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Neural circuits mediating motivation deficits in an Alzheimer's disease rat model

Award Number: R01AG092798
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Neural circuits mediating motivation deficits in an Alzheimer's disease rat model - Project Summary Alzheimer’s disease (AD) is characterized by memory impairments and underlying neuropathology, including plaques, amyloid- peptides, neurofibrillary tangles, and neuronal loss. AD patients with neuropsychiatric symptoms including apathy, anhedonia, and depression show more severe cognitive decline and poorer prognosis than AD patients without these symptoms. As such, determining the underlying neural circuits that underlie motivation deficits and/or a show a lack of consideration for the consequences of their actions may help target different alleviate future cognitive decline in patients with neuropsychiatric symptoms. The severity of apathy in AD is correlated with deformation of the nucleus accumbens (NAc), a brain region critical in motivative behavior. In addition, the ventral tegmental area (VTA), the primary mesolimbic dopamine input, into the NAc also shows dysfunction in AD patients. Transgenic rats (TgF344-AD, “AD rats”), created to overexpress mutant human amyloid precursor protein and presenilin 1, develop age-dependent amyloid and tau pathology show changes in the nucleus accumbens (NAc) prior to the development of pathology and memory deficits. We show that AD rats show specific deficits in anticipatory drives towards reward predictive cues and a loss of invigoration. Given that the VTA input into the NAc is critical for reward-related motivated behavior, we hypothesize that dampened VTA input into the NAc contributes to behavioral deficits observed in the AD rat model. Our goal is to determine the underlying circuit-level mechanism that mediates conditioned approach and vigor in the AD rat and target circuits to rescue function using optogenetics, in vivo electrophysiology, and fiber photometry. In Aim 1, we will characterize and manipulate VTA and NAc signaling to link a loss anticipatory drive to reward predictive cues (Pavlovian conditioning) in a transgenic AD rat model. In Aim 2, we will characterize and manipulate VTA and NAc signaling to link a loss of invigoration (Operant conditioning). Together, these aims will characterize the contribution of mesolimbic dopamine function in motivation deficits in a transgenic AD rat model.


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: 2026 ( Subtotal = $526,953 )
2026	2026	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Aging Research	000	1	8/14/2026	NEW	$526,953
														Subtotal = $526,953

Grand Total All Awards = $526,953

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Neural circuits mediating motivation deficits in an Alzheimer's disease rat model

Award Number: R01AG092798

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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