Gene Expression in the Human Alcoholic Brain

Project Summary/Abstract We and others have provided evidence that changes in brain function are caused by neuroadaptations throughout the addiction cycle. Large-scale DNA and RNA sequencing, bioinformatics, and computational approaches have greatly advanced addiction neurobiology. Our newly proposed research will use single cell RNA sequencing to define the transcriptome in human alcoholic and CIE-exposed mouse brain in unprecedented detail. In addition to the similar alcohol-responsive expression changes found in alcoholics and CIE-treated mice, CIE vapor produces escalations in voluntary drinking and is a well-established animal model of alcohol dependence. CIE as well as chronic voluntary consumption models also induce neurobiological and behavioral adaptations in mice that mimic those found in human alcoholics. Unlike whole tissue sequencing, the single cell approach is much more sensitive and prevents dilution of cell-specific expression changes. This proposal will provide the first single cell resolution of convergent genes in human and mouse brain that are associated with alcohol dependence and escalation in drinking. High-priority genes will be functionally validated in mice, and new computational approaches based on integrated single cell-transcriptomic data will then be used to predict and test drugs for efficacy to reduce drinking in mice. Our overarching hypothesis is that conserved cell-type-induced transcriptome changes will reveal specific neurobiological mechanisms and improved drug targets for excessive alcohol drinking. Integrated data from mouse and human brain enhance our ability to predict pathways and drugs with translational relevance in humans.