Dataset Information

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

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.

SUBMITTER: Bogenpohl JW

PROVIDER: S-EPMC6701453 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Bogenpohl James W JW Smith Maren L ML Farris Sean P SP Dumur Catherine I CI Lopez Marcelo F MF Becker Howard C HC Grant Kathleen A KA Miles Michael F MF

Frontiers in molecular neuroscience 20190813

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 tar ...[more]

PMID: 31456662

Similar Datasets

Project description: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 nonhuman 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 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.

Project description:Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. There is growing evidence that glucocorticoids might also modulate behavioral responses to ethanol ( EtOH ). Acute EtOH activates the hypothalamic-pituitary-adrenal axis, causing the release of adrenal glucocorticoid hormones. Our prior genomic studies suggest that glucocorticoids play a role in regulating gene expression in the prefrontal cortex (PFC) of DBA2/J (D2) mice following acute EtOH administration. However, few studies have analyzed the role of glucocorticoid signaling in behavioral responses to acute EtOH . Such work could be significant, given the predictive value for the level of response to acute EtOH in the risk for alcoholism.We studied whether the glucocorticoid receptor (GR) antagonist, RU-486, or adrenalectomy (ADX) altered male D2 mouse behavioral responses to acute (locomotor activation, anxiolysis, or loss-of-righting reflex [LORR]) or repeated (sensitization) EtOH treatment. Whole-genome microarray analysis and bioinformatics approaches were used to identify PFC candidate genes possibly responsible for altered behavioral responses to EtOH following ADX.ADX and RU-486 both impaired acute EtOH (2 g/kg)-induced locomotor activation in D2 mice without affecting basal locomotor activity. However, neither ADX nor RU-486 altered the initiation of EtOH sensitization (locomotor activation or jump counts), EtOH -induced anxiolysis, or LORR. ADX mice showed microarray gene expression changes in PFC that significantly overlapped with acute EtOH -responsive gene sets derived by our prior microarray studies. Q-rtPCR analysis verified that ADX decreased PFC expression of Fkbp5 while significantly increasing Gpr6 expression. In addition, high-dose RU-486 pretreatment blunted EtOH -induced Fkbp5 expression.Our studies suggest that EtOH 's activation of adrenal glucocorticoid release and subsequent GR activation may partially modulate EtOH 's acute locomotor activation in male D2 mice. Furthermore, because adrenal glucocorticoid basal tone regulated PFC gene expression, including a significant set of acute EtOH -responsive genes, this suggests that glucocorticoid-regulated PFC gene expression may be an important factor modulating acute behavioral responses to EtOH .

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets