Dataset Information

Molecular profiles of drinking alcohol to intoxication in C57BL/6J mice.

ABSTRACT: Alcohol addiction develops through a series of stages, and mechanistic studies are needed to understand the transition from initial drug use to sustained controlled alcohol consumption followed by abuse and physical dependence. The focus of this study was to examine the effects of voluntary alcohol consumption on brain gene expression profiles using a mouse model of binge drinking. The main goal was to identify alcohol-responsive genes and functional categories after a single episode of drinking to intoxication.We used a modification of a "Drinking In the Dark" (DID) procedure (Rhodes et al., 2005) that allows mice to experience physiologically relevant amounts of alcohol in a non-stressful environment and also allows for detection of alcohol-sensitive molecular changes in a dose-dependent manner. C57BL/6J male mice were exposed to either 20% ethanol solution or water (single bottle) starting 3 hours after lights off for 4 hours and brains were harvested immediately after the drinking session. cDNA microarrays were used to assess the effects of voluntary drinking on global gene expression in 6 brain regions. We employed three statistical approaches to analyze microarray data.A commonly used approach that applies a strict statistical threshold identified the eight top statistically significant genes whose expression was significantly correlated with blood ethanol concentration (BEC) in one of the brain regions. We then used a systems network approach to examine brain region-specific transcriptomes and identify modules of co-expressed (correlated) genes. In each brain region, we identified alcohol-responsive modules, i.e., modules significantly enriched for genes whose expression was correlated with BEC. A functional over-representation analysis was then applied to examine the organizing principles of alcohol-responsive modules. Genes were clustered into modules according to their roles in different physiological processes, functional groups, and cell types, including blood circulation, signal transduction, cell-cell communication, and striatal neurons. Finally, a meta-analysis across all brain regions suggested a global role of increasing alcohol dose in coordination of brain blood circulation and reaction of astrocytes.This study showed that acute drinking resulted in small but consistent changes in brain gene expression which occurred in a dose-dependent manner. We identified both general and region-specific changes, some of which represent adaptive changes in response to increasing alcohol dose, which may play a role in alcohol-related behaviours, such as tolerance and consumption. Our systems approach allowed us to estimate the functional values of individual genes in the context of their genetic networks and formulate new refined hypotheses. An integrative analysis including other alcohol studies suggested several top candidates for functional validation, including Mt2, Gstm1, Scn4b, Prkcz, and Park7.

SUBMITTER: Mulligan MK

PROVIDER: S-EPMC3066294 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Molecular profiles of drinking alcohol to intoxication in C57BL/6J mice.

Mulligan Megan K MK Rhodes Justin S JS Crabbe John C JC Mayfield R Dayne RD Harris R Adron RA Ponomarev Igor I

Alcoholism, clinical and experimental research 20110111 4

<h4>Background</h4>Alcohol addiction develops through a series of stages, and mechanistic studies are needed to understand the transition from initial drug use to sustained controlled alcohol consumption followed by abuse and physical dependence. The focus of this study was to examine the effects of voluntary alcohol consumption on brain gene expression profiles using a mouse model of binge drinking. The main goal was to identify alcohol-responsive genes and functional categories after a single ...[more]

PMID: 21223303

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Project description:We previously reported that commercially-sourced C57BL/6J (B6) male mice with a history of adult-onset binge-drinking exhibit anxiety-like behavior in early withdrawal, while the negative affective state incubates during protracted withdrawal in adolescent-onset binge-drinking males. As the results of such studies are potentially confounded by age-related differences in reactivity to environmental stress, we employed a 2-bottle-choice DID procedure (20 and 40% alcohol; 20?min habituation to the drinking cage) to examine the effects of binge-drinking on negative affect in male and female, adult and adolescent, B6 mice from our university colony. Unexpectedly, the mice in the initial experiment exhibited very low alcohol intake, with little sign of withdrawal-induced negative affect. This failure to replicate prompted us to examine how the duration of drinking cage habituation, the number of alcohol concentrations presented and the animal source might influence the propensity to binge-drink. Herein, we show that both male and female adult mice from our colony will binge-drink when allowed 45?min to habituate to the drinking cages, irrespective of whether mice are offered a choice between 2, 3 or 4 alcohol concentrations. Further, when drinking under 4-bottle-choice procedures (5, 10, 20 and 40% alcohol), adult-onset binge-drinking females exhibit robust negative affect in early withdrawal akin to that reported previously for adult males; however, the negative affective state persists for at least 30?days into withdrawal. Also unlike males, adolescent-onset binge-drinking females exhibit some signs of negative affect, as well as potentiated alcohol intake, in early withdrawal, which persist into later withdrawal. These latter data suggest that the age-related differences in the temporal patterning of the negative affective state produced by alcohol withdrawal may vary as a function of sex, which may have implications for understanding sex differences in the etiology of affective disorders and alcoholism co-morbidity.

Project description:Prenatal alcohol exposure can result in fetal alcohol spectrum disorders (FASD). Not all women who consume alcohol during pregnancy have children with FASD and studies have shown that genetic factors can play a role in ethanol teratogenesis. We examined gene expression in embryos and placentae from C57BL/6J (B6) and DBA/2J (D2) mice following prenatal alcohol exposure. B6 fetuses are susceptible to morphological malformations following prenatal alcohol exposure while D2 are relatively resistant.Male and female B6 and D2 mice were mated for 2 hours in the morning, producing 4 embryonic genotypes: true-bred B6B6 and D2D2, and reciprocal B6D2 and D2B6. On gestational day 9, dams were intubated with 5.8 g/kg ethanol, an isocaloric amount of maltose dextrin, or nothing. Four hours later, dams were sacrificed and embryos and placentae were harvested. RNA was extracted, labeled and hybridized to Affymetrix Mouse Genome 430 v2 microarray chips. Data were normalized, subjected to analysis of variance and tested for enrichment of gene ontology molecular function and biological process using the Database for Annotation, Visualization and Integrated Discovery (DAVID).Several gene classes were differentially expressed in B6 and D2 regardless of treatment, including genes involved in polysaccharide binding and mitosis. Prenatal alcohol exposure altered expression of a subset of genes, including genes involved in methylation, chromatin remodeling, protein synthesis, and mRNA splicing. Very few genes were differentially expressed between maltose-exposed tissues and tissues that received nothing, so we combined these groups for comparisons with ethanol. While we observed many expression changes specific to B6 following prenatal alcohol exposure, none were specific for D2. Gene classes up- or down-regulated in B6 following prenatal alcohol exposure included genes involved in mRNA splicing, transcription, and translation.Our study identified several classes of genes with altered expression following prenatal alcohol exposure, including many specific for B6, a strain susceptible to ethanol teratogenesis. Lack of strain specific effects in D2 suggests there are few gene expression changes that confer resistance. Future studies will begin to analyze functional significance of the expression changes.

Dataset Information

Molecular profiles of drinking alcohol to intoxication in C57BL/6J mice.

Publications

Molecular profiles of drinking alcohol to intoxication in C57BL/6J mice.

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