Normal aging is widely assumed to result in moderate and diffusely distributed neuron loss that contributes to decline across a variety of cognitive domains. Recent studies using modern stereological methods challenge this view, establishing that frank neuronal degeneration in aging is both limited in magnitude and regionally selective. The proposed project builds on this foundation of findings to document the structural status of the aged hippocampal formation and related brain regions that support normal learning and memory. A unifying theme of the experiments is that quantitative morphometric results will be evaluated in the context of data on cognitive function the same subjects. Capitalizing on a convergence of neuropsychological evidence across species, parallel neuronanatomical studies will be conducted in rat an nonhuman primate models. The proposal addresses three of the objectives identified for the Program Project as a whole. One set of investigations will utilize modern stereological techniques to systematically examine neuron number in cortical and subcortical brain systems implicated in age-related cognitive decline (Program Objective 1). These analyses will focus on: 1) the entorhinal and perirhinal cortices that are now understood to comprise critical components of the medial temporal lobe memory system, 2) defined basal forebrain cell groups that prominently influence hippocampal and cortical function, and 3) subdivisions of the prefrontal cortex that support cognitive processes sensitive to aging. A second set of experiments is based on the observation that aging is accompanied by a robust glial response, providing a potential window on the neurobiological mechanisms responsible for age-related cognitive decline (Program Objective 4). These investigations will define the effects of aging on the number and size of astrocytes, focusing especially on the neuroanatomical selectivity of those effects that predict the cognitive status of aged individuals. A final component of the research examines the proposal that subtle changes in hippocampal connectivity are a more prominent signature of normal cognitive aging than frank neuronal degeneration (Program Objective 2). Taking advantage of the dentate gyrus as relatively simple model system, image analysis methods will be used to examine whether the laminar organization of neuroanatomically and neurochemically defined inputs to the hippocampus is altered during aging. Taken together, the studies represent an important step toward establishing a quantitative neuroanatomy of cognitive aging.
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