Effect of chronic ethanol consumption in rhesus macaques on the nucleus accumbens core transcriptome.

Abstract

The nucleus accumbens core (NAcc) has been repeatedly demonstrated to be a key component of the circuitry associated with excessive ethanol consumption. Previous studies have illustrated that in a nonhuman primate (NHP) model of chronic ethanol consumption, there is significant epigenetic remodeling of the NAcc. In the current study, RNA-Seq was used to examine genome-wide gene expression in eight each of control, low/binge (LD*), and high/very high (HD*) rhesus macaque drinkers. Using an FDR < 0.05, zero genes were significantly differentially expressed (DE) between LD* and controls, six genes between HD* and LD*, and 734 genes between HD* and controls. Focusing on HD* versus control DE genes, the upregulated genes (N = 366) were enriched in genes with annotations associated with signal recognition particle (SRP)-dependent co-translational protein targeting to membrane (FDR < 3 × 10−59), structural constituent of ribosome (FDR < 3 × 10−47), and ribosomal subunit (FDR < 5 × 10−48). Downregulated genes (N = 363) were enriched in annotations associated with behavior (FDR < 2 × 10−4), membrane organization (FDR < 1 × 10−4), inorganic cation transmembrane transporter activity (FDR < 2 × 10−3), synapse part (FDR < 4 × 10−10), glutamatergic synapse (FDR < 1 × 10−6), and GABAergic synapse (FDR < 6 × 10−4). Ingenuity Pathway Analysis (IPA) revealed that EIF2 signaling and mTOR pathways were significantly upregulated in HD* animals (FDR < 3 × 10−33 and <2 × 10−16, respectively). Overall, the data supported our working hypothesis; excessive consumption would be associated with transcriptional differences in GABA/glutamate-related genes.