Cross-Species Co-analysis of Prefrontal Cortex Chronic Ethanol Transcriptome Responses in Mice and Monkeys.

James W Bogenpohl,Marcelo F Lopez,Catherine I Dumur,Maren L Smith,Sean P Farris,Michael F Miles,Kathleen A Grant,Kathleen A Grant,Howard C Becker

doi:10.3389/fnmol.2019.00197

Abstract

Despite recent extensive genomic and genetic studies on behavioral responses to ethanol, relatively few new therapeutic targets for the treatment of alcohol use disorder have been validated. Here, we describe a cross-species genomic approach focused on identifying gene networks associated with chronic ethanol consumption. To identify brain mechanisms underlying a chronic ethanol consumption phenotype highly relevant to human alcohol use disorder, and to elucidate potential future therapeutic targets, we conducted a genomic study in a non-human primate model of chronic open-access ethanol consumption. Microarray analysis of RNA expression in anterior cingulate and subgenual cortices from rhesus macaques was performed across multiple cohorts of animals. Gene networks correlating with ethanol consumption or showing enrichment for ethanol-regulated genes were identified, as were major ethanol-related hub genes within these networks. A subsequent consensus module analysis was used to co-analyze monkey data with expression data from a chronic intermittent ethanol vapor-exposure and consumption model in C57BL/6J mice. Ethanol-related gene networks conserved between primates and rodents were enriched for genes involved in discrete biological functions, including; myelination, synaptic transmission, chromatin modification, Golgi apparatus function, translation, cellular respiration, and RNA processing. The myelin-related network, in particular, showed strong correlations with ethanol consumption behavior and displayed marked network reorganization between control and ethanol-drinking animals. Further bioinformatics analysis revealed that these networks also showed highly significant overlap with other ethanol-regulated gene sets. Altogether, these studies provide robust primate and rodent cross-species validation of gene networks associated with chronic ethanol consumption. Our results also suggest potential novel focal points for future therapeutic interventions in alcohol use disorder.

Highlights

Alcohol abuse and dependence, clinically defined as “alcohol exposure to ethanol consumption, we identified brain genomeuse disorder (AUD),” represents a serious public health wide expression changes using microarray analysis of anterior problem in the United States and worldwide
Results for gene networks related to ethanol consumption, we Alcohol use disorder (AUD) is strongly influenced by genetic performed a cross-species analysis of the rhesus data with a factors, and recent findings suggest that many genes of small chronic exposure model in mice (Becker and Lopez, 2004; Smith effect size likely contribute to alcohol-related phenotypes (Kerns et al, 2016; van der Vaart et al, 2017)
Our results identify several novel gene expression networks significantly associated with alcoholism, mostly genes involved in correlating with chronic ethanol consumption in rhesus alcohol metabolism (Zuo et al, 2014; Hart and Kranzler, 2015). macaques

Summary

Introduction

Clinically defined as “alcohol exposure to ethanol consumption, we identified brain genomeuse disorder (AUD),” represents a serious public health wide expression changes using microarray analysis of anterior problem in the United States and worldwide. Results for gene networks related to ethanol consumption, we Alcohol use disorder (AUD) is strongly influenced by genetic performed a cross-species analysis of the rhesus data with a factors, and recent findings suggest that many genes of small chronic exposure model in mice (Becker and Lopez, 2004; Smith effect size likely contribute to alcohol-related phenotypes (Kerns et al, 2016; van der Vaart et al, 2017). Such an analysis could et al, 2005; Mulligan et al, 2006; Tabakoff et al, 2008; Wolen provide independent confirmation of networks identified in a et al, 2012). Human genome-wide association single species and prioritize targets for future mechanistic studies

Results

Discussion

Conclusion