Deconstruction of a Hypothalamic Exercise-responsive Circuit for Neuroprotection

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.

Grant Number: 5R01AG079877-03
NIH Institute/Center: NIH
Principal Investigator: Erik Bloss