# The role of lncRNA Gas5 in Glucocorticoid-Mediated Ethanol Dependence Phenotypes

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $48,974

## Abstract

Project Summary
Alcohol use disorder (AUD) is a chronic, relapsing brain disease that imposes a tremendous socioeconomic cost
in the United States. Although the diagnostic criteria for AUD have been established, the underlying molecular
pathogenesis is largely unknown. Prior AUD studies have demonstrated a critical role for dysregulation of
glucocorticoid signaling throughout multiple brain-regions, including the medial prefrontal cortex (mPFC).
Specific alterations in glucocorticoid receptor (GR) activity are important for the progression of alcohol
dependence, a critical facet of AUD that contributes to escalation of alcohol consumption, withdrawal, and
anxiety-like phenotypes. The overwhelming majority of GR studies for understanding AUD have focused on
protein-coding genes despite less than 2% of the genome being protein-coding. Non-coding RNAs play vital
roles in basic cellular functions in physiology and disease. This proposal will test a novel hypothesis that the long
non-coding RNA (lncRNA) growth arrest specific 5 (Gas5) is a sex-dependent and [neuron]-specific modulator
of alcohol responsive GR-dependent gene expression and behavior. Gas5 is a known repressor of GR activity
and has previously been linked to AUD phenotypes in mice and humans. Our previous studies have shown that
changes in the expression of Gas5, particularly in mPFC neurons, are related to chronic alcohol-induced
withdrawal and escalated ethanol consumption in male mice. However, the biological mechanism(s) for these
Gas5-associated changes in male animals are unknown. Additionally, no concurrent studies have been
conducted in female animals to determine potential sex-dependent effects of Gas5 for chronic alcohol-induced
behaviors. This project will directly study the role of mPFC neuronal Gas5 in the alcohol dependent transcriptome
and behavioral phenotypes related to GR in both sexes. To accomplish this, the chronic intermittent ethanol
vapor exposure (CIEV) model will be used in tandem with stereotaxic injections of an adeno-associated virus
(AAV) to induce CRISPR/Cas9-mediated knockdown (KD) of Gas5 in mPFC neurons. The three aims of this
study will determine the molecular and behavioral outcomes of mPFC neuron-specific Gas5 KD and CIEV. The
first aim of this study uses RNA immunoprecipitation followed by real time, quantitative PCR (RIP-qPCR) to
define changes in mPFC Gas5-GR binding. The second aim uses [next-generation RNA Sequencing (3’Tag-
Seq) to determine neuron-specific] alterations in the GR-dependent transcriptome. The third aim employs a
comprehensive battery to assay chronic ethanol exposure-related behavioral phenotypes. This project is a vital
step in the functional characterization of Gas5 in AUD and how GR-dependent phenotypes emerge. The
proposed studies may aid in rational development of more effective GR-mediated pharmacotherapies for AUD
and co-morbid disorders (e.g., chronic stress and anxiety).

## Key facts

- **NIH application ID:** 10916294
- **Project number:** 5F31AA031168-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Rachel Rice
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916294

## Citation

> US National Institutes of Health, RePORTER application 10916294, The role of lncRNA Gas5 in Glucocorticoid-Mediated Ethanol Dependence Phenotypes (5F31AA031168-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10916294. Licensed CC0.

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