PROJECT SUMMARY Exercise slows the cognitive declines associated with aging and protects against the development and progression of neurodegenerative diseases such as Alzheimer's disease (AD). At the cellular level, exercise enhances synaptic connectivity and reduces markers of neuroinflammation in aging cortical circuits. Exactly how exercise signals in the brain generate these neuroprotective effects remains unknown. Our preliminary experiments have identified a set of neurons in the mouse ventromedial hypothalamus (VMH) expressing Steroidogenic Factor 1 (SF-1) that robustly increase their activity in response to exercise. We have found that the VMH SF-1 neural activity signal is potentiated severalfold following repeated exercise, suggesting that the exercise signals generated by VMH SF-1 neurons are plastic and shaped by experience. Furthermore, we have found that direct stimulation of SF-1 neurons substantially increases subsequent endurance capacity, suggesting VMH Sf-1 neurons are an important neural node controlling the physiological benefits of exercise. However, several important questions remain unknown. First, which features of VMH SF-1 neurons enables plasticity of activity signals following repeated exercise? Second, which specific sets of VMH SF-1 output neurons transmit exercise-relevant signals? Last, is it possible to stimulate VMH SF-1 neurons and generate the neuroprotective effects of exercise on cognition and neural circuitry in the aging brain or in AD-like states? The proposed experiments will leverage advanced neuroanatomical and neurophysiological tools with preclinical genetic models to gain insights into these questions. In Aim 1, we will pair large-volume, high-resolution, and cell-type specific array tomographic neuroanatomical reconstructions with in vivo calcium imaging and neuronal activity perturbations to determine how exercise shapes the synaptic architecture of VMH SF-1 neurons. These experiments will define how changes in the synaptic inputs to these neurons might physically `store' exercise history within VMH circuitry. In Aim 2, we will use advanced viral mapping and in vivo single-cell functional imaging techniques to identify which neurons are activated by exercise and understand how these exercise signals are transmitted to specific circuits downstream of the VMH. These experiments will define the organization and logic by which exercise-related activity in VMH neurons drives functional changes in the brain. In Aim 3, we will take advantage of advanced preclinical genetic mouse models of early- and late-onset AD to determine whether stimulating activity in VMH neurons might recapitulate the neuroprotective effects of exercise observed in cortical circuits. These experiments will increase our understanding of how signals in the VMH could be harnessed for therapeutic manipulation in disease states. By leveraging the synergistic expertise of the team of investigators assembled to address this problem, insights from these experiments will advance our fundamental understanding of how the beneficial effects of exercise are mediated by specific synapses, cell- types, and circuits, and whether these features are potential therapeutic targets for intervention in disease states.

PROJECT NARRATIVE Repeated exercise has beneficial effects on the brain and body and has been shown to reduce the progression of neurodegenerative diseases such as Alzheimer's disease (AD). We have found that artificial stimulation of a specific set of exercise-responsive neurons in the mouse hypothalamus modulates subsequent exercise endurance, but whether such stimulation can also generate the beneficial effects of exercise in the brain remains unknown. By leveraging new technologies that permit a detailed structural and functional deconstruction of this exercise-responsive circuit, our goal is to determine whether generating activity within this circuit promotes enhanced cognition and neuroprotection during aging and in AD.