# Ethanol & Anxiety: Cellular Mechanisms

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $345,506

## Abstract

Ethanol abuse produces marked changes in behavior and neurobiological function. Among the behavioral
manifestations critical for continued abuse are the profound increases in anxiety-like and reward-seeking
behaviors. These outcomes are intimately related and together drive subsequent ethanol abuse. The
lateral/basolateral amygdala plays a critical role in the regulation of both anxiety and reward-seeking. Recent
work with conditioned behaviors in drug naïve animals suggests that segregated but intermingled populations
basolateral amygdala principal neurons independently participate within `reward'- and `aversion'-related
circuits. Importantly, this segregation is also reflected at the synaptic level with reward or aversion influencing
glutamatergic synapses onto these populations in a circuit-specific and mutually exclusive manner. Yet, in
spite of this functional segregation in the naïve condition, reward-seeking and `aversion' are typically are co-
expressed in drug-experienced animals. And, we have shown that dependence-like ethanol exposure robustly
alters BLA synaptic function in what appears to be a non-segregated fashion. The juxtaposition of reward-/
affective-circuit control within the BLA, and the effects of chronic ethanol across neurons participating in these
circuits, suggests possible cellular mechanisms driving coincidental reward-seeking and negative affect
following alcohol dependence. This leads to the CENTRAL HYPOTHESIS of the current application that
cooperative synaptic plasticity at distinct BLA inputs controls the interaction between reward-seeking and
negative affective states that follow chronic ethanol exposure. To test this hypothesis, we propose three specific
aims. Aim 1 will test the working hypothesis that chronic ethanol, unlike naturally conditioned behaviors,
facilitates BLA synaptic function at principal neurons independent of their projection target. We will integrate
retrograde tracing and electrophysiological approaches to measure both synaptic function and intrinsic
properties of differentially `valenced' BLA neurons participating within distinct `reward' and `aversion' circuits.
Aim 2 will test the working hypothesis that presynaptic facilitation by chronic ethanol is necessary and
sufficient for the development of postsynaptic plasticity at distinct synapses. We this `ethanol-induced
heterosynaptic cooperation' by integrating optogenetics, chemogentics, and in vitro electrophysiology to 1)
assay functional coupling between defined inputs (prelimbic and agranular insular cortex) and 2) disrupt their
functional interaction. Finally, for Aim 3, we will test the working hypothesis that ethanol dysregulation of
BLA-PrL synapses governs both negative affect and reward seeking following chronic ethanol by integrating
chemogenetics with dependence-related ethanol drinking and anxiety-like behavior. The proposed work is
both technically innovative and significant because it utilizes state-of-the-art circuit-based ...

## Key facts

- **NIH application ID:** 9838133
- **Project number:** 5R01AA014445-15
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** BRIAN A MCCOOL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,506
- **Award type:** 5
- **Project period:** 2004-05-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838133

## Citation

> US National Institutes of Health, RePORTER application 9838133, Ethanol & Anxiety: Cellular Mechanisms (5R01AA014445-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838133. Licensed CC0.

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