Abstract
Alcohol use disorder (AUD) is a complex psychiatric disorder with strong genetic and environmental risk factors. We studied the molecular perturbations underlying risky drinking behavior by measuring transcriptome changes across the neurocircuitry of addiction in a genetic mouse model of binge drinking. Sixteen generations of selective breeding for high blood alcohol levels after a binge drinking session produced global changes in brain gene expression in alcohol-naïve High Drinking in the Dark (HDID-1) mice. Using gene expression profiles to generate circuit-level hypotheses, we developed a systems approach that integrated regulation of gene coexpression networks across multiple brain regions, neuron-specific transcriptional signatures, and knowledgebase analytics. Whole-cell, voltage-clamp recordings from nucleus accumbens shell neurons projecting to the ventral tegmental area showed differential ethanol-induced plasticity in HDID-1 and control mice and provided support for one of the hypotheses. There were similarities in gene networks between HDID-1 mouse brains and postmortem brains of human alcoholics, suggesting that some gene expression patterns associated with high alcohol consumption are conserved across species. This study demonstrated the value of gene networks for data integration across biological modalities and species to study mechanisms of disease.
Highlights
Binge drinking is a dangerous pattern of alcohol drinking that produces blood alcohol levels (BALs) of 0.08 g/dL or higher [1]
We investigated the effects of genetic selection on genome-wide gene expression in seven brain areas implicated in regulating alcohol consumption [prefrontal cortex (PFC), nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), bed nucleus of the stria terminalis (BNST), basolateral amygdala (BLA), central nucleus of the amygdala (CeA), and ventral tegmental area (VTA)]
Differential expression analysis showed that genetic selection for high BALs produced global changes in brain gene expression, with 4,122 genes differing between HDID-1 and HS/Npt mice in at least one brain region (Table 1; full differential expression results are reported in Table S1 in Online Resource 2)
Summary
Binge drinking is a dangerous pattern of alcohol (ethanol) drinking that produces blood alcohol levels (BALs) of 0.08 g/dL or higher [1]. Binge drinking increases the risk of developing alcohol use disorder (AUD) and poses serious. Investigating the biological basis of binge drinking will help guide the development or repurposing of suitable interventions to reduce this hazardous behavior. High Drinking in the Dark (HDID-1) mice are selectively bred from the HS/Npt stock to drink consistently to BALs of 0.1 g/dL or greater in the DID behavioral test, a procedure used to model binge-like drinking in which ethanol is available for a limited time during the circadian dark cycle [5, 6]. A review by Crabbe and colleagues provides detailed discussion of DID and other preclinical models of binge drinking [7]
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