Wednesday, August 20, 2025 8/20/2025

Hypocretin/orexin modulation of cognitive correlates of brain aging

Award Number: R01AG050518
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Hypocretin/orexin modulation of cognitive correlates of brain aging - The primary neurotransmitter hallmark of Alzheimer’s Disease (AD) is a loss of acetylcholine, produced by neurons of the basal forebrain cholinergic system (BFCS). Cholinergic cell loss or dysfunction is also a prominent component of Lewy Body Dementia and vascular dementia, respectively. Thus the BFCS contributes to several aspects of cognitive function that are negatively impacted in AD and related dementias, including attention, learning and memory. Regulation of the BFCS by afferent inputs, including those from the hypothalamus, is important for integration of homeostatic and cognitive functions. Because homeostatic and physiological disturbances, such as altered food intake or sleep-wake cycles, often precede and predict cognitive decline in AD, understanding these interactions may lead to novel points of intervention to treat or delay cognitive decline in conditions such as AD. An important source of this afferent regulation is the hypothalamic orexin/hypocretin neuropeptide system, which activates cholinergic neurons in response to stimuli that signal physiological valence. We have previously shown that aging, the strongest risk factor for AD, is associated with reduced orexin expression. Recently, orexin transmission has been shown to play a role in limiting neuroinflammation, suggesting that a diminished orexin system in aging may promote neuroinflammatory processes that further negatively impact cholinergic-dependent signaling and cognition. In this renewal application, we will dissect the mechanisms underlying the association between loss of orexin signaling, neuroinflammation and subsequent cholinergic dysfunction and neurodegeneration in an aged rodent model using virus-mediated gene transfer, neurochemical, pharmacological and cognitive behavioral approaches. We will further test the hypothesis that chronic restoration and maintenance of orexin function beginning in early aging will preserve the integrity of the BFCS by modulating local microglial dynamics. The proposed studies will begin to delineate the mechanisms by which age-related loss of orexin signaling drives cholinergic dysfunction and cognitive decline and suggest the potential for orexin-targeted therapies in preventing or ameliorating AD or related dementias, all of which are characterized by neuroinflammation and cholinergic dysfunction.


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 = $362,434 )
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	7	8/12/2025	EXTENSION WITH OR WITHOUT FUNDS	$362,434
														Subtotal = $362,434

Issue Date FY: 2023 ( Subtotal = -$4,367 )
2023	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	5	10/25/2022	NON-COMPETING CONTINUATION	-$4,367
														Subtotal = -$4,367

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	5	5/7/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $279,604 )
2019	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	5	5/27/2019	NON-COMPETING CONTINUATION	$279,604
														Subtotal = $279,604

Issue Date FY: 2018 ( Subtotal = $279,604 )
2018	2018	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Aging Research	000	4	5/22/2018	NON-COMPETING CONTINUATION	$279,604
														Subtotal = $279,604

Issue Date FY: 2017 ( Subtotal = $279,604 )
2017	2017	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Aging Research	000	3	6/19/2017	NON-COMPETING CONTINUATION	$279,604
														Subtotal = $279,604

Issue Date FY: 2016 ( Subtotal = $279,604 )
2016	2016	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	2	6/7/2016	NON-COMPETING CONTINUATION	$279,604
														Subtotal = $279,604

Issue Date FY: 2015 ( Subtotal = $286,471 )
2015	2015	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	1	8/5/2015	NEW	$286,471
														Subtotal = $286,471

Grand Total All Awards = $1,762,954

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Hypocretin/orexin modulation of cognitive correlates of brain aging

Award Number: R01AG050518

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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