# Project 1: Epigenetic control of transcription dynamics in long-term alcohol neuroadaptation

> **NIH NIH P20** · UNIVERSITY OF PUERTO RICO MED SCIENCES · 2021 · $210,433

## Abstract

Alcohol addiction is a devastating condition perpetuated by enduring physiological and behavioral adaptations.
At the core of these adaptations is the long-term rearrangement of neuronal gene expression in the brain of the
addicted individual. However, the mechanisms by which alcohol consumption produces this rearrangement
and leads to lasting changes in behavior remains unresolved. Epigenetic histone modifications have recently
emerged as important modulators of gene expression and are thought to represent a form of transcriptional
memory that is directly imprinted on the chromosome. Some histone modifications affect transcription by
modulating the accessibility of the underlying DNA while others have been proposed to serve as marks read by
transcription factors as a 'histone code' that helps to specify the expression level of a gene. While the effects of
some epigenetic modifications on the transcriptional activity of genes is well known, little is known about the
temporal dynamics of these modifications and their relative contribution to the initiation and maintenance of
alcohol-induced transcriptional changes. The objective of this application is to investigate the temporal role
of epigenetic modulators underlying long-term functional alcohol tolerance —a key component of the addictive
process. In flies, a single alcohol sedation induces a tolerance phenotype that lasts over 10 days. This
phenotype is a direct product of neural adaptations to the drug that also give rise to equally lasting withdrawal
symptoms. The central hypothesis is that acute exposure to alcohol causes a sequence of lasting changes in
histone modifications that lead to the reprogramming of the brain transcriptome. Different modifications are
believed to have distinct effects on the initiation and/or the perdurance of alcohol tolerance. To test this
hypothesis, this proposal combines a thorough examination of histone modifications with the power of
Drosophila genetics to identify and characterize the epigenetic modulators that contribute to the temporal
dynamics of tolerance to alcohol. A comprehensive survey of alcohol-induced histone modifications will be
performed on flies that have been exposed to alcohol. Different time-points will be assessed in order to capture
the entire span of the alcohol-tolerance phenotype. In parallel, the activity of independent histone modification
enzymes will be manipulated in the fly nervous system to determine their contribution to the dynamics of this
phenotype. Finally, targeted removal of epigenetic marks at specific candidate gene loci will be performed in an
attempt to revert the development of tolerance to alcohol. Achieving these goals will help identify and evaluate
the temporal role of epigenetic histone modifications on the neural adaptations that underlie alcohol tolerance
and will contribute to the understanding of how alcohol consumption perpetuates changes in expression that
promote addiction. Targeting these regulatory mec...

## Key facts

- **NIH application ID:** 10212406
- **Project number:** 5P20GM103642-09
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MED SCIENCES
- **Principal Investigator:** Alfredo Ghezzi
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $210,433
- **Award type:** 5
- **Project period:** 2013-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212406

## Citation

> US National Institutes of Health, RePORTER application 10212406, Project 1: Epigenetic control of transcription dynamics in long-term alcohol neuroadaptation (5P20GM103642-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10212406. Licensed CC0.

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