LNCRNA REGULATION OF GENE EXPRESSION & BEHAVIOR

PROJECT SUMMARY Alcohol use disorder (AUD) is a major socioeconomic problem in the modern world. Acute and chronic alcohol exposure is known to lead to system-wide changes in gene expression throughout multiple brain-regions and cell-types. The mammalian genome is comprised of both protein-coding and non-protein-coding transcripts, with less than 2% being protein-coding. Despite outnumbering protein-coding genes, the biological function of most non-coding transcripts remains largely unknown. The largest class of non-coding transcripts are long non-coding RNAs (lncRNAs), which are operationally defined as transcripts longer than 200 nucleotides in length that do not encode for proteins. Most studies conducted to-date for lncRNAs have shown a critical role of lncRNAs in regulation of gene expression. Additionally, lncRNAs are important for alternative splicing of protein-coding transcripts, a biological process necessary for achieving cellular and molecular diversity of proteins. Alternative splicing is crucial for mounting context-dependent responses of the immune system. Chronic alcohol exposure has been previously shown to activate the neuroimmune system, altering CNS plasticity and behavior. Astrocytes are a specialized glial cell-type, outnumbering neurons, and other glial cells in the central nervous system (CNS). Astrocytes contiguously tile the entire CNS, playing a key role in numerous biological functions including responding to CNS insults, activation of neuroimmune pathways, and modulating behavior. Astrocytes are known to be involved in ethanol sensitivity and consumption; however, the contribution of lncRNAs to regulation of neuroimmune pathways in astrocytes and ethanol-related behaviors is unknown. This research proposal will test the overall hypothesis that the expression of lncRNAs in astrocytes is important for coordinating ethanol-induced neuroimmune activation, alternative splicing, and ethanol-related behaviors. Using a combination of in vitro and in vivo approaches this proposal will use advanced genomic approaches to determine the causal relationship of lncRNAs in mediating astrocyte activation and ethanol- related behaviors. Overall, our studies will establish novel molecular mechanisms for regulating gene expression in response to excessive alcohol exposure and contribute to a better understanding of the pathogenesis of AUD.