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Deconstruction of a Hypothalamic Exercise-responsive Circuit for Neuroprotection

Award Number: R01AG079877
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $783,186 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	3	12/19/2024	NON-COMPETING CONTINUATION	$719,253
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	001	3	8/4/2025	NON-COMPETING CONTINUATION	$63,933
														Subtotal = $783,186

Issue Date FY: 2024 ( Subtotal = $770,664 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	001	2	5/17/2024	NON-COMPETING CONTINUATION	$68,340
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	2	2/9/2024	NON-COMPETING CONTINUATION	$702,324
														Subtotal = $770,664

Issue Date FY: 2023 ( Subtotal = $767,084 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	1	3/31/2023	NEW	$767,084
														Subtotal = $767,084

Grand Total All Awards = $2,320,934

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Deconstruction of a Hypothalamic Exercise-responsive Circuit for Neuroprotection

Award Number: R01AG079877

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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