Our research program under this funding mechanism has provided evidence for specific effects of aging on medial temporal lobe (MTL) circuits that contribute to individual differences in cognitive outcomes in aging. Because advancing age represents the strongest risk factor for Alzheimer’s Disease (AD), individual differences in aging itself may confer risk or resilience for that disease, indicating potential relevance beyond the limited condition of age-related cognitive impairment. Project 2 investigates circuit-specific mechanisms within the broad memory system network that underlie individual differences in both impaired and preserved cognitive outcomes, and considers sex as a potential factor for differential vulnerability to decline. As first described in our research with outbred Long-Evans male rats characterized for age-related impaired memory (AI), a condition of neural overactivity in the MTL translated in clinical observational studies of elderly individuals, with further augmentation in aMCI patients at greater risk for late onset AD. Within the aged rat study population, our background research demonstrated that neural overactivity contributes to memory impairment by using experimental intervention with therapeutics, a finding that has also translated therapeutically in clinical studies. Alongside those achievements, accumulating evidence suggests that adaptive recruitment of inhibitory function beneficially supports resilience to memory decline in aged unimpaired rats (AU). Research in Project 2 will now examine the functional significance of inhibitory recruitment as a potentially adaptive mechanism in the preservation of cognitive function in aging. In that context, Project 2 will investigate a mechanism for homeostatic regulation, to examine loss of function in AI and potential gain of function in AU. Project 2 will study the condition of this mechanism across the EC/hippocampal system with anatomical methods for circuit-specific alterations. The CA2 hippocampal subfield has become an additional subregion of high interest in our model; loss of function contributes to excess activity possibly contributing to the AI condition while greater recruitment may occur in AU rats, giving a bi-directional role for homeostatic control in both late life outcomes. Project 2 will also lead in the use of experimental tools with potential therapeutic relevance, as it has in the past with the Sv2a agent levetiracetam. Studies under Aim 4 in Project 2 will test agents that act as allosteric modulators of GABAA α5 receptors. These receptors have highly restricted localization in the mammalian brain and may offer greater precision for targeting the neurobiological conditions underlying impairment in AI and providing a test for the functional significance of AU biomarkers, which have indicated augmented inhibition to maintain excitatory/inhibitory balance in brain aging. Thus, in the research plans in the current application, Project 2 maintains a str...