# Neuroimmune glutamatergic regulation of cortico-limbic circuits in ethanol self-administration

> **NIH NIH P60** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $267,908

## Abstract

Project Summary/Abstract
Neuroimmune activation and signaling contribute to increased ethanol drinking and possibly alcoholism.
Preclinical studies have shown that ethanol preference and drinking are modulated by neuroimmune gene
expression and that cycles of ethanol exposure lead to long-lasting changes in expression of neuroimmune
genes, including neuronal Toll-like receptor 3 (TLR3). These are highly relevant findings given that we have
shown that TLR3 expression in post-mortem human alcoholic brains correlates with lifetime ethanol
consumption. Therefore it is important to understand the interaction between neuroimmune signaling and
ethanol drinking, and the impact of neuroimmune activation on neurobiological changes that can drive
escalated ethanol drinking. As such, the focus of this application is on the effects of the TLR3 agonist
Polyinosinic:polycytidylic acid (Poly(I:C)) on escalations in operant ethanol self-administration (SA), the
underlying neuroimmune and glutamatergic changes (specifically in relation to metabotropic glutamate
receptor 2/3; mGluR2/3) in the nucleus accumbens (Acb) and insular cortex (IC), and the role of the ICAcb
circuit. As such, the primary hypothesis of this application is that neuroimmune signaling (i.e., TLR3 activation)
induces glutamatergic adaptations in the Acb and ICAcb circuitry that drive escalations in ethanol SA.
Experiments in Aim 1 will examine changes in neuroimmune signaling and glutamatergic targets in Acb and IC
in ethanol SA trained rats following Poly(I:C)-TLR3 activation, and parallel functional glutamatergic adaptations
in the AcbC in collaboration with Component 5. Experiments in Aim 2 will examine the ability of an mGluR2/3
agonist and antagonist to block and potentiate, respectively, the escalation in ethanol SA following TLR3
activation, and the role of Acb mGluR2/3. Experiments in Aim 3 will utilize a chemogenetic approach by the
incorporation of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to examine the
effects of inhibition and activation of ICAcbC projections on the escalation in ethanol SA following TLR3
activation. Next, fMRI will be used to assess cortico-accumbal functional connectively as a consequence of
ethanol SA history, TLR3 activation, and mGluR2/3 activation in conjunction with the Scientific Core. This
proposal tests novel neuroimmune signaling and IC-reward circuits that integrate into, benefit from and
contribute to the Alcohol Research Center’s focus on neurocircuit plasticity induced by ethanol. The proposed
studies investigate novel mechanisms and circuits associated with the development of alcohol use disorders
that could lead to new therapies.

## Key facts

- **NIH application ID:** 10078816
- **Project number:** 5P60AA011605-24
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Joyce Besheer
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $267,908
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078816

## Citation

> US National Institutes of Health, RePORTER application 10078816, Neuroimmune glutamatergic regulation of cortico-limbic circuits in ethanol self-administration (5P60AA011605-24). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10078816. Licensed CC0.

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