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. 2021 Sep;26(5):e13021.
doi: 10.1111/adb.13021. Epub 2021 May 4.

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

Nicole Walter  1 , Rita Cervera-Juanes  2 , Christina Zheng  3 , Priscila Darakjian  2   4 , Denesa Lockwood  4 , Verginia Cuzon-Carlson  1 , Karina Ray  2 , Suzanne Fei  2 , Don Conrad  2 , Robert Searles  5 , Kathleen Grant  1   4 , Robert Hitzemann  4
Affiliations

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

Nicole Walter et al. Addict Biol. 2021 Sep.

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.

Keywords: chronic ethanol consumption; nonhuman primate; nucleus accumbens core.

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Conflict of interest statement

DISCLOSURE/CONFLICT OF INTEREST

No conflicts are declared.

Figures

FIGURE 1
FIGURE 1
Network representation of three GO-enriched pathways. Genes in (a) and (b) were downregulated while in (c) was upregulated in heavy drinkers as compared with controls. Networks were created using String v11.0. Networks were built using text mining, experiments, databases, and co-expression datasets. The nodes represent proteins encoded by the differentially expressed genes. Edges represent protein–protein interactions. The edge confidence is represented by the thickness of the edge (as shown in the edge confidence description in the figure). Networks are clustered using k-means clustering
FIGURE 2
FIGURE 2
Ingenuity Pathway Analysis observed and predicted impact on mTOR signaling in HD versus control. Red and green indicate observed increased and decreased expression, respectively. Orange and blue indicate predicted activation and inhibition, respectively
FIGURE 3
FIGURE 3
Summary of the gene expression profiles of six genes analyzed by qPCR. The relative expression of ARHGEF7 (a), JAKMIP1 (b), KIRREL3 (c), GRM5 (d), GRM7 (e), and GRIA (f) between controls (ʹC) and heavy/very heavy (HD) drinkers is shown; independent t-test with Bonferroni correction for multiple comparisons, *p < 0.05, **p < 0.01, ****p < 0.0001. Error bars are mean +/− SEM
See this image and copyright information in PMC

References

    1. Cervera-Juanes R, Wilhelm LJ, Park B, Grant KA, Ferguson B. Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking. Alcohol 2017;60:103–113. - PMC - PubMed
    1. Cervera-Juanes R, Wilhelm LJ, Park B, Grant KA, Ferguson B. Alcohol-dose-dependent DNA methylation and expression in the nucleus accumbens identifies coordinated regulation of synaptic genes. Transl Psychiatry 2017;7(1):1–10, e994. - PMC - PubMed
    1. Roberts DC, Koob GF, Klonoff P, Fibiger HC. Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 1980;12(5): 781–787. - PubMed
    1. Joyce EM, Koob GF. Amphetamine-, scopolamine- and caffeine-induced locomotor activity following 6-hydroxydopamine lesions of the mesolimbic dopamine system. Psychopharmacology (Berl) 1981;73 (4):311–313. - PubMed
    1. Wise RA, Bozarth MA. Brain reward circuitry: four circuit elements “wired” in apparent series. Brain Res Bull 1984;12(2):203–208. - PubMed

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