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On the Relationships in Rhesus Macaques between Chronic Ethanol Consumption and the Brain Transcriptome (Central Nucleus of the Amigdala - CeA)

ABSTRACT: This is the first description of the effects of chronic ethanol consumption on the brain transcriptome in a non-human primate (rhesus macaque). Thirty male animals self-administered ethanol on a daily basis for over 12 months. Gene expression was measured with RNA-Seq in the central nucleus of the amygdala (CeA). Genes negatively correlated with consumption were enriched in functional annotations associated with translation and included clusters of ribosomal and mitochondrial ribosomal proteins. Genes positively correlated with consumption were enriched in membrane annotations including neuron and synapse part. Genes in the latter category included Ctnna2, Shank1, Vamp2, and Syn1. Gene-level expression data were clustered using the Weighted Gene Coexpression Network Analysis (WGCNA) algorithm to identify hub nodes affected by excessive consumption. Key hubs included Nf1, Nkain2, Tmem108 and Penk. The data were also analyzed for alternative exon usage (Iancu et al., 2015). Additional translation and membrane related genes affected by excessive consumption were detected. These included Grm2, Dpysl2 and Kcnc4. Overall, the data illustrate that the effects of excessive ethanol consumption are broad, consistent with the observation that ethanol affects the expression of numerous hub genes.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE84332 | GEO | 2017/01/13

SECONDARY ACCESSION(S): PRJNA328925

REPOSITORIES: GEO

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Project description:Purpose: Genetic factors significantly affect alcohol consumption and vulnerability to withdrawal. Some genetic models that show predisposition to severe withdrawal are also predisposed to low ethanol consumption and vice versa, even when tested independently in naïve animals. The study was undertaken to understand gene and network differences between mice selectively bred for high withdrawal/low withdrawal or low withdrawal/high consumption. Methods: Beginning with a C57BL/6J×DBA/2J F2 intercross founder population, animals were simultaneously selectively bred for both high alcohol consumption and low acute withdrawal (SOT line), or vice versa (NOT line). Using randomly chosen fourth selected generation (S4) mice (N= 18-22/sex/line), RNA-Seq was employed to assess genome-wide gene expression in the ventral striatum. The Mega-MUGA array was used to detect genome-wide genotypic differences. Differential gene expression and the weighted gene co-expression network analysis (WGCNA) were implemented. Results: The new selection of the SOT and NOT lines was similar to that reported previously (Metten et al. 2014). One thousand eight hundred and fifteen transcripts were detected as being differentially expressed between the lines. For the genes overexpressed in the SOT line there was enrichment in genes associated with cell adhesion, synapse organization and post-synaptic membrane. The genes with a cell adhesion annotation included 23 protocadherins, Mpdz & Dlg2. Genes with a postsynaptic membrane annotation included Gabrb3, Gphn, Grid1, Grin2b, Grin2c & Grm3. The genes overexpressed in the NOT line were enriched in a network module (red) with annotations associated with mitochondrial function. Several of these genes were module hub nodes and these included Nedd8, Guk1, Elof1, Ndufa8, & Atp6v1f. Conclusions: Marked effects of selection on gene expression were detected. The NOT line was characterized by the increased expression of hub nodes associated with mitochondrial function. Genes overexpressed in the SOT aligned with previous findings e.g. Colville et al. (2017) that high ethanol preference and consumption is associated with effects on cell adhesion and glutamate synaptic plasticity.

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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On the Relationships in Rhesus Macaques between Chronic Ethanol Consumption and the Brain Transcriptome (Central Nucleus of the Amigdala - CeA)

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