# Ethanol drinking and the basal ganglia circuitry

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $334,007

## Abstract

ABSTRACT
Alcohol use disorder (AUD) is characterized by inflexible compulsive drinking despite negative consequences.
This behavioral inflexibility is associated with deficits in reversal learning. The thalamus and the dorsomedial
striatum (DMS) are critical reversal learning in flexible behavior. The DMS contains principal medium spiny
neurons (MSNs). MSNs are located either in the direct-pathway (dMSNs) or indirect-pathway (iMSNs) of the
basal ganglia. Both dMSNs and iMSNs receive cortical inputs and positively and negatively regulate the
selection of “Go” actions, respectively. The DMS also contains cholinergic interneurons (CINs). CIN release
acetylcholine to modulate MSN activity. During reversal learning, thalamic inputs excite DMS CINs to generate
burst-pause firing and stop ongoing actions. It is not known how thalamically evoked CIN activity regulates
MSNs in AUD and contributes to inflexible behavior. The goal of this application is to study how excessive
ethanol intake alters thalamostriatal transmission, leading to behavioral inflexibility. Our long-term objective is
to develop new therapeutics to restore behavioral flexibility and treat AUD. The hypothesis, based in part on
applicant’s preliminary results, is that excessive ethanol intake compromises thalamic regulation of DMS CINs
and CIN-mediated regulation of cortical inputs onto dMSNs and iMSN, leading to inflexible behaviors, which
can be counteracted by optogenetic excitation of thalamostriatal transmission onto CINs. We will test this
hypothesis by pursuing the following three specific aims. (1) Investigate whether excessive ethanol intake
reduces the burst-pause response of DMS CINs and acetylcholine release from CINs. (2) Determine whether
excessive ethanol intake compromises CIN-mediated regulation of corticostriatal transmission in DMS MSNs.
And (3) evaluate the ability of optogenetic excitation of thalamic inputs onto DMS CINs to improve reversal
learning in animals with a history of excessive ethanol intake. This research is conceptually innovative because
it focuses on the relatively neglected area of the cholinergic contribution to AUD. It is technically innovative in
its use of combined genetically encoded acetylcholine sensors, dual-channel optogenetics, and rabies-
mediated expression systems at a synapse with defined pre- and postsynaptic sites to determine the
cholinergic contribution to ethanol-mediated inflexibility. These essential research questions cannot be
addressed using conventional methodologies. Knowledge generated from this proposal will provide novel
strategies for reversing inflexible behavior and thereby reduce excessive ethanol intake in AUD.

## Key facts

- **NIH application ID:** 10190746
- **Project number:** 5R01AA027768-02
- **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:** 2021
- **Award amount:** $334,007
- **Award type:** 5
- **Project period:** 2020-06-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190746

## Citation

> US National Institutes of Health, RePORTER application 10190746, Ethanol drinking and the basal ganglia circuitry (5R01AA027768-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10190746. Licensed CC0.

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