Cross-species co-analysis of prefrontal cortex chronic ethanol transcriptome responses in mice and monkeys
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PROVIDER: PRJNA555563 | ENA |
REPOSITORIES: ENA
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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.
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Project description:Fyn kinase has been implicated in multiple behavioral responses to ethanol and in the regulation of myelin gene expression. Here we tested whether Fyn kinase modulated basal or ethanol-responsive expression of genes regulated by acute ethanol in brain regions of the mesolimbocortical dopamine pathway. Using expression profiling, we sought to define Fyn-dependent gene networks underlying ethanol behavioral traits; with emphasis on ethanol-induced loss of righting reflex (LORR) due to the reproducible association of Fyn kinase genotype with this behavioral phenotype (Miyakawa et al., 1997, Boehm et al., 2003, Yaka et al., 2003, Boehm et al., 2004b). Our expression profiling and bioinformatics results suggest multiple Fyn-related mechanisms, especially those affecting a network of myelin-related gene expression within the medial PFC, as contributing to the sedative-hypnotic properties of ethanol. Variation in the expression of these Fyn-dependent gene networks may be critical molecular endophenotypes affecting the behavioral level of response to acute ethanol, and subsequently, the long-term risk for alcohol use disorders. Adult male control (B6129SF2/J) and Fyn-kinase null (B6;129S7-Fyntm1Sor/J) mice were treated with saline or ethanol (3.0 g/kg x 4 hours) and brain regions harvested by microdissection for total RNA expression profiling by Affymetrix microarrays. Samples were randomly assigned to batch groups prior to total RNA extraction, cRNA synthesis and hybridization. Each microarray represents a pooling of 3 animals and 3 arrays were analyzed per treatment group for a total of 12 arrays per brain region. Statistical and bioinformatics analysis was used to identify Fyn-dependent effects on basal and ethanol-responsive gene expression, with a particular focus on myelin-related gene expression. This series of samples includes medial prefrontal cortex (PFC).
2014-08-31 | E-GEOD-49028 | 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 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.
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Project description:Animal models provide opportunity to study neurobiological aspects of human alcoholism. Changes in gene expression have been implicated in mediating brain function, including reward system and addiction. The current study aimed to identify novel genes that may underlie ethanol preference. Microarray analysis comparing gene expression in nucleus accumbens (NAc), hippocampus (HP) and prefrontal medial cortex (mPFC) was performed in two rat strains selected for extreme levels of ethanol preference - Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP). The identified candidate genes may underlie differential ethanol preference in rat model of alcoholism. This is analysis of 18 RNA samples, including 9 technical replicates. Two strains of rats selected for extreme levels of ethanol preference (low preferring WLP and high preferring WHP) were compared. Three brain areas (nucleus accumbens, prefrontal medial cortex and hippocampus) were studied. For each brain area, 6 RNA samples (including 3 technical replicates) were analyzed. Each RNA sample consist of of equal amounts of total RNA from 3 male rats. Comparisons: Nucleus accumbens of WHP vs. Nucleus accumbens of WLP; Prefrontal medial cortex of WHP vs. Prefrontal medial cortex of WLP; Hippocampus of WHP vs. Hippocampus of WLP. 3 biological replicates in each comparison.
2015-01-17 | E-GEOD-65064 | biostudies-arrayexpress
Project description:In order to elucidate the molecular mechanisms underlying individual variation in sensitivity to ethanol we profiled the prefrontal cortex transcriptomes of two inbred strains that exhibit divergent responses to acute ethanol, the C57BL6/J (B6) and DBA/2J (D2) strains, as well as 27 members of the BXD recombinant inbred panel, which was derived from a B6 x D2 cross. With this dataset we were able to identify several gene co-expression networks that were robustly altered by acute ethanol across the BXD panel. These ethanol-responsive gene-enriched networks were heavily populated by genes regulating synaptic transmission and neuroplasticity, and showed strong genetic linkage to discreet chromosomal loci. Network-based measurements of node importance identified several hub genes as established regulators of ethanol response phenotypes, while other hubs represent novel candidate modulators of ethanol responses. Animals were injected intraperitoneally (IP) with saline or 1.8 g/kg of ethanol. As part of a parallel study of ethanol induced anxiolysis, all mice underwent behavioral testing that included 15 minutes of restraint in a 50 mL conical tube followed by 10 minutes in a light-dark chamber. Mice were killed by cervical dislocation four hours following IP injection. Immediately thereafter, brains were extracted and chilled for 1 minute in iced phosphate buffer before being microdissected into 8 constituent regions, including the medial prefrontal cortex. Samples were randomly assigned to batch groups prior to total RNA extraction, cRNA synthesis and hybridization. Each microarray represent a pooling of 4-5 animals.
2011-12-01 | E-GEOD-28515 | biostudies-arrayexpress
Project description:The prefrontal cortex is greatly associated with a wide range of mental health illnesses including schizophrenia, depression, bipolar disorder, anxiety and autism spectrum disorders. It richly expresses neuroreceptors which are the target for typical and atypical antipsychotics. However as the precise mechanism of action of antipsychotic medications are not known, proteomic studies of the effects of antipsychotic drugs on the brain are warranted. In the current study we aimed to characterise protein expression in the adult rodent prefrontal cortex (n=5 per group) following low dose treatment with the atypical antipsychotic Risperidone or saline (control) in adolescence (postnatal days 34-47). The prefrontal cortex was examined by triplicate one hour runs of label-free LC-MS/MS. The raw mass spectral data were analyzed with the MaxQuantTM software. Statistical analysis was carried out using SAS Version 9.1. Functional and pathway analysis was performed with DAVID.nih and Ingenuity Pathway Analysis respectively and the top five most implicated pathways were found to be clathrin mediated endocytosis, the tri cyclic acid cycle, remodelling of epithelial junctions, rho family GTPase signalling and mitochondrial dysfunction.This brief report summarises the proteomic data obtained from the study described, adds to the current repertoire of data available concerning the effects of atypical antipsychotic drugs on the brain and sheds light on their biological mechanisms.
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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.
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