What about humans? To answer this question, Small teamed up with Gage to extend the green-dot study to include humans as well. Their study piggy-backed on an exercise study that was conducted by Small’s colleague, Richard Sloan, a behavioral psychologist at Columbia University. Small decided to take a peek at the dente gyrus of eleven people who were in the Sloan experiment. After the researchers scanned the brains of the humans, they found pretty much what they’d found in mice. The humans who had exercised the most had twice the blood flow as the non-exercisers and the increase occurred in the dente gyrus. What’s more, the dentate gyrus blood flow jumped the most in those who became the most fit as measured by their level of VO2 max, or the maximum amount of oxygen they took in as they exercised, the gold standard for measuring fitness.

If one must qualify the human study, it is that the researchers could not cut open their subjects’ brains nor could they inject dye that tag new cells as in the mice experiments. So their study did not technically prove that exercise gave birth to new neurons. Still, because of the striking increase in blood flow – a measure that is correlated directly with the growth of brain cells in mice – Small and others feel confident in saying that exercising is a promising way to birth new neurons, mice or humans.

But what does memory have to do with new neurons? How are these two things related? Gage has a theory. He believes that like other cells in our body, brain cells are crucial all the days of our lives, which means we have evolved to grow new ones even as we get older. In particular, he believes the new neurons help us fold new experiences in our existing memory bank.

Our memories are notoriously unreliable, partly because we are constantly pulling up old memories and “retagging” them with new information. Gage believes that baby neurons help us with that process, tying together different sensations that occur at the same time, thus helping us fit the new with the old. An example: suppose you hear a Beach Boys song and smell the salt from the beach. Those two impressions – a song and the sea, will forever be tied together in time and place. And the more new neurons you have, the more you are able to link the two sensations together into a pattern that will hang together in your brain. This is the essence of learning. What exercise does is facilitate that memory association and learning process by stimulating neurogenesis and the appearance of those precious little green “shoots”, the baby neurons.

But how much exercise does the brain needs? Fortunately, there are legions of studies which point to some pretty concrete advice. A 2003 study by Art Kramer, a neuroscientist at the University of Illinois at Urbana-Champaign, found that those who over 60 who exercised regularly and vigorously (that meant such exercise as running or brisk walking), had less brain tissue loss than non-exercisers. Kramer’s 2003 study is consistent with a 1999 Nature paper (also led by him) which reported that a group of 124 relatively unfit people over age 60, after walking briskly at 17.7 minutes per mile for 45 minutes three days a week were much better at complex tests, in particular those that involved task-switching. The exercisers were also better at focusing and ignoring irrelevant information, a sign that exercise has boosted the performance of the frontal lobe, the crucial executive area of the brain that controls judgement, planning and decision-making. Research on the exercise-brain health connection is ongoing; much remains to be learned. But already, many neuroscientists like Kramer are positively convinced about the benefits of exercise for the brain. Kramer himself is so convinced that he set out to do what he can to keep fit, including training his middle-aged body and brain – for a triathlon.


This post is based on the New York Times bestseller by Barbara Strauch, The Secret Life of the Grown-Up Brain, Viking, 2010.

Scientific Articles
Fred Gage (1999), “Running Enhances Neurogenesis, Learning, and Long-Term Potentiation in Mice,” PNAS 96:23, Nov 9, 1999.

Scott Small et al. (2007), “An In Vivo Correlate of Exercise-Induced Neurogenesis in the Adult Dentate Gyrus”, Proceedings of the National Academy of Science (PNAS), 104: 13, March, 27 2007.

Karen Weintraub, (2019), “The Adult Brain Does Grow New Neurons After All, Study Says”, Scentific American, Mar 25, 2019. Link: https://www.scientificamerican.com/article/the-adult-brain-does-grow-new-neurons-after-all-study-

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