# Striatal Microcircuit Dynamics of Ethanol Habits

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $434,646

## Abstract

Project Summary
We recently demonstrated that dorsolateral striatum fast-spiking interneurons (FSIs) are necessary for
compulsive alcohol drinking, which is a cardinal feature of alcohol use disorder. This proposal seeks to
understand the impact of ethanol on this critical interneuron population at molecular, neural circuit, and
behavioral levels to advance novel therapeutic strategies targeting compulsive alcohol use. While chronic
intermittent ethanol exposure exerts little effect on excitatory inputs to FSIs and FSI intrinsic excitability, it
dramatically downregulates inhibitory synaptic control of FSIs – positioning FSIs to activate without regulation
to underlie pathological compulsive drinking behavior. Our substantial preliminary data points to a framework
wherein ethanol acutely potentiates GABAergic input to FSIs and, following repeated intermittent exposure to
ethanol, GABAergic inputs are homeostatically downregulated by a degradation of the extracellular matrix that
surrounds FSIs, the so-called perineuronal nets that stabilize inhibitory input onto FSIs. Thus, we herein
hypothesize that this dramatic loss of GABAergic input to FSIs is mediated by a degradation of perineuronal
nets. This will be tested with three interrelated yet fully independent experimental aims using cutting-edge
approaches. Aim 1 will examine circuit-specific synaptic mechanisms governing the acute ethanol potentiation
of GABAergic input to FSIs using molecular tools and whole-cell patch clamp electrophysiology. Aim 2 will
determine the fate of GABAergic inputs to FSIs that are downregulated by chronic intermittent ethanol using a
suite of advance cellular and molecular imaging techniques. Aim 3 will explore the causal interaction of acute
ethanol potentiation of GABAergic input and the perineuronal net-mediated downregulation of these inputs
following chronic intermittent ethanol exposure using a powerful combination of slice electrophysiology,
perineuronal net imaging, in vivo chemogenetics, and compulsive alcohol drinking analyses. This multilevel,
orthogonal experimental approach positions this project to yield vertical advances toward novel therapeutics
targeting compulsive alcohol consumption and insight to myriad neuropsychiatric disorders involving dorsal
striatal dysfunction.

## Key facts

- **NIH application ID:** 10809661
- **Project number:** 5R01AA024845-07
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** BRIAN NEIL MATHUR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $434,646
- **Award type:** 5
- **Project period:** 2016-07-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809661

## Citation

> US National Institutes of Health, RePORTER application 10809661, Striatal Microcircuit Dynamics of Ethanol Habits (5R01AA024845-07). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10809661. Licensed CC0.

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