# Anterior Insula Projections for Alcohol Drinking/Anxiety Interactions in Female and Male Rats

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $523,683

## Abstract

Abstract
Alcohol Use Disorder (AUD) extracts substantial medical, social, and economic costs, and compulsion-like
alcohol drinking (CLAD), where intake persists despite negative consequences, can be a particular obstacle to
treatment. Also concerning is that problem drinking in women has risen dramatically, and women can have
greater alcohol problems. However, mechanisms underlying sex differences remain poorly understood,
although anxiety-like states can strongly contribute to alcohol drinking, and women have greater prevalence of
mood disorders and AUD/anxiety comorbidity. Also, our rat studies suggest that females have greater
persistence in responding for alcohol, as well as greater anxiety-like responding. Thus, to help develop better,
personalized therapies, it is essential to understand sex differences and similarities in mechanisms underlying
excessive drinking and comorbidity with anxiety. Alcohol intake is likely driven by its salient motivational
properties, and anterior insula (aINS) is a critical regulator of responding to important situations and regulating
accompanying emotional states. We find that specific aINS projections (including aINS-Nucleus Accumbens,
NAcb) promote male CLAD, with little impact on alcohol-only drinking (AOD); in agreement, compulsion-like
responding for alcohol in women and men with AUD activates a similar aINS circuit. However, very little is
known about specific aINS mechanisms for alcohol drinking in females, or overcoming higher
challenge more generally. Also, global aINS inhibition reduces AOD, but the underlying aINS projection(s)
remain completely undiscovered. Here, we address the overarching hypothesis that different aINS circuits
drive CLAD vs AOD, and, especially, that particular aINS circuits mediate both CLAD and anxiety-like behavior
(ALB) in higher-anxiety individuals, which is especially cogent in females. Aim 1 uses projection-specific
optogenetic inhibition to examine particular aINS projections for AOD and CLAD: aINS-NAcb and aINS-
amygdala for CLAD, and aINS-posterior insula (pINS) for AOD. aINS-pINS projection is large, and pINS
inhibition decreases drinking, but aINS-pINS is nearly unstudied in rodent. Also, to best understand how aINS
outputs regulate behavior, it is critical to identify actual activity patterns within specific aINS projections. Thus,
Aim 2 uses cutting edge in vivo electrophysiology recording methods with “opto-tagging” to identify firing
patterns within specific aINS projections, especially predicted higher activity in females that underlies greater
persistence for alcohol. Finally, Aim 3 examines potential sex differences in the relation between ALB and
alcohol drinking, aINS encoding of these behaviors, and the impact of optogenetic inhibition of specific aINS
projections on both ALB and drinking. We predict that higher ALB rats will have greater aINS encoding of both
ALB and drinking, and greater optogenetic inhibition of ALB and intake, particularly in females. ...

## Key facts

- **NIH application ID:** 10931348
- **Project number:** 5R01AA030710-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Frederic Woodward Hopf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $523,683
- **Award type:** 5
- **Project period:** 2023-09-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931348

## Citation

> US National Institutes of Health, RePORTER application 10931348, Anterior Insula Projections for Alcohol Drinking/Anxiety Interactions in Female and Male Rats (5R01AA030710-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10931348. Licensed CC0.

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