Gene (mRNA) expression profiling in frontal cortex of ethanol-treated mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50427 | GEO | 2014/08/24
SECONDARY ACCESSION(S): PRJNA217473
REPOSITORIES: GEO
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Project description:Analysis of early stages of alcohol dependence at the gene expression level. The hypothesis tested in the present study was that ethanol-treatment impact gene expression in a mouse model of high ethanol consumption. Results provide important information of genes and pathways being affected by ethanol actions in the mouse frontal cortex. Total RNA obtained from frontal cortex from mice treated with 20% ethanol solution for 20 days. Control group is composed of untreated animals. Frontal cortex (FCtx) tissue was dissected to produce a 2-mm coronal section from the most rostral portion of the mouse brain devoid of olfactory bulbs (coordinates Bregma +1.56 to +3.56). The dorsal part of this coronal section, cut immediately above the forceps minor of the corpus callosum as the anatomical landmark, was used for RNA extraction. This section of the cortex is mostly composed of frontal associated cortex (FrA), cingulate cortex area 1 (Cg1), prelimbic cortex (PrL), and primary (M1) and secondary (M2) motor cortices, as depicted in the mouse brain atlas (Franklin and Paxinos 2007). Samples from both alcohol-treated and control groups were always included in each batch of extracted RNA. Total RNA was extracted using the mirVanaM-BM-. miRNA Isolation kit (Ambion, Austin, TX) according to the manufacturerM-bM-^@M-^Ys instructions. Yield and quality of the total RNA preparation was determined using the Agilent 2100 Bioanalyzer (Agilent, Palo Alto, CA). For mRNA expression profiling, biotin-labeled cRNA was prepared using Illumina TotalPrep RNA Amplification kit (Ambion, Austin, TX) and then hybridized to Illumina MouseRef-8 v2.0 Expression BeadChips (Illumina, San Diego, CA). The quality of the Illumina bead summary data was assessed using the Bioconductor packages Lumi and arrayQualityMetrics. Data preprocessing included variance stabilization and quantile normalization using the Lumi package. Statistical analysis comparing ethanol-treated and control groups was performed using the Bioconductor package limma, which implements an empirical Bayes approach in R (Smyth 2005). False discovery rate (FDR) was assessed using the Benjamini-Hochberg method.
2014-08-24 | E-GEOD-50427 | biostudies-arrayexpress
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.
2019-09-03 | GSE134546 | GEO
Project description:Transcriptional study to investigate differences in prefrontal cortex and striatum of mice that consumed ethanol despite negative consequences, which resembles the compulsive aspect of alcohol addiction. The transcriptional analysis performed in the striatum and prefrontal cortex revealed genes and biological pathways differentially regulated specifically in animals of the group Inflexible Drinkers that could be involved with the loss of control over voluntary ethanol consumption (da Silva E Silva et al., 2016; de Paiva Lima et al., 2017).
2018-11-30 | GSE123114 | GEO
Project description:Moderate alcohol consumption during pregnancy can result in a heterogeneous range of neurobehavioural and cognitive effects, termed fetal alcohol spectrum disorders (FASD). We have developed a mouse moder of FASD that involves moderate ethanol exposure throughout gestation achieved by voluntary maternal consumption. This model results in phenotypes relevant to FASD. Since ethanol is known to directly affect the expression of genes in the developing brain leading to abnormal cell death, changes to cell proliferation, migration, and differentiation, and potential changes to epigenetic patterning, we hypothesize that this leaves a long-term footprint on the adult brain. However, the long-term effects of prenatal ethanol exposure on brain gene expression, when behavioural phenotypes are apparent, are unclear. We used two independent microarray experiments and focused on the genes identified by both to evaluate the genome-wide alterations to the adult brain transcriptome caused by prenatal ethanol exposure via moderate maternal drinking.
2011-12-10 | GSE34305 | GEO
Project description:Mitochondrial dysfunction is one of many key factors in the etiology of alcoholic liver disease (ALD). Lysine acetylation is known to regulate numerous mitochondrial metabolic pathways and recent reports demonstrate that alcohol-induced protein acylation negatively impacts these processes. To identify regulatory mechanisms attributed to alcohol-induced protein post-translational modifications, we employed a model of alcohol consumption within the context of wild type (WT), sirtuin 3 knockout (SIRT3 KO), and sirtuin 5 knockout(SIRT5 KO) mice to manipulate hepatic mitochondrial protein acylation. Mitochondrial fractions were examined by label-free quantitative HPLC-MS/MS to reveal competition between lysine acetylation and succinylation. A class of proteins defined as “differential acyl switching proteins” demonstrate select sensitivity to alcohol-induced protein acylation. A number of these proteins reveal saturated lysine-site occupancy, suggesting a significant level of differential stoichiometry in the setting of ethanol consumption. We hypothesize that ethanol downregulates numerous mitochondrial metabolic pathways through differential acyl switching proteins.
