# Role of insula circuitry in the regulation of the aversive properties of ethanol

> **NIH NIH P60** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $256,807

## Abstract

Project Summary/Abstract
Excessive ethanol consumption is a major public health issue that can drive a range of serious health problems.
There are multiple mechanisms that contribute to the motivation to consume ethanol, and it has been shown that
ethanol has both aversive and rewarding properties. Considerable attention has been paid to the reinforcing
effects of ethanol and how these effects motivate ethanol intake. However, another factor that contributes to the
motivation to consume ethanol is the sensitivity to the aversive effects. It has been hypothesized that tolerance
to the aversive properties of ethanol contributes to excessive intake. One pre-clinical behavioral assay for the
aversive effects of ethanol is the development of conditioned taste aversion (CTA). When a taste is paired with
a treatment which produces aversive internal symptoms, a strong aversion to the taste develops. Studies
comparing different rodent strains suggest a link between sensitivity to the aversive effects of ethanol and the
propensity to voluntarily ingest ethanol. Importantly, it has been shown that as a dependence-like state emerges
in mice, sensitivity to the aversive effects of ethanol also declines as measured by CTA. This would suggest that
the tolerance to the aversive effects of ethanol that emerges with dependence may be another factor that drives
dependence-induced ethanol drinking. Because the neurocircuitry underlying the aversive effects of ethanol is
still poorly understood, we propose to combine cutting-edge tools to characterize the neurocircuit and molecular
mechanisms that regulate tolerance to the aversive properties of ethanol. Based on previous studies and
compelling pilot data, we will test the hypothesis that aversive properties of ethanol are encoded in the insular
cortex (aIC) and that chronic ethanol disrupts excitatory/inhibitory (E/I) balance in the aIC, disrupting the
aversive properties of ethanol, contributing to escalated ethanol consumption. Specific Aim 1 will use
electrophysiology and chemogenetic approaches to explore the plasticity in aIC to BLA outputs (aICBLA) as well
as the necessity of PV interneurons (aICPV) during retrieval of ethanol-induced CTA. Specific Aim 2 will use
chemogenetics and electrophysiology to explore plasticity in both aICPV and aICBLA neurons during retrieval of
ethanol CTA following long-term ethanol drinking. Specific Aim 3 is a collaborative aim and it will incorporate
slice physiology as well as channelrhodopsin-assisted circuit mapping to explore changes in frontal-limbic
connectivity between aIC, nucleus accumbens (Acb), and BLA. In addition, using fiber photometry we will
measure activity of pyramidal neurons and interneurons simultaneously in the aIC and BLA. Together, all these
studies will help us to identify a novel circuit mechanism that drives tolerance to the aversive properties of
ethanol, which is a hallmark of alcohol use disorder (AUD).

## Key facts

- **NIH application ID:** 10758601
- **Project number:** 5P60AA011605-27
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Thomas L. Kash
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $256,807
- **Award type:** 5
- **Project period:** 1997-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758601

## Citation

> US National Institutes of Health, RePORTER application 10758601, Role of insula circuitry in the regulation of the aversive properties of ethanol (5P60AA011605-27). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10758601. Licensed CC0.

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