# Project 2 Title: The brain brush border and microglial activation in response to ethanol

> **NIH NIH P50** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $273,861

## Abstract

ABSTRACT
Exposure to alcohol during development or adulthood may result in damage to the brain. Binge alcohol
consumption is a growing problem in the US, particularly among adolescents and young adults whose brains
are continuing to develop and are thus more susceptible to the harmful effects of binge drinking on brain function.
Both clinical and preclinical evidence suggest that microglia –the brain’s resident immune cells– play a key role
in modulating alcohol-induced neurotoxicity. Indeed, brain inflammation following alcohol binge can impair brain
development and function. In addition, activation of microglia promotes drinking preference in mouse models of
chronic alcohol exposure. However, the cellular or molecular mechanisms through which microglia could mediate
neuronal damage and alter animal behavior in response to alcohol in the adult or the adolescent brain have not
been identified. Moreover, the effects of alcohol on microglia-neuronal interactions at the structural or functional
level have not been studied, mostly due to technological limitations. We previously performed in vivo imaging
using two-photon microscopy and discovered the dynamic nature of microglia, providing the first real-time
demonstration of their tissue surveillance function. We also revealed their previously unknown ability to rapidly
respond to changes in their microenvironment. Following systemic inflammatory challenges microglia become
activated, and increase their interactions with the surrounding brain tissue. Acute and chronic alcohol exposure
increases pro-inflammatory cytokines systemically, which can in turn directly or indirectly affect blood-brain
barrier (BBB) integrity, and promote neuro-inflammatory and neurotoxic effects in different brain regions. Our
preliminary results in models of excessive ethanol exposure show microglial activation, BBB disruption, and
neuronal loss in the prefrontal cortex (PFC) of mice, a brain region implicated in alcohol-induced impairments in
humans. Also, monocyte-specific deletion of MyD88, a key adaptor protein downstream of Toll-like receptor 4,
abrogated microglial activation, BBB damage, and neuronal loss following ethanol abuse, and prevented ethanol-
induced impairments in mice. Based on these findings, our proposed studies will test the hypotheses that
increasing ethanol exposure causes localized BBB damage and microglial activation, which is required for
regional structural and functional disruption of neuronal networks, and for alcohol-induced behavioral
impairments.

## Key facts

- **NIH application ID:** 10817860
- **Project number:** 5P50AA024333-09
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Dimitrios Davalos
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $273,861
- **Award type:** 5
- **Project period:** 2016-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817860

## Citation

> US National Institutes of Health, RePORTER application 10817860, Project 2 Title: The brain brush border and microglial activation in response to ethanol (5P50AA024333-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10817860. Licensed CC0.

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