# The Role and Mechanisms of Clic4 in Modifying Ethanol-Related Behaviors

> **NIH NIH F30** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $28,624

## Abstract

PROJECT SUMMARY
Alcohol use disorder (AUD) has many risk factors, both environmental and genetic, and represents a complex
behavioral trait producing profound biomedical and social consequences. Identifying genes that engender AUD
risk and contribute to the underlying neurobiological mechanisms represents an important first step in
designing effective treatments. Published and preliminary studies make it apparent that chloride intracellular
channel 4 (Clic4) expression has a major influence on ethanol sensitivity, a major risk factor for alcohol
dependence in humans. Recent unpublished data has also defined a role for Clic4 in determining ethanol
preference and intake. Together, these studies underscore the potential impact of Clic4 on the molecular basis
of AUD and validate further investigation. In the work proposed here, Clic4 will be deleted separately in
neurons and oligodendrocytes in the prefrontal cortex (PFC) of mice and the cell type-specific roles of Clic4 in
drinking behavior, ethanol sensitivity, and anxiety-like behavior will be evaluated. These deletions will be
performed through stereotactic microinjection of AAV-Cre into adult Clic4-floxed mice. Behaviors will be
evaluated using 3-bottle-choice intermittent ethanol access, loss of righting reflex, and the light/dark box test.
In addition to describing the role of Clic4 in ethanol-related behavior, a novel and impactful characterization of
its mechanisms will be conducted. CLIC4 has been shown to translocate to the nucleus and interact with
transcription factors thereby altering gene expression. Studying the ethanol-Clic4 interactome by manipulating
Clic4 in the presence of ethanol could reveal the mechanistic framework underlying its role in ethanol-related
behavior. This potential will be evaluated by characterizing the transcriptomic changes in the PFC that follow
ethanol exposure in mice deficient for Clic4 in neurons and oligodendrocytes. Cell type-specific deletions of
Clic4 will be performed in adult mice using a tamoxifen-inducible Cre/loxP system. RNAseq will provide
identification of differential gene expression and downstream bioinformatic analysis will identify enriched
biological pathways and relevant gene networks. The studies defined in this proposal will characterize the
extent which Clic4 modifies ethanol-related behavior and provide an important first step towards understanding
the mechanism.

## Key facts

- **NIH application ID:** 10228593
- **Project number:** 5F30AA026497-05
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Rory Michael Weston
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $28,624
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-05-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228593

## Citation

> US National Institutes of Health, RePORTER application 10228593, The Role and Mechanisms of Clic4 in Modifying Ethanol-Related Behaviors (5F30AA026497-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10228593. Licensed CC0.

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