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

Laura B. Ferguson, Lingling Zhang, Daniel Kircher, Shi Wang, R. Dayne Mayfield, John C. Crabbe, Richard A. Morrisett, R. Adron Harris, Igor Ponomarev

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2791-2810
Number of pages20
JournalMolecular Neurobiology
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2019

Keywords

  • Binge drinking
  • Gene expression
  • Gene networks
  • HDID mice
  • Transcriptome

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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    Ferguson, L. B., Zhang, L., Kircher, D., Wang, S., Mayfield, R. D., Crabbe, J. C., Morrisett, R. A., Harris, R. A., & Ponomarev, I. (2019). Dissecting Brain Networks Underlying Alcohol Binge Drinking Using a Systems Genomics Approach. Molecular Neurobiology, 56(4), 2791-2810. https://doi.org/10.1007/s12035-018-1252-0