This research program represents a multidisciplinary, integrated approach to understanding the effects of normal aging on a critical brain system that supports cognitive functions affected in humans as they age. We focus on brain aging in hippocampal/cortical circuits using Long Evans rats, an outbred strain that exhibits individual differences in aging outcomes in well-characterized cognitive assessments. At older ages (24-26 month) cognitive impairment affects 50-60% of healthy male rats in this population, while the remaining aged cohorts fall within the range of young adults (4-6 months). Research under this mechanism of support has identified alterations in the brain that are tightly coupled to these cognitive outcomes, including the deleterious effects of heightened neural activity in specific hippocampal circuits on memory function in aging. The current proposal will include a direct comparison of individual differnces in neurocognitive aging in both male and female outbred Long Evans rats (Core B). Our proposed plans will build on our achievements to leverage new findings that will advance understanding of episodic memory in basic research with application to clinical problems in aging. Our research program to date has translated successfully in studies of human aging. Now in reverse-translation we will examine the homeostatic control of network/circuit function by a mechanism that clinical studies have implicated in late-life cognitive outcomes as well as in risk and resilience for late-onset AD; Its failure across the spectrum of aging/AD in the human brain is closely tied to cognitive impairment. Our studies on homeostasis regulated by NPTX2/GluA4 will provide the first systematic basic research in aging focused on hippocampal circuitry where loss of inhibitory control has been identified in the condition of impairment in the Long Evans model. Further studies, including those on NPTX2/PV-interneurons will focus on evidence for an augmentation of inhibition in aged rats with preserved cognitive function, relative to young adults. We are testing the functional significance of that condition as serving a potential role in adaptive aging to maintain excitatory/inhibitory balance and cognitive performance. New tools and methods for the study of brain aging will advance the overall research program together with direct comparisons for individual differences in aged female and male rats. To that end, three Cores (Administrative, Animal Resource, and Bioinformatics/Data Management) will serve all of the participating investigators conducting research in the four proposed projects.