# Ethanol drinking and the basal ganglia circuitry

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2022 · $334,961

## Abstract

The proposed research is a logical expansion of Aims 2 and 3 of the parent grant, R01AA027768-
02, which determines whether "excessive ethanol intake compromises thalamic regulation of striatal
cholinergic interneurons (CINs) and CIN-mediated regulation of direct-pathway medium spiny neurons
(dMSNs), leading to inflexible behaviors." This expansion includes how the alcohol-induced reduction of
cholinergic activity contributes to the onset and progression of cognitive deficit in Alzheimer's disease and
related dementias (ADRD), which further improve our understanding of the pathogenesis of
alcohol use disorder superimposed on ADRD. Therefore, this research is relevant to ADRD.
 Alcohol use disorder is characterized by inflexible compulsive drinking, despite negative consequences.
Similar cognitive inflexibility is a hallmark of Alzheimer's disease. Deficits in cognitive flexibility in both
diseases are likely mediated by reduced cholinergic activity. The striatum contains dMSNs and CINs.
dMSN activity is enhanced by excessive alcohol intake. Preliminary studies found that dMSNs sent GABAergic
projections to inhibit striatal CINs and cholinergic projection neurons (CPNs) in the basal forebrain. Striatal
CINs also receive glutamatergic inputs from the thalamus. Studies from the parent grant found that excessive
alcohol intake reduces thalamic inputs to CINs and CIN activity, impairing flexibility in reversal learning. It is
not known how alcohol regulates cholinergic activity in the context of Alzheimer's disease. This research
explores how excessive alcohol intake reduces CIN and CPN activity in the 5xFAD mouse model
of Alzheimer's disease. The hypothesis is that excessive alcohol intake exacerbates the onset and extent of
enhanced inhibitory dMSN→CIN (or CPN) transmission and reduces glutamatergic thalamic inputs to CINs,
leading to hypocholinergic activity in the 5xFAD mouse model of Alzheimer's disease. We will test this
hypothesis via the following two specific aims: (1) Test whether excessive ethanol intake enhances dMSN→CIN
or dMSN→CPN transmission to a greater extent in 5xFAD mice than in wild-type controls; (2) Determine
whether excessive ethanol intake reduces thalamostriatal transmission in DMS CINs to a greater extent in
5xFAD mice than in wild-type controls. This research is conceptually innovative because it focuses on the
relatively neglected area of the striatum-mediated hypocholinergic mechanisms in both disorders. It is
technically innovative in its combined use of triple transgenic mice and optogenetic stimulation to selectively
measure three neural circuits and determine their contributions to hypocholinergic activity in both diseases.
Knowledge generated from this proposal will provide novel strategies for improving cholinergic activity and
cognitive flexibility, thereby informing the treatment of alcohol use disorder and Alzheimer's disease.

## Key facts

- **NIH application ID:** 10507961
- **Project number:** 3R01AA027768-03S1
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Jun Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $334,961
- **Award type:** 3
- **Project period:** 2020-06-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10507961

## Citation

> US National Institutes of Health, RePORTER application 10507961, Ethanol drinking and the basal ganglia circuitry (3R01AA027768-03S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10507961. Licensed CC0.

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