Dissecting Brain Networks Underlying Alcohol Binge Drinking Using a Systems Genomics Approach

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.

Effects of Pharmacologically Targeting Neuroimmune Pathways on Alcohol Drinking in Mice Selectively Bred to Drink to Intoxication

“…Starting with a genetically heterogeneous progenitor stock (HS/NPT), selective breeding was carried out to create 2 unique High Drinking in the Dark (HDID‐1, HDID‐2) mouse lines that represent models of genetic risk for binge‐like drinking (Crabbe et al, ; Crabbe et al, ). HDID and HS/NPT mice have been extensively characterized (Barkley‐Levenson and Crabbe, ; Barkley‐Levenson and Crabbe, ; Barkley‐Levenson and Crabbe, ; Barkley‐Levenson and Crabbe, ; Barkley‐Levenson et al, ; Barkley‐Levenson et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Crabbe et al, ; Ferguson et al, ; Ferguson et al, ; Fritz et al, ; Iancu et al, ; Iancu et al, ; Metten et al, ). Of particular relevance to the current studies are the findings that HDID mice exhibit behavioral impairment after DID (Crabbe et al, ), withdrawal after a single binge‐drinking session (Crabbe et al, ), and do not exhibit altered preference for saccharin or avoidance of quinine solutions (Crabbe et al, ) or alcohol clearance rates (Crabbe et al, ).…”

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

“…Furthermore, Ferguson et al (2019) found many changes in brain gene expression between ethanol-naïve HDID-1 and HS/Npt mice, specifically in glutamatergic and GABAergic signaling pathways in the NAc (shell) [59]. The brain regions used in Ferguson et al (2019) represent circuitry well known to be involved in motivated behaviors, as well as alcohol drinking [59]. Hdac4 was identified in selection responsive modules as functionally overrepresented.…”

Effects of Tacrolimus and Other Immune Targeting Compounds on Binge-Like Ethanol Drinking in High Drinking in the Dark Mice

“… 5 Both HDID lines display marked differences in brain gene co-expression patterns compared to HS/NPT. 6 - 8 Compared to HDID-2, HDID-1 are further along in selection and maintain a much greater genetic distance from that of C57BL/6J, of which many of the chosen pharmacotherapies have already been tested. 6 Therefore, the following work caters to the unique genetic diversity of HDID-1.…”