# Alterations in Microglial function moderate the development of maladaptive drinking behaviors following early life stress and are exacerbated by ethanol consumption

> **NIH NIH F31** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $35,079

## Abstract

PROJECT SUMMARY
Currently 14.5 million people suffer from alcohol use disorder (AUD) in the United States. Identifying early risk
factors that increase the likelihood of developing AUD could help elucidate potential models for preventative
care and mitigate the impact AUD has on society. One highly studied risk factor associated with developing
AUD is early life stress (ELS). The mechanisms that facilitate ELS's impact on the development of AUD is
poorly understood. One consistent finding in ELS literature shows a role of microglia in the development of a
host of neurological disorders including AUD. Over the past several years, new evidence has been uncovered
identifying a role of microglia in the development and maintenance of AUD. To expand this field of work and
discover novel targets for treatment, my project seeks to implement a model of early life stress: periadolescent
social stress (PSS) and a model to promote voluntary binge-like consumption of ethanol: drinking in the dark.
Using these models, I will identify how microglia respond to these factors in isolation and when combined. Over
the past two years, I have run experiments to optimize the PSS paradigm and drinking in the dark protocol. I
have performed immunohistochemical staining and run qPCR to determine how microglia respond to these
stimuli. I have found that combined PSS and binge ethanol consumption decrease microglia number, increase
microglial reactivity, and alter microglia morphology in the ventral hippocampus. In addition, markers related to
homeostasis are reduced following PSS and binge ethanol consumption. While these results are interesting,
evidence suggest that microglia are present heterogeneously throughout the brain and serve a variety of
functions. To better characterize the effects of early life stress and ethanol consumption on microglia function,
my proposal aims to identify key regions that demonstrate alterations in microglia count, reactivity, and
phenotype; and identify how these changes relate to changes in microglial RNA. To determine these key
regions, I will use light sheet microscopy. This approach will provide us an opportunity to create an unbiased
3D reconstruction of the whole brain with single microglia resolution. I will use this technique to identify how
microglia are distributed throughout the brain and phenotypically altered due to these environmental
exposures. Focusing on the regions identified with light sheet microscopy, I will perform targeted purification of
polysomal mRNA sequencing (TRAP-seq). Using a CX3CR1CreER transgenic mouse line that primarily labels
for microglia in GFP, I will sort microglia from other cell types and identify changes in microglial RNA
expression due to PSS and ethanol exposure. Following each of these main experiments, I will determine
whether microglia inhibition during PSS will prevent changes in binge-like ethanol consumption and microglial
adaptations. This work will mark a significant advancement in the ...

## Key facts

- **NIH application ID:** 10839787
- **Project number:** 5F31AA030928-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Stephen Christopher Gironda
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,079
- **Award type:** 5
- **Project period:** 2023-07-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839787

## Citation

> US National Institutes of Health, RePORTER application 10839787, Alterations in Microglial function moderate the development of maladaptive drinking behaviors following early life stress and are exacerbated by ethanol consumption (5F31AA030928-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10839787. Licensed CC0.

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