# Sex Specific Effects of Adolescent Alcohol Exposure on BNST Plasticity

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2021 · $320,552

## Abstract

Project Summary/Abstract: Adolescent alcohol use is a known risk factor for the development
of alcohol use disorders (AUDs); latent maladaptive plasticity associated with adolescent use
likely underlies this increased risk in adults. The bed nucleus of the stria terminalis (BNST) is a
sexually dimorphic brain region and critically involved in stress and negative affect-associated
relapse in AUDs, and therefore is a prime target for this maladaptive plasticity. Using a model of
adolescent intermittent ethanol exposure (AIE) in male and female mice, we find disrupted
BNST glutamatergic transmission and plasticity, but the mechanisms differ across sex (GluN2B-
NMDAR-mediated in males and mGluR1/5-mediated in females). When tested during
adulthood, both forms of BNST plasticity return to control levels but exposure to restraint stress
produced a re-emergence of AIE-induced that were sex-specific. AIE also increased glutamate
release in the BNST and this effect appears be mitigated through modulation of presynaptic
CRFR1. AIE and adult stress also produce sex-specific negative affect behavioral phenotypes
(novelty-induced hypophagia test in females, foot shock-induce freezing in males). As the BNST
sits at the intersection between cortical inputs and downstream amygdalar and hypothalamic
targets, this enhanced drive to the BNST and subsequent inter BNST plasticity likely sensitize
the stress response and the expression of negative affect behaviors. Using a combination of
molecular, electrophysiological, genetic, and behavioral approaches, we will evaluate the ability
of AIE to prime the BNST to adult stress sex-specific manner. I hypothesize that that AIE and
adult stress act to synergistically enhance glutamate release in the BNST via activation of
CRFR1 in male mice but not female mice (Aim 1). Modulation of CRFR1 transmission will be
examined for its ability to block the effects of stress on glutamate release and plasticity and
evaluate stress sensitive inputs. Next, I propose that the sex difference in BNST plasticity occur
in distinct projection regions (CeA, LH, or VTA). Finally, BNST-specific deletion, BNST
DREADD activation, and pharmacological antagonism of GluN2B-NMDARs and mGluR5s
(depending on the sex) will be used to assess the role of these receptors in the development of
sex-specific negative affect phenotypes. The goal of this work is to identify potential
pharmacotherapies to treat AUDs and our work suggest that these likely need to be distinct for
males and females.

## Key facts

- **NIH application ID:** 10120879
- **Project number:** 1R01AA028011-01A1
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Tiffany A Wills
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $320,552
- **Award type:** 1
- **Project period:** 2021-05-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120879

## Citation

> US National Institutes of Health, RePORTER application 10120879, Sex Specific Effects of Adolescent Alcohol Exposure on BNST Plasticity (1R01AA028011-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10120879. Licensed CC0.

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