# Synaptic changes in the medial prefrontal cortex in the development of compulsive alcohol drinking

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2022 · $362,517

## Abstract

SUMMARY:
The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-
associated cues. Repeated alcohol exposure induces neuroadaptations that persist beyond acute withdrawal, and which
increase alcohol’s incentive salience, leading to escalation of alcohol intake and aversion-resistant alcohol seeking. Alcohol
use also causes deficits in cognitive functions associated with the medial prefrontal cortex (mPFC), which further fuel
compulsive drinking and relapse. In rodents, alcohol seeking activates specialized networks within the ventral (infralimbic,
IL) and prelimbic (PL) regions of the mPFC, which play largely opposite roles in the control of relapse behavior. While
activation of the PL drives reinstatement, neurons in the IL facilitate extinction learning and inhibit drug-seeking through
their projections to the Nucleus Accumbens shell, as well as the basolateral amygdala (BLA). However, the synaptic
mechanisms that drive maladaptive plasticity in these circuits during the transition from controlled to compulsive alcohol-
seeking remain largely unclear. The experiments in this application will provide a better understanding of network-specific
mechanisms through which chronic alcohol exposure and withdrawal affect executive cognitive functions of the mPFC and
diminish inhibitory control over goal-directed behavior.
In Aim 1 we use patch-clamp electrophysiology and optogenetic stimulation to determine changes in long-range
glutamatergic inputs from the BLA onto identified projection neurons in the IL and PL following extended access to alcohol,
as well as under postdependent conditions. We will use Targeted Recombination in Active Populations (TRAP2) with Fos2A-
iCreER mice to express channelrhodopsin selectively in those BLA afferents to the mPFC that are activated during withdrawal,
and we will determine how alterations in these inputs develop over time (from goal-directed to compulsive alcohol-
seeking). We will perform voltage-clamp recordings from retrogradely-labeled neurons that project back to the BLA, and
we will determine alcohol-induced changes in postsynaptic glutamate receptor function and presynaptic release following
reinstatement. Experiments in Aim 2 will use combinational retrograde Cre delivery and a Cre-dependent reporter to label
the same IL and PL projection neurons for high-resolution morphometric analyses of spines and glutamate receptor
expression in order to compare changes specifically in those neurons that contribute to relapse behavior (visualized via
co-labeling for the activity marker phospho-CREB) and those that do not (pCREB-negative cells). In Aim 3 we will again
use TRAP2 mice to test whether optogenetic manipulations of specific ensembles in the mPFC, or of inputs from the BLA
to the mPFC (each again TRAPed during withdrawal) can reverse alcohol-induced cognitive deficits and reduce drug-
seeking.
Taken together, these studies will provide impor...

## Key facts

- **NIH application ID:** 10367079
- **Project number:** 1R01AA028861-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** SVEN KROENER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,517
- **Award type:** 1
- **Project period:** 2022-02-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367079

## Citation

> US National Institutes of Health, RePORTER application 10367079, Synaptic changes in the medial prefrontal cortex in the development of compulsive alcohol drinking (1R01AA028861-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10367079. Licensed CC0.

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