This Project will continue its focus on signaling and plasticity as a basis for individual differences in agingoutcomes. Against a background of largely preserved structural integrity, alterations in the function ofneurons in the medial temporal lobe provide the most reliable indicators of cognitive abilities that depend onthis circuitry. The background and preliminary data for this research plan indicate a basis for distinguishingtwo subpopulations of aged rats that each differ from young. Consistent with recent findings in othercomponents of the overall research program, the CAS region of the hippocampus is particularly noteworthyas an area that undergoes pronounced alterations associated with cognitive impairment. A distinctive profileis also found in this region in aged animals with preserved cognitive function.
The Specific Aims of thisproject will 1) extend the regional analysis of broad molecular profiling in behaviorally characterized agedrats to a paradigm for measuring learning-activated transcription (Aim 2), and 2) assess the efficacy ofinterventions to gain control over the dysregulaton of cellular function in impaired aged rats and determinewhether the such treatments normalize indicators in the molecular profile in both basal and learningactivatedconditions along with improved behavioral outcomes (Aim 3). The purpose of studies usinginterventions based on data in the model is twofold, 1) to allow the test of specific scientific hypotheses, and2) to examine new avenues into translation approaches for therapy. Test agents under study in the proposedwork include 1) antiepileptics (valproate and ABT 769), 2) HDAC inhibitors (sodium butyrate and MS 275),and 3) agonists selective for GABA-A a5 receptors.
In Specific Aim 4 we will examine the basis fordifferential adaptive aging in rats that perform on a par with young adults. That work will explore a newhypothesis concerning alterations in middle-age that may serve an adaptive function in aging outcomes, bothneuroprotective and behavioral. Such adaptations would be consistent with a switch in plasticity mechanismsobserved in aged unimpaired rats. Finally, research under this project will examine whether signatures ofneurocognitive aging in subregions of the hippocampal system in rats have a counterpart in aged monkeybrains. Importantly those studies, similar to our research with aged rodents, will use brain tissue obtainedfrom behaviorally characterized young and aged rhesus monkeys. We will ask questions that are based onthe conditions of different aging outcomes in the rodent, including 1) overall profiles that relate to cognitivestatus in the aging primate (e.g. impaired and adaptive), 2) the status of specific genes that are markers ofneurocognitive aging in the rodent (CAS and CA1 regions), and 3) pre- and post-synaptic gene expressionpatterns in arrays of dentate gyrus and entorhinal cortex that may serve as a basis for synaptic failure in theconnections formed by the perforant path.
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