# Histone methylation as a potential mechanism for myelin deficits and behavioral alterations following adolescent binge ethanol

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $348,750

## Abstract

Project Summary:
Adolescents’ overwhelming drug of choice is alcohol, and when they drink, it is in binges, consuming more
than four drinks in a few hours. Ongoing frontal cortex development makes adolescent drinkers particularly
vulnerable to long-term consequences of binge ethanol. Early alcohol use is associated with cognitive
impairments, reduced white matter content, and synaptic pruning in the frontal cortex. The risk for developing
an alcohol use disorder increases the younger one begins to drink. However, the molecular mechanisms
underlying alcohol-induced persistent changes in prefrontal cortex development are not fully understood. We
recently reported that adolescent binge ethanol altered ethanol sensitivity and increased cognitive deficits that
persist into adulthood. These behavioral changes were accompanied by reduced expression of genes
responsible for regulating histone methylation and myelination, suggesting that binge ethanol alters the
transcriptional landscape and the development of myelin in the frontal cortex. This proposal will test the
hypothesis that regulation of histone methylation by binge ethanol may be a mechanism underlying the
reduction of myelin in the frontal cortex and consequent behavioral changes that persist into adulthood. This
proposal will test these hypotheses using chromatin immunoprecipitation coupled with massively parallel RNA-
sequencing to identify the epigenetic loci and concurrent gene expression profiles altered by adolescent binge
ethanol and transcript profiles that persist into adulthood. We will first characterize the trajectory of ethanol’s
insults on oligodendrocyte development using a time course and dose response in adolescents. We will
investigate the role of histone methylation on oligodendrocyte maturation by directly interrogating the
responsible genes in oligodendrocyte-enriched cell populations in the frontal cortex. Finally, we will
mechanistically test the effects of modulating histone methylation levels using viral vector delivery to rescue
the adult cognitive and ethanol sensitive behaviors. These studies will use developmental and sex dependent
models to perform a combined epigenetic, genomic, and behavioral analysis of the response to adolescent
ethanol exposure. Our goals in this proposal are to identify the mechanisms underlying the immediate and long
lasting transcriptional changes in the PFC and determine their contributions to the persistent cognitive deficits
and increased ethanol sensitivity resulting from binge ethanol during adolescence. These studies will begin to
identify and mechanistically test possible novel therapeutic targets for intervention in early alcoholism or
alcohol-related neurological disease.

## Key facts

- **NIH application ID:** 10169191
- **Project number:** 5R01AA026347-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** JENNIFER T WOLSTENHOLME
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $348,750
- **Award type:** 5
- **Project period:** 2018-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169191

## Citation

> US National Institutes of Health, RePORTER application 10169191, Histone methylation as a potential mechanism for myelin deficits and behavioral alterations following adolescent binge ethanol (5R01AA026347-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169191. Licensed CC0.

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