# Role of afferents to the rostromedial tegmental nucleus in symptoms of withdrawal from chronic ethanol exposure

> **NIH NIH F31** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $45,972

## Abstract

ABSTRACT
A significant number of individuals with alcohol use disorder struggle to maintain sobriety as a result of withdrawal
symptoms that emerge during early abstinence. Despite this, the neural mechanisms underlying symptoms of
withdrawal are not well understood. The rostromedial tegmental nucleus (RMTg) is a GABAergic region that
plays a critical role in avoidance behavior, aversive signaling, pain, and importantly, alcohol-related behaviors.
Recent work from our lab provides evidence of RMTg hyperactivity during acute withdrawal from chronic
intermittent ethanol (CIE) exposure. In addition, we showed that pharmacological inhibition of the RMTg
attenuates withdrawal-induced anxiety-like behavior. The afferents that drive RMTg-mediated withdrawal
symptoms are currently unknown. However, previously published studies have implicated the lateral habenula
(LHb) – a region that provides dense input to the RMTg – in withdrawal-induced negative affect similar to our
work in the RMTg. In addition, our preliminary data revealed significant cFos induction in RMTg-projecting LHb
neurons during acute withdrawal in CIE-exposed rats compared to AIR controls. Interestingly, the LHb is heavily
enriched in mu-opioid receptors (MORs), which are known to regulate both pain and affect. Oprm1, the gene
that encodes MOR, is hypermethylated in individuals with AUD suggestive of a potential mechanism by which
chronic ethanol exposure drives decreases in Oprm1 expression. However, the effect of withdrawal on MORs in
the LHb is unclear. Together, these data lead us to hypothesize that LHb afferents to the RMTg are
mechanistically involved in withdrawal from chronic ethanol and that epigenetic dysregulation of the Oprm1 gene
may contribute to this mechanism. Three specific aims will be used to test this hypothesis. In Aim 1, in vivo
chemogenetics will be used to determine whether selective inhibition of RMTg-projecting LHb neurons reverses
symptoms of withdrawal. Oprm1 expression and methylation levels will be assessed in RMTg-projecting LHb
neurons in Aim 2 using fluorescent in situ hybridization and MethylMiner. Tract tracing will be combined with ex
vivo whole-cell patch-clamp slice electrophysiology in Aim 3 to investigate withdrawal-induced changes in
epigenetic regulation of MOR receptor-mediated firing in RMTg-projecting LHb neurons. These studies will
provide the applicant with new training in cutting-edge neuroscience techniques while also providing new insight
into the role of the LHb-RMTg circuit in ethanol withdrawal.

## Key facts

- **NIH application ID:** 10864805
- **Project number:** 5F31AA031178-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Hyerim Yang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,972
- **Award type:** 5
- **Project period:** 2023-06-16 → 2025-06-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864805

## Citation

> US National Institutes of Health, RePORTER application 10864805, Role of afferents to the rostromedial tegmental nucleus in symptoms of withdrawal from chronic ethanol exposure (5F31AA031178-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10864805. Licensed CC0.

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