During aging and Alzheimer's disease (AD) the cerebral cortex entorhinal cortex and hippocampus show neuronal loss, cellular and subcellular changes indicating a slow degenerative process. Cerebral cortical pathology is usually associated with degenerative changes in anatomically linked regions. The proposed experiments are aimed. at determining neuronal function, vulnerability, degeneration and repair in anatomical regions prone to AD. I will investigate (1) The resulting pathology and functional consequences of neuronal loss in cerebral cortex, entorhinal cortex and hippocampus. (2) Animal models that mimic mechanisms for slow progressive neuronal loss. (3) Methods that protect intercortical and subcortical systems from degeneration. The specific hypotheses will be tested in models of excitotoxic neuronal degeneration in the rat. The initial neuronal death in these models is induced by exposure of brain regions to N-Methyl-D-Aspartate. To test neuronal stress and vulnerability, local excitotoxic lesion will be made in target deprived cortical and subcortical regions, determining responses to secondary insults likely to occur during neurodegenerative disease. Specific neuronal tracer techniques in combination with morphological, molecular and quantitative neurochemistry will yield results a bout the cellular regulation of neuronal survival. By implanting neuroblasts or genetically engineered cells producing trophic factors into the primary lesions we will investigate the basic capacity for neuronal protection, repair and recovery of function. In particular, entorhinal cortical neuronal damage will be studied at both the cellular and behavioral level to examine the basis for memory dysfunction observed in our preliminary studies. Our focus on pathology and remodeling in regions known to be involved in both AD and aging, as well as creating in vivo conditions simulating accelerated neuronal loss, may reveal basic neurobiological mechanisms underlying these conditions and contribute to discoveries of effective treatments.
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