Aging is associated with declining function across a broad spectrum of behavioral and biological measures. This component of the program project will pursue neuropsychological studies aimed at determining the nature and range of cognitive deficits associated with aging, and electrophysiological studies aimed at characterizing hippocampal integrative processing at multiple levels. Direct collaborations with other members of the project will pursue specific program project objectives: PROGRAM OBJECTIVE #1: To assess the differential vulnerability of cortical and subcortical neurons associated with aging, we will characterize the range of decline in hippocampal-dependent memory function and dissociate deficits in hippocampal-dependent memory performance from impairments in cognitive abilities associated with prefrontal cortex function. In collaboration Rapp, we will correlate age-related changes in neuron number in the medial and orbital prefrontal cortex with declines in performance on spatial and odor-guided memory performance that are differentially dependent on these brain areas. PROGRAM OBJECTIVE #2: To assess the structural integrity of the hippocampus we will characterize age-related changes in neurophysiological function in terms of (1) qualitative and quantitative differences in neural coding by single neurons and neural ensembles during spatial information processing and their plasticity in response to task alterations, and (2) septo-hippocampal integration reflected in synchronization of afferent information processing with the hippocampal theta rhythm during exploratory behavior. In collaboration with Rapp we will correlate changes in cholinergic and noncholinergic cell number with age-related decline in septo-hippocampal integration. PROGRAM OBJECTIVE #3: To assess functional alterations in signal transduction pathways we will employ a newly developed behavioral- electrophysiological paradigm for producing learning-related alterations in synaptic efficacy in specific hippocampal pathways. In collaborations with Gallagher and Wolfe we will correlate postranslational PKC and glutamate receptor phosphorylation in the hippocampus with age-related decline in acquisition and decay of learning related synaptic plasticity. Each of these experiments is designed to test specific hypotheses about the nature of age related cognitive decline: that aging associated with decline in prefrontal- as well as hippocampal-dependent cognitive functions, and that at least some aspect of age-related cognitive involves loss of basal forebrain regulation of hippocampal processing, and consequent limitations in the range of stimuli encoded, the flexibility of representations in response to change, and the plasticity of hippocampal synaptic mechanisms.
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