2019-01-23 | PXD012089 | Pride
Project description:Purpose: Alcohol dependence results in microglia proliferation in brain and changes in microglia morphology and function. However, it remains unknown if microglia initiate or simply amplify the neuroadaptations that lead to alcohol dependence. Here we determined microglia function in chronic intermittent ethanol exposure behaviors using a colony stimulating factor 1 receptor inhibitor (PLX5622) and 3’UTR biased-sequencing. Therefore, the purpose of this study was to provide insight into how microglia may regulate neuroadaptations due to alcohol dependence. Methods: We performed 3’UTR biased transcriptome sequencing (3’Tag-seq) on total homogenate isolated from the prefrontal cortex (PFC) and central nucleus of the amygdala (CeA) of C57BL6/J mice following microglia depletion and chronic intermittent ethanol exposure. Results: Differential expression analysis and WGCNA network analysis revealed that microglia depletion prevents both immune and synaptic gene expression changes that are linked with the formation of alcohol dependence. This suggested that microglia are key regulators of the transition from alcohol misuse to alcohol dependence. Conclusion: Taken together our behavioral and transcriptional data indicate that microglia are the primary effector cell responsible for regulation of alcohol dependence. In addition, our data represents a novel resource for groups interested in transcriptional effects of microglia depletion after alcohol dependence.
2020-11-27 | GSE142571 | GEO
Project description:Lasting behavioral and physiological changes such as abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to these brain adaptations leading to ethanol toxicity and abuse. Here we employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has previously been shown to induce progressive ethanol consumption in rodents. Brain regional expression networks contributing to CIE-induced behavioral changes were identified by microarray analysis across five brain regions in the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-120 hours following the last cycle of CIE. Weighted Gene Correlated Network Analysis (WGCNA) was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis of CIE vs. air-treated controls showed that long-lasting gene regulation occurred 5-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC) and hippocampus. In the majority of brain-regions, however, ethanol regulated gene expression changes occurred only immediately following CIE or within the first 8-hours of removal from ethanol. Bioinformatics analysis of modules identified by WGCNA showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC). In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Strikingly, bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a complex temporal and regional pattern of widespread gene network responses involving neuroinflammatory and neuroplasticity related genes as contributing to physiological and behavioral responses to chronic ethanol. In particular, our identification of a potential role for Let-7 miRNAs and a Bdnf-related expression network in long-lasting expression changes after CIE may lead to future druggable gene target identification for novel intervention in AUD.
2016-04-15 | GSE72507 | GEO
Project description:Moderate alcohol exposure during pregnancy can result in a heterogeneous range of neurobehavioural and cognitive effects, termed fetal alcohol spectrum disorders (FASD). We have developed a mouse model of FASD that involves moderate ethanol exposure throughout gestation achieved by voluntary maternal consumption. This model results in phenotypes relevant to FASD. Since ethanol is known to directly affect the expression of genes in the developing brain leading to abnormal cell death, changes to cell proliferation, migration, and differentiation, and potential changes to epigenetic patterning, we hypothesize that this leaves a long-term footprint on the adult brain. However, the long-term effects of prenatal ethanol exposure on brain gene expression, when behavioural phenotypes are apparent, are unclear. We used a microarray experiment and focused on the genes identified by both to evaluate the genome-wide alterations to the adult brain transcriptome caused by prenatal ethanol exposure.
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Project description:The prefrontal cortex is a crucial regulator of escalation of alcohol drinking, dependence, and other behavioral criteria associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms mediating the escalation of alcohol use and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) on ~150,000 single nuclei from the medial prefrontal cortex (mPFC) obtained from C57BL/6J mice exposed to the chronic intermittent ethanol exposure (CIE) paradigm which models phenotypes associated with alcohol dependence. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Here, we present a comprehensive atlas of cell-type specific alcohol dependence related gene expression changes in the mPFC.
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