ROLE OF CLIC4 AND THE SYNAPTIC TRANSCRIPTOME IN THE BEHAVIORAL AND MOLECULAR NEUROBIOLOGY OF ETHANOL

Author

Rory M. Weston, Virginia Commonwealth UniversityFollow

DOI

https://doi.org/10.25772/72Z3-8G88

Defense Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Neuroscience

First Advisor

Michael F. Miles

Abstract

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Published studies have identified chloride intracellular channel 4 (Clic4) as an ethanol-regulated gene in brain capable of modulating sensitivity to sedation in multiple species. The functions of Clic4 are not well understood but have been associated with diverse biological processes including ion channel activity, cellular stress, cytoskeleton remodeling, intracellular trafficking, and oxidoreductase reactions. In this series of studies, we have characterized gene expression changes specific to frontal cortex synapses after acute and repeated ethanol exposures. We additionally identified genes differentially regulated in response to knockdown of Drosophila ortholog Clic and deletion of Clic4 in mice, both implicating oxidation-reduction-related processes as potentially mechanistic to their involvement in ethanol sedation sensitivity. Lastly, we show that CLIC4 is robustly expressed in oligodendrocytes where deletion of Clic4 produces altered ethanol consumption and anxiety-like behaviors in mice. Considering its abundant expression in oligodendrocytes, induction by acute ethanol, and function in modulating ethanol consumption, our work here suggests that Clic4 has an important role in the molecular response to ethanol in brain and development of maladaptive ethanol-related behaviors.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

4-9-2020