# Translational examination of alcohol-associated epigenetic signatures: from primates to rodents

> **NIH NIH P60** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $235,219

## Abstract

PROJECT ABSTRACT
Although approximately 54% of Americans over the age of 18 consume alcohol, only 6.5% meet the criteria for
an alcohol use disorder (AUD). To date, there are three FDA approved medications to treat AUD, each having
varying efficacy on an individual basis. Understanding the molecular mechanisms underlying circuit-specific
changes that lead to AUD is essential to developing novel, targeted, and effective treatments for AUD. In
advancement of this goal, we have begun to identify genome-wide DNA methylation (DNAm) signals within the
nucleus accumbens core (NAcC) that distinguish low and heavy ethanol drinking monkeys. A subset of these
differential DNAm (D-DNAm) signals were associated with the expression of genes that play a role in
modulating neurotransmission. In particular, we found D-DNAm signals in genes that are functionally
associated with different compartments of the tetrapartite synapse that includes pre- and postsynaptic
elements, astroglial processes, and the extracellular matrix. Glutamatergic inputs into the NAcC arise from
brain regions outside of the NAcC, including Brodmann area 32 (A32, in primates; prelimbic cortex (PL) in
rodents). By investigating A32 inputs into NAcC, we will begin to elucidate circuit-specific DNAm signals that
distinguish low from heavy/very heavy ethanol drinkers. We will use to advantage the highly relevant and well-
characterized nonhuman primate (NHP) alcohol drinking model in which rhesus macaques imbibe alcohol daily
for over 12 months and self-select into low and heavy drinkers. Genome-wide DNAm sequencing (GW-DNAm)
will be used to identify alcohol-dose associated differentially methylated cytosines (DMCs) and regions (DMRs)
in the A32 and NAcC. Using a combination of a neuron specific antibody (NeuN) with a fluorescent tag and
fluorescence-activated cell sorting, we will begin to elucidate cell specificity (i.e. neuron-specific) in the DNAm
signals of the NHP A32. In parallel, we will examine the DNAm state of these same NHP A32 targets using
amplicon bisulfite sequencing in PL in high-ethanol preference mice that have consumed alcohol for 3 months
and self-select into low and heavy drinkers. These studies will yield gene/regulatory regions as targets that are
highly correlated with ethanol dose, based on differences in consumption, conserved across species and play
a role in the tetrapartite synapse. Using engineered viral vectors that alter the expression, function or
methylation level of gene targets, we will perform a mouse functional assay that will test their role in ethanol
drinking (self-administration of ethanol for 3 months) and in the PL-NAcC circuit (tested using ex vivo slice
electrophysiology). The most efficacious targets from the mouse functional assay will be tested in ex vivo slices
obtained from chronic ethanol drinking NHPs for their ability to alter A32 and NAcC circuitry. In total, this work
will identify alcohol dose-dependent DNAm modifications that are specifi...

## Key facts

- **NIH application ID:** 10056068
- **Project number:** 2P60AA010760-26
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Verginia Carmella Cuzon Carlson
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $235,219
- **Award type:** 2
- **Project period:** 1996-12-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056068

## Citation

> US National Institutes of Health, RePORTER application 10056068, Translational examination of alcohol-associated epigenetic signatures: from primates to rodents (2P60AA010760-26). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10056068. Licensed CC0.

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