Neural circuits mediating motivation deficits in an alzheimer's disease RAT model

The National Institute on Aging awarded RU School of Osteopathic Medicine $526,953 on August 15, 2026, under the Aging Research program (CFDA 93.866) to investigate neural circuits mediating motivation deficits in an Alzheimer's disease rat model.

The recipient will characterize and manipulate ventral tegmental area and nucleus accumbens signaling in transgenic AD rats using optogenetics, in vivo electrophysiology, and fiber photometry to determine circuit-level mechanisms underlying deficits in anticipatory drive toward reward-predictive cues and loss of behavioral invigoration. The work addresses the correlation between apathy severity in Alzheimer's disease patients and nucleus accumbens deformation, with the goal of identifying therapeutic targets to rescue motivational function and potentially alleviate cognitive decline in AD patients with neuropsychiatric symptoms including apathy, anhedonia, and depression.

Performance occurs in Stratford, New Jersey. The period of performance runs through May 31, 2031.

Abstract

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.