Individuals of several species develop age-associated impairments in cognition/memory and motor functions. These clinical signs are due to alterations in specific neuronal circuits (e.g., memory deficits are related, in part, to alterations of basal forebrain cholinergic systems, entorhinal neurons, and, possibly, anterior thalamic neurons, whereas impaired motor performance results from lesions of the dopaminergic nigrostriatal system). Some of these cell populations are responsive to trophic factors. Because nerve growth factor (NGF) preserves the phenotype and, possibly, promotes the survival of axotomized basal forebrain cholinergic neurons, we will test the effects of NGF on the behavioral performance of aged rats and monkeys. Members of the neurotrophin family (i.e., NGF, brain-derived neurotrophic factor [BDNF], and neurotrophin-3 [NT-3]) act on specific subsets of neurons, and we plan to assess the short- and long-term effects of these neurotrophins on basal forebrain neurons in animals with complete transections of the fimbria-fornix. Moreover, because in vitro studies suggest that BDNF may influence nigral neurons, we will also examine the ability of BDNF to prevent degeneration of nigral neurons experimentally damaged by injections of 6-hydroxydopamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Finally, we will characterize models of axotomy-induced retrograde degeneration of enthorinal and anterior thalamic neurons, two cell populations that are vulnerable in Alzheimer's disease. These models will be used to test whether trophic factors influence the phenotype and/or promote the survival of these axotomized neurons. The results of these studies will provide important new information concerning the potential efficacies of neurotrophins in preventing degeneration of specific neuronal populations in the central nervous system.
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