# The Unfolding Role of Microglia in Alcohol Withdrawal

> **NIH NIH R21** · SEATTLE INST FOR BIOMEDICAL/CLINICAL RES · 2022 · $161,738

## Abstract

Abstract
Alcohol withdrawal is a medical emergency and a behavioral barrier to reducing alcohol abuse. Unlike
withdrawal to other drugs, there is ample evidence that withdrawal to alcohol becomes worse after multiple
cycles of alcohol consumption and abstinence, increasing the risks for serious adverse complications including
seizures, delirium tremens, and death. Furthermore, the negative reinforcement inherent to cycles of alcohol
abstinence and relapse to alcohol consumption complicates any behavioral interventions to reduce alcohol
abuse. Many clues suggest that neuroinflammation is involved in both alcohol tolerance as well as withdrawal,
but this realization has not led to new treatments for alcohol use disorder. The purpose of this proposal is to
develop our hypothesis that chronic, intermittent alcohol exposure alters the way microglia, the innate immune
cells that reside in the brain, modulate neuroimmune as well as neuronal synaptic signaling. In pilot
experiments using RNA sequencing of ribosome-associated RNA from microglia after multiple cycles of alcohol
exposure and abstinence, we found that alcohol withdrawal causes oxidative stress in microglia and activates
the “unfolded protein response” (UPR), a mechanism that is involved in cellular stress responses leading to
neuroinflammatory signaling and derangements in microglia function that can lead to cell death.
We propose to block the full activation of the microglial UPR by knocking out CHOP, a key transcription factor
involved in this pathway that was dramatically upregulated in microglia during withdrawal, using a recently
developed, selective cre-driver mouse line, Tmem119-2A-Cre-ERT2/TdTomato, crossed with commercially
available floxed CHOP mice to investigate this biology. We will examine how blunting UPR signaling alters the
signs of alcohol withdrawal by testing if CHOP knockout alters several behavioral manifestations and reduces
microglia morphological and gene expression changes associated with withdrawal. Using in vivo two-photon
time lapse microscopy, we will examine if CHOP knockout from microglia changes morphology and motility
associated during alcohol withdrawal. We will also test whether microglial CHOP impacts the motivation to
drink alcohol in a model of voluntary alcohol drinking after multiple cycles of ethanol vapor exposure and
withdrawal. Together, these experiments examine the role of neuroinflammation in the mechanisms of alcohol
dependence and withdrawal from a new angle that has not been previously considered and is well matched to
the R21 mechanism due to its high novelty and potential to develop new treatments.

## Key facts

- **NIH application ID:** 10491273
- **Project number:** 5R21AA029601-02
- **Recipient organization:** SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
- **Principal Investigator:** John F Neumaier
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $161,738
- **Award type:** 5
- **Project period:** 2021-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491273

## Citation

> US National Institutes of Health, RePORTER application 10491273, The Unfolding Role of Microglia in Alcohol Withdrawal (5R21AA029601-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10491273. Licensed CC0.

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