Project 6 is designed to determine, in several experimental paradigms, the degree to which intraventricular nerve growth factor (NGF) and peripheral nerve grafts restore the properties and prevent degeneration of neurons of the basal forebrain magnocellular complex (BFMC). First, we will examine the efficacy of NGF to prevent degeneration of medial septal neurons following resection of the fimbria-fornix; responses of cells to injury and to NGF administration will be evaluated with techniques of cellular/molecular biology. Second, in animals in which the fornix is resected, we will test the ability of nerve grafts (with or without NGF) to maintain the viability of septal neurons, to promote regeneration of their axons into nerve grafts, and to reinnervate hippocampal targets; experimental and control groups will be evaluated with approaches ranging from behavioral tests to cellular/molecular approaches. Third, we will examine the potential for NGF to improve memory functions in subsets of aged rodents showing impairments on memory tasks; brains will be analyzed to delineate recovery-related responses of BFMC neurons. With these rodent studies as a background, we will be in a position to extend these approaches (i.e., effects of NGF and grafts on axotomized neurons) to investigations of nonhuman primates. Finally, once these investigations are complete, we will be in a position to test the efficacy of NGF in improving memory performance of behaviorally characterized old macaques and to assess the effects of NGF on BFMC neurons in these animals. Our laboratory has considerable experience in research relevant to this work including: investigations of anatomical/physiological organization of the BFMC; studies of the consequences of lesions of this system on animal behavior (rats and monkeys); assessment of the neural and functional consequences of neural grafts; and delineation of the cellular abnormalities of BFMC neurons in experimental disorders and in a variety of human diseases, including Alzheimer's disease and Parkinson's disease. We believe that these experiments hold great promise for illuminating mechanisms underlying recovery processes in brain that may, ultimately, be used to treat neurological disorders that occur in humans.
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