# Dissecting the Role of Nucleus Basalis Magnocellularis Circuitry in Basolateral Amygdala Physiology and Regulation of Anxiety Following Chronic Ethanol Exposure and Withdrawal

> **NIH NIH F31** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $46,036

## Abstract

PROJECT SUMMARY
Anxiety during alcohol withdrawal contributes to high relapse rates and remains an obstacle for alcohol use
disorder (AUD) treatment. The basolateral amygdala (BLA) is a brain region involved in the progression of
alcohol dependence that facilitates reward-seeking and emotional behaviors like anxiety. Our laboratory has
shown that input-specific alterations in glutamate/GABA neurotransmission occur following chronic
ethanol/withdrawal. For example, stria terminalis (ST) glutamatergic afferents exhibit presynaptic facilitation
during withdrawal. Lateral paracupsular cells (LPCs) and local interneurons of the BLA GABAergic system
express different outcomes to chronic ethanol: LPCs show an attenuation of GABA release, while local
interneurons show no significant change. Together, these alterations in GABAergic/glutamatergic afferents
yield a hyperexcitable state in BLA pyramidal neurons during alcohol withdrawal. However, it remains unclear
how ethanol alters the neurophysiology of upstream modulatory systems, or whether these projections
influence the generation of anxiety-like behaviors. The BLA receives dense cholinergic projections from the
nucleus basalis magnocellularis (NBM) to modulate neuronal excitability and neurotransmitt er release by
acting on GABAergic interneurons, glutamatergic terminals, and BLA pyramidal neurons. These distinct
neuronal compartments contain different combinations of nicotinic and muscarinic acetylcholine receptors
(n/mAChRs) that collectively function to regulate the formation of aversive memories. The effects of chronic
ethanol on NBM synaptic physiology and their roles in mediating withdrawal-induced anxiety-like behavior in
the BLA is unknown. Our preliminary data leads to the central hypothesis that chronic ethanol dysregulates
cholinergic modulation of BLA afferents and potentiates the neurophysiological symptoms of withdrawal. We
will address this hypothesis through two Specific Aims. In Aim 1, we will primarily employ optogenetic and
excitotoxic lesion studies to manipulate the activity of NBM terminals and measure GABA/glutamate
neurophysiology with whole-cell patch clamp electrophysiology. We hypothesize that chronic
ethanol/withdrawal upregulates NBM cholinergic input and enhances glutamatergic and GABAergic
presynaptic plasticity. In Aim 2, we will use chemogenetics and lesion experiments to manipulate the
cholinergic inputs and measure anxiety-like behavior using assays like the elevated zero maze, light/dark box,
and open field test. We hypothesize that disruption of the cholinergic circuit will ameliorate the progression of
anxiety-like behaviors. Understanding the NBM-BLA circuit might lead to potential novel targets for more
effective treatments of alcohol withdrawal-induced anxiety in the clinical setting.

## Key facts

- **NIH application ID:** 10232872
- **Project number:** 1F31AA028722-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Sarah Elizabeth Sizer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232872

## Citation

> US National Institutes of Health, RePORTER application 10232872, Dissecting the Role of Nucleus Basalis Magnocellularis Circuitry in Basolateral Amygdala Physiology and Regulation of Anxiety Following Chronic Ethanol Exposure and Withdrawal (1F31AA028722-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10232872. Licensed CC0.

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