Evidence in humans that a structured exercise training program increases neurogenesis.

A new study led by researchers at Columbia University provides the first evidence in humans that a structured exercise training program increases neurogenesis—the birth and development of new nerve cells—in a memory hub of the brain. The area, a subregion of the hippocampus called the dentate gyrus, is one of only two brain regions for which the evidence for lifelong neurogenesis is incontrovertible, and it is particularly vulnerable to age-related degeneration. Exercise-induced hippocampal neurogenesis is already well-established in rodents. Studies from various laboratories have found two- to three-fold increases in the rate of new neurons when mice or rats are allowed to freely run on an exercise wheel. (Unlike humans, rodents tend to be natural runners, and need no prodding to get on the treadmill.) From Mouse to Human Researchers measure neurogenesis in animals by sacrificing the critters and counting newly generated cells, which are tagged with a chemical marker to make them stand out. Until now, there has been no reliable way to measure neurogenesis in humans. Columbia neuroscientist Scott Small and colleagues appear to have found a way around this problem. First, they put mice that had been running voluntarily for two weeks into a magnetic resonance imager to map exercise-induced changes in cerebral blood volume, a measure of increased blood vessel formation in the dentate gyrus. Then, by sacrificing the animals and counting new neurons, they were able to correlate the neuronal proliferation they observed with changes in blood volume. The researchers then conducted magnetic resonance tests on a small group of middle-aged people who had been exercising about an hour a day, four times a week, for three months. By charting exercise-induced changes in cerebral blood volume in the human hippocampal region and applying the same algorithms used in the mice, they were able to deduce that neurogenesis was also occurring in the humans. Changes in blood volume in the dentate gyrus, they concluded, provide a correlate of neurogenesis in humans. ects. Based on our findings, I think it’s fair to say that at least some of the benefit of exercise in aging individuals is mediated through dentate gyrus function, and specifically through neurogenesis.” While the study does not show neurogenesis directly in humans, it provides what is at this point the only marker scientists have for tracking new neuron growth in living people—an advance that has many experts excited. “I am very encouraged by these findings, and believe they can be immediately applied and developed further,” says Salk Institute neurobiologist Fred Gage, one of the pre-eminent neurogenesis investigators worldwide and a co-author of the recent study. “We can now go back and forth between human and animal studies to validate and discover new mechanisms of action.” The study was published in the March 12-16 early online edition of Proceedings of the National Academy of Sciences. Art Kramer, whose research at the University of Illinois, Urbana-Champaign, focuses on the cognitive benefits of exercise in humans, cautions that the study needs to be replicated in a larger group of people, preferably in the context of a randomized, controlled clinical trial. Still, he says, “I think it’s a pretty neat demonstration of scaling up a technique from animal research to human research. It suggests that you might be able to use a measure of cerebral blood volume as a proxy, or a biomarker, for neurogenesis in the hippocampus of humans.” Exercise to ‘Protect Your Mind’ The new study adds to a growing base of evidence for the brain benefits of exercise, from animal studies, human epidemiological studies, and, increasingly, clinical trials. “There is certainly increasing research in humans as well as animals, from a variety of different kinds of studies, that suggest that physical activity and exercise will protect your mind and brain throughout your lifetime,” Kramer says. These benefits included enhancing “executive” cognition, which includes higher-order functions such as planning and reasoning; improving some types of learning; and attenuating neural damage from stress. There is also emerging evidence that physical activity may be protective against neurological disorders, including Alzheimer’s and dementia, Parkinson’s disease, stroke, and spinal cord injury. Animal studies have begun to tease apart the potential molecular mechanisms that may underlie the brain benefits of exercise. Certainly, neurogenesis is one possible explanation. Synaptogenesis, the development of new synaptic connections, is another. Exercise also seems to benefit glial cells, the nonneuronal brain cells that support synaptic transmission and ensheathe neural fibers with myelin, a fatty substance that speeds nerve signaling. Each of these effects may be driven in part by increased blood flow to the brain, a well-documented benefit of physical activity. “Exercise mobilizes the molecular machinery to improve brain health and cognition,” says Carl Cotman, a neurobiologist at the University of California, Irvine. “It increases metabolism in the brain and generally makes brain cells healthier; it even helps clear out Alzheimer’s pathology in mouse models.” The question of how exercise does all this is still incompletely answered. “It really is sort of startling to think about,” Small says. “Physical exercise induces a series of biochemical processes within neurons that induces the birth of new cells. How that happens is a big black box. There are a lot of missing pieces at the molecular level.” Cotman, for one, believes the key is a group of chemicals called nerve growth factors, particularly brain-derived neurotrophic factor, or BDNF. His studies and others have found increased BDNF levels in exercising animals, and these increases have been correlated both with neurogenesis and with improved learning. “I think that BDNF is the central regulatory molecule for the cascade of cellular changes that get activated by exercise,” Cotman says. “It’s kind of the gatekeeper for all of the other effects of exercise.”

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