This revised research plan is organized around the overarching themes of the Program Project, aimed at rapidly advancing progress on the basis of neurocognitive aging, and the rational development of effective nterventions. A comprehensive understanding hinges on the critical interactions between multiple memory systems. Investigations addressing this issue will use a recently validated plus maze procedure to document the effects of aging on cognitive control and flexibility in rats. This task will be used in conjunction with postmortem quantification of in situ hybridization for expression of the plasticity related gene Arc, testing the possibility that aging is associated with functional reorganization across the prefrontal cortex, dorsal striatum, and the hippocampus. Recent evidence indicates that: 1) chromatin remodeling mechanisms contribute to the transcriptional coordination of events critical for memory-related synaptic plasticity, 2) epigenetic control is altered in relation to cognitive aging (results in Progress Report), and 3) pharmacological administration of histone deacetylase (HDAC) inhibitors enhances synaptic plasticity and memory in normal young rats. These findings raise the possibility that treatments targeting epigenetic transcriptional control may improve neurocognitive outcomes in aging. The proposed experiments will test this prediction in both rats and monkeys using test compounds with varying HDAC inhibitor specificities. Neurobiological read-outs in rats will include an analysis of treatment effects on epigenetic coding in the hippocampus. Leveraging the unique resource of an independently funded project, the proposed intervention trials in monkeys will be coordinated with an assessment of regional brain metabolic activity, measured by fluorodeoxyglucose positron emission tomography and corresponding structural MRI. Closely related experiments aim to determine whether altered epigenetic control provides a basis for successful and impaired cognitive aging. As a starting point, total and acetylated histone content will be measured in microdissected subregions of the hippocampus from behaviorally characterized young and aged rats. These parameters will also be determined in the hippocampus of subjects that receive water maze training prior to sacrifice, yielding a window on dynamic transcriptional control. Neuronal activity regulates intracellular trafficking of histone deacetylases that influence chromatin remodeling, and accordingly, immunohistochemical localization studies will be conducted to quantify the relative nuclear and cytoplasmic compartmentalization of multiple HDAC's in the hippocampus of young and aged rats, under basal and behaviorally activated conditions. Together, the results are expected to advance progress toward understanding the basis of normal cognitive aging, breaking entirely new ground on several fronts, including the indentification and validation of targets for effective intervention.
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