This revised research plan is organized around the overarching themes of the Program Project, aimed atrapidly advancing progress on the basis of neurocognitive aging, and the rational development of effectiventerventions. A comprehensive understanding hinges on the critical interactions between multiple memorysystems. Investigations addressing this issue will use a recently validated plus maze procedure to documentthe effects of aging on cognitive control and flexibility in rats. This task will be used in conjunction with postmortemquantification of in situ hybridization for expression of the plasticity related gene Arc, testing thepossibility 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 tothe transcriptional coordination of events critical for memory-related synaptic plasticity, 2) epigenetic controlis altered in relation to cognitive aging (results in Progress Report), and 3) pharmacological administration ofhistone deacetylase (HDAC) inhibitors enhances synaptic plasticity and memory in normal young rats. Thesefindings raise the possibility that treatments targeting epigenetic transcriptional control may improveneurocognitive outcomes in aging. The proposed experiments will test this prediction in both rats andmonkeys using test compounds with varying HDAC inhibitor specificities. Neurobiological read-outs in ratswill include an analysis of treatment effects on epigenetic coding in the hippocampus. Leveraging the uniqueresource of an independently funded project, the proposed intervention trials in monkeys will be coordinatedwith an assessment of regional brain metabolic activity, measured by fluorodeoxyglucose positron emissiontomography and corresponding structural MRI. Closely related experiments aim to determine whether alteredepigenetic control provides a basis for successful and impaired cognitive aging. As a starting point, total andacetylated histone content will be measured in microdissected subregions of the hippocampus frombehaviorally characterized young and aged rats. These parameters will also be determined in thehippocampus of subjects that receive water maze training prior to sacrifice, yielding a window on dynamictranscriptional control. Neuronal activity regulates intracellular trafficking of histone deacetylases thatinfluence chromatin remodeling, and accordingly, immunohistochemical localization studies will beconducted to quantify the relative nuclear and cytoplasmic compartmentalization of multiple HDAC's in thehippocampus of young and aged rats, under basal and behaviorally activated conditions.Together, the results are expected to advance progress toward understanding the basis of normalcognitive aging, breaking entirely new ground on several fronts, including the indentification and validation oftargets for effective intervention.
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