Epigenetic mechanisms of anhedonia and fear in AUD

University Of Illinois At Chicago, Chicago IL

Investigators

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Abstract

Summary/Abstract The overarching hypothesis of the Center for Alcohol Research in Epigenetics (CARE) is that withdrawal from chronic alcohol exposure produces cell-type specific epigenetic and transcriptomic changes that alter brain function during the pathogenesis of alcohol use disorder (AUD). Further, we hypothesize that these cell-type specific epigenetic and transcriptomic neuroadaptations promote maladaptive phenotypes that are common following dependence and withdrawal. During the current funding period, we found upregulation of the epigenetic modifier HDAC5 and genes associated with neuroimmune regulation: Stat3, Ptgs2, Irf7, Irf9, and Crhbp in the hippocampus during withdrawal. Emerging evidence suggests dysregulated neuroimmune signaling in the hippocampus affects its neuronal structure and function and contributes to AUD pathology as well as emergence of comorbidities including depression, panic disorder and PTSD. This research project will investigate the role of cell-type specific epigenetic and transcriptomic mechanisms regulating immune genes within the hippocampus during withdrawal and mechanistically link these changes with withdrawal-induced increases in depression- and fear-relevant behaviors associated with panic disorder and PTSD. In Aim 1, experiments will identify epigenetic mechanisms driving transcriptional changes in genes identified from bulk RNA seq and ATAC-seq using chromatin immunoprecipitation and qPCR. We will also translate these findings using human postmortem hippocampus and determine the effect of HDAC5 inhibition of depression- and fear-relevant behaviors. In Aim 2, experiments will leverage the Epigenetics Core and single cell “10x genomics” strategies to identify cell-type specific epigenetic and transcriptional changes following alcohol withdrawal in hippocampus. These studies will confirm differential expression of genes identified in Aim1, identify new targets and improve spatial resolution of our findings. In Aim 3, experiments will use CRISPR-mediated epigenetic editing will be used to reverse withdrawal-induced cell-type specific epigenetic changes on specific genes identified in Aim 2. The same approach will be used to rescue withdrawal-induced changes in depression-, panic disorder- and PTSD-relevant behaviors, as well as glutamatergic neurotransmission using slice electrophysiology. The proposed experiments integrate well with CARE’s core mission to understand epigenetic regulation of the molecular mechanisms underlying neuroadaptations and behaviors associated with AUD. Together with the other components, these studies form a comprehensive investigation of epigenetic mechanisms underlying AUD outcomes with strong potential to reveal new targets for the development of pharmacotherapeutics aimed at treating AUD.