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Farris SP, Robinson GR, Mayfield RD, Harris RA

Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, United States of America

Persistent changes in gene expression within the CNS may facilitate the development and continuation of an alcohol use disorder (AUD). To better understand the underlying mechanisms related to an AUD, we conducted an unbiased whole-transcriptome sequencing (RNA-Seq) analysis of three human postmortem brain regions associated with addiction: superior prefrontal cortex, basolateral amygdala, and central nucleus of amygdala. Differential gene expression analysis revealed a consistent up-regulation of genes involved in immune-related responses across all of these regions. AUD expression signatures were also significantly enriched in genes associated with microglia, the primary neuroimmune cells of the CNS. These results suggest that chronic alcohol abuse causes dynamic changes in neuroimmune signaling through the activation of microglial. We tested this hypothesis by isolating microglia from adult C57BL/6J mice consuming alcohol in a 2-bottle choice every-other-day drinking paradigm. Comparison of alcohol-responsive changes in neuroimmune gene expression in mouse and humans showed that these changes were largely conserved across species. Applying weighted correlation coexpression network analysis, a unique cluster of alcohol-responsive neuroimmune genes was identified within a microglia network compared to total homogenate networks. Notably, the network containing 1,135 genes encompassed numerous known microglia markers (Cx3cr1, Gpr34, P2ry13, Abi3, Csf1r, Siglech, Tmem119, C1qa, C1qb, C1qc, Trem2, Susd3, Aif1, Sparc, Ctss, Mpeg1, and Itgam). Previous studies from our laboratory have shown null mouse mutants for the microglial gene Ctss exhibit decreased alcohol consumption and preference, indicating that this cellular approach can identify genes that regulate drinking behavior. Coordinate expression of genes within the microglia network may also identify novel transcripts, such as select long non-coding RNAs (e.g. Gm10790), with important roles in neuroimmune function and chronic alcohol consumption. Overall, our results demonstrate the potential role of a conserved microglia network in the neurobiology of disease, which may facilitate drug-repurposing efforts in the treatment of AUDs. This work was supported by NIAAA R01AA012404, U01AA020926, and T32AA007471.