Michelle W. Voss, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Given the rising proportion of older adults worldwide and the progressive decline in brain function with advancing age, there is a pressing need to develop novel interventions that protect the aging brain. The predominant approach for implementing exercise training to improve brain function is to increase cardiovascular fitness. However, there is mixed empirical support for the effectiveness of this approach. Further, there are also acute effects of exercise within one hour of the cessation of a single exercise session. These effects occur before adaptations related to fitness could occur and animal studies have shown they occur in the same brain regions that benefit from longer-term exercise training. Therefore, we propose the acute paradigm is a tool to probe this early, direct response from exercise in order to determine how best to maximize the long-term benefit of exercise training on the aging brain. This presents a critical need to determine the mechanistic relation between acute and long-term effects of exercise on the aging brain. Our long-term goal is to determine how exercise protects the brain from the adverse effects of aging. In turn, our specific objective in this R21 proposal is to support or refute the concept that a single session of exercise produces acute increases in functional synchrony of clinically relevant brain networks that are related to accrued exercise-training effects in the same brain systems. Our central hypothesis is that the effects of moderate intensity exercise will increase the functional synchrony of the hippocampus with the Default Mode Network, and the Prefrontal Cortex with the Fronto- Executive Network, in the same fashion as a 12-week moderate intensity exercise training program. This hypothesis is based on data showing acute effects of exercise on factors related to neuronal plasticity and excitability in the same brain regions that show long-term effects of exercise in animals. The contribution of the proposed research is significant because it will determine the extent to which the acute exercise paradigm can provide insight into how regular exercise protects the brain from adverse effects of aging. The proposed research is innovative because for the first time we will examine the overlapping neural systems and outcomes associated with acute and chronic exercise in the same individuals. Overall, success in this project will enable future research to study how varying exercise parameters such as mode or intensity affect exercise-induced change in brain function and the timecourse of these effects, as well as the neurobiological mechanisms associated with the direct effects of exercise on the aging brain.

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.