Epigenetic mechanisms of cognitive and nociceptive impairments in AUD

University Of Illinois At Chicago, Chicago IL

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Abstract

PROJECT SUMMARY A significant number of individuals struggle to maintain sobriety as a result of withdrawal symptoms that emerge during early abstinence from alcohol. While preclinical studies have focused on negative affective symptoms of withdrawal, heightened pain sensitivity and cognitive impairment are also commonly reported during early abstinence. Yet, the precise neurobiological mechanisms underlying these symptoms are not well-understood. The medial prefrontal cortex (mPFC) is critically involved in cognition. Although less well-appreciated, this brain region also plays an important role in regulating pain. During the current and previous funding period, we uncovered a number of significant epigenetic and transcriptional changes in the mPFC of individuals with and without alcohol use disorder (AUD). Merger of bulk RNA-seq results from mPFC of control and AUD subjects with those from mPFC of control and withdrawn male and female rats revealed concordant differential expression of genes regulating neuroimmune signaling and synaptic plasticity in AUD/withdrawn subjects. These results were validated in a rodent model of alcohol dependence and our preliminary data points to an epigenetic mechanism driving the observed changes in gene expression. Importantly, these changes occur at the same period of withdrawal during which we also observe deficits in decision making and hyperalgesia. Altogether, these data lead us to hypothesize that epigenetic dysregulation of the expression of key genes in the mPFC that mediate neuroimmune signaling and synaptic plasticity promotes neuroadaptations that facilitate cognitive and nociceptive symptoms of withdrawal. Experiments in the current proposal are designed to test this hypothesis by determining the cell-type specificity of epigenomic and transcriptomic changes and subsequently leveraging a gene editing approach (CRISPR-dCas9) to reverse cell-type-specific withdrawal-induced epigenetic modifications. The effect of dCas9-mediated reversal of withdrawal-induced effects on mPFC physiology, cell morphology, and behavioral symptoms of withdrawal will be measured in a rodent model of AUD and findings will be translated by validating the observed changes in postmortem mPFC from individuals with and without AUD. Results from these experiments will provide new insight into the neurobiological mechanisms underlying AUD and have the potential to uncover new targets for the development of pharmacotherapeutics aimed at treating symptoms of withdrawal in individuals with AUD.