# Dependence induced dysfunction of decision-making circuits

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $440,061

## Abstract

Project Summary
Aberrant cognitive function is a hallmark of alcohol use disorders (AUD), disrupting daily function and
contributing to alcohol abuse and relapse. Identifying the nature of these deficits is challenged by a lack of
understanding of involved cortical circuits and mechanisms. AUD shows altered orbital frontal (OFC) and
pre-supplementary motor area (Pre-SMA) cortical function, regions implicated in cognitive functions necessary
for decision-making. The mechanisms underlying behavioral and circuit dysfunction are not clear. OFC
hypoactivity resulted in a loss of value-based control over goal-directed behavior; however additional cortical
circuits have been implicated in behavioral flexibility, including Pre-SMA, whose rodent homologue is the
secondary motor cortex (M2), and its output to DS. Increased Pre-SMA/M2 activity is correlated with behavioral
inflexibility and impulsivity in AUD; however, no preclinical studies have examined effects of chronic alcohol
exposure on M2 circuit function or its output to DS. The overarching hypothesis of this work is that AUD
alters OFC and Pre-SMA/M2 circuit function and striatal output, resulting in inflexible behavior
underlying dysfunctional decision-making. The current proposal addresses this through three Aims with
experiments to be conducted in mice. Aim 1 examines the influence of chronic alcohol on OFC output to M2
contributing to behavioral flexibility. A series of ex vivo slice physiology and in vivo activity monitoring and
manipulation experiments will test the hypothesis that chronic intermittent ethanol exposure and repeated
withdrawal (CIE) decreases OFC-M2 transmission important for behavioral flexibility. In Aim 2, effects of
chronic alcohol on M2 function and its contribution to ethanol self-administration will be examined. By
examining effects of chronic ethanol on identified M2 cell type transmission ex vivo and the dynamics and
functional contribution of such output to ethanol self-administration in vivo, this aim will address the hypothesis
that CIE alters M2 transmission and results in hyperactivity of M2 excitatory populations to contribute to
inflexible alcohol self-administration. Lastly, Aim 3 will examine effects of CIE on M2-DS output and control
over ethanol-seeking. An integrative ex vivo and in vivo approach will be taken to address the hypothesis that
CIE produces aberrant control over striatal processes through increased activation and output of motor-related
circuits. Together, these aims will inform how CIE affects cortical circuits and alters their recruitment of striatum
to disrupt goal-directed control, thereby identifying novel targets for AUD treatment. Identifying the
mechanisms underlying chronic alcohol-induced alterations to cortico-cortical and cortico-striatal circuits is a
critical step towards understanding how their disruption contributes to AUD.

## Key facts

- **NIH application ID:** 10705757
- **Project number:** 5R01AA026077-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christina M. Gremel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $440,061
- **Award type:** 5
- **Project period:** 2017-09-10 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705757

## Citation

> US National Institutes of Health, RePORTER application 10705757, Dependence induced dysfunction of decision-making circuits (5R01AA026077-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10705757. Licensed CC0.

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