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Voluntary exercise, treadmill activity, skills training, and forced limb use have been utilized in animal studies to promote brain plasticity and functional change. Motor enrichment may prime the brain to respond more adaptively to injury, in part by upregulating trophic factors such as GDNF, FGF-2, or BDNF. Discontinuation of exercise in advance of brain injury may cause levels of trophic factor expression to plummet below baseline, which may leave the brain more vulnerable to degeneration. Underfeeding and motor enrichment induce remarkably similar molecular and cellular changes that could underlie their beneficial effects in the aged or injured brain. Exercise begun before focal ischemic injury increases BDNF and other defenses against cell death and can maintain or expand motor representations defined by cortical microstimulation. Interfering with BDNF synthesis causes the motor representations to recede or disappear. Injury to the brain, even in sedentary rats, causes a small, gradual increase in astrocytic expression of neurotrophic factors in both local and remote brain regions. The neurotrophic factors may inoculate those areas against further damage and enable brain repair and use-dependent synaptogenesis associated with recovery of function or compensatory motor learning. Plasticity mechanisms are particularly active during time-windows early after focal cortical damage or exposure to dopamine neurotoxins. Motor and cognitive impairments may contribute to self-imposed behavioral impoverishment, leading to a reduced plasticity. For slow degenerative models, early forced forelimb use or exercise has been shown to halt cell loss, whereas delayed rehabilitation training is ineffective and disuse is prodegenerative. However, it is possible that, in the chronic stages after brain injury, a regimen of exercise would reactivate mechanisms of plasticity and thus enhance rehabilitation targeting residual functional deficits.