Project Summary Given the rising proportion of older adults and the progressive cognitive decline with aging, there is a pressing need for therapeutics that remediate age-related cognitive decline. Animal models robustly support that endurance exercise protects brain areas vulnerable to aging such as the hippocampus and that these benefits lead to better learning. In contrast, there are mixed findings from human studies on the cognitive benefits of exercise with healthy older adults. This contrast indicates we still do not understand how exercise could change the course of cognitive decline in aging adults. However, no human studies have comprehensively tested exercise effects on cognition in older adults with learning tasks inspired from basic exercise neuroscience. Our objective in the proposed research is to fill this translational gap by determining if exercise improves the same kinds of learning in older adults that have been shown to improve in animal models by improving hippocampal function. This will bring us closer to our long-term goal of determining how exercise protects the brain from adverse effects of aging in order to develop interventions that minimize age-related cognitive decline. Our overall hypothesis is that exercise improves learning when it increases functional hippocampal-cortical communication that otherwise declines with aging. We will test this in a sample of healthy older adults by determining if increases in functional hippocampal-cortical connectivity from moderate intensity exercise improve learning on an array of tasks that require the hippocampus for acquisition of new relational memories but not in tasks that do not require the hippocampus to learn such as motor or response learning. We further pursue mechanistic insight on the direct effects of exercise by determining if individual differences in the rapid effects of moderate intensity exercise on hippocampal-cortical connectivity predict training-related change in connectivity and learning, and by determining if training-related changes in cardiorespiratory fitness are a critical factor. Our results will be significant because early prevention has the biggest impact and determining how exercise counteracts mechanisms of cognitive aging leads to understanding how such plasticity is possible and informs prevention strategies. The proposed work is innovative because we test how exercise affects cognition by bringing together conceptually advanced measures of hippocampal-dependent learning and memory processes with novel conceptualizations for how to capture the physiological changes induced by exercise that change hippocampal-cortical connectivity. Because hippocampal connectivity deteriorates with Alzheimer's, results could also lead to an understanding of the mechanisms by which exercise reduces risk of this devastating and costly disease.