In a related story, Carl Cotman and Nicole Berchtold of the University of California, Irvine, detail the effects of exercise on brain plasticity in an Opinion article in next month's Trends in Neuroscience that is part review, part original research paper. In the last five or so years, they write, researchers have realized that the cognitive benefits of exercise are not merely a result of improved cerebral blood flow and general health. Rather, exercise appears to "act directly on the molecular machinery of the brain itself," they write.
One way in which this may happen is through brain-derived neurotrophic factor (BDNF), a protein long known to support the growth and survival of neurons and to mediate use-dependent plasticity of neuronal connections (Barde, 1994; Lindvall et al., 1994; McAllister et al., 1999). In a voluntary wheel running experiment with rats, Cotman and Berchtold discovered, to their surprise, that running affected not only motor-sensory parts of the brain, as they expected, but also increased BDNF mRNA and protein levels in the hippocampus. They saw this increase in neurons of the dentate gyrus and CA3 regions, which die early in Alzheimer's pathogenesis. BDNF levels increased after days and remained high during weeks of voluntary running. The links between BDNF and plasticity are reciprocal: once stimulated, BNDF facilitates learning (a functional endpoint of plasticity), yet learning also increases BDNF expression, Cotman and Berchtold write.
The authors review how neurotransmitter interactions in the medial septum of the hippocampus might mediate BDNF expression after exercise. Estrogen and BDNF are also linked. Estrogen is necessary for exercise to increase BDNF expression, and the absence of estrogen makes animals less active.
To identify additional molecular targets of exercise, Cotman and colleagues used oligonucleotide microarrays to examine changes in expression profiles in hippocampus of about 5,000 genes in rats after three weeks of exercise (Tong et al, 2001.) They saw altered expression of many genes involved in neurotrophic factor trafficking, synaptic plasticity and growth. Expression of synaptic marker genes, including synaptotagmin, Ves1, and AP17 went up, suggesting that exercise modulates brain physiology via direct effects on hippocampal synapses, the authors write.
Cotman and Berchtold also suggest that trophic factors, such as BDNF and IGF-1, might mediate the exercise-induced increase in hippocampal neurogenesis. BDNF increases occur in the dentate gyrus, the progenitor-cell layer of the hippocampus. Besides citing prior work that supports this link, the authors write that their microarray analysis has revealed the neurogenesis-modulating genes Krox-24 and VGF as being more highly expressed after exercise.
In conclusion, Cotman and Berchtold write, exercise appears to activate a variety of use-dependent molecular cascades that support plasticity at the synaptic and at the cellular level. These processes prime neurons to encode new information from the environment and protect them from age-related insults.—Gabrielle Strobel