Chronic Voluntary Ethanol Drinking in Cynomolgus Macaques Elicits Gene Expression Changes in Prefrontal Cortical Area 46

• Published in: Alcoholism, clinical and experimental research Vol. 44; no. 2; pp. 470 - 478
• Main Authors: Walter, Nicole A. R., Zheng, Christina L., Searles, Robert P., McWeeney, Shannon K., Grant, Kathleen A., Hitzemann, Robert
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.02.2020
• Subjects: Alcohol Drinking - genetics; Alcohol Drinking - metabolism; Animals; Brain Gene Expression; Cortex; Cynomolgus Macaque; Ethanol - administration & dosage; EtOH; Gene Expression; Gene Expression Profiling - methods; Macaca fascicularis; Male; Neuroscience; Original; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; Self Administration; Brain Gene Expression; EtOH; Cynomolgus Macaque; Cortex
• ISSN: 0145-6008; 1530-0277; 1530-0277
• DOI: 10.1111/acer.14259

Background Genome‐wide profiling to examine brain transcriptional features associated with excessive ethanol (EtOH) consumption has been applied to a variety of species including rodents, nonhuman primates (NHPs), and humans. However, these data were obtained from cross‐sectional samples which are particularly vulnerable to individual variation when obtained from small outbred populations typical of human and NHP studies. In the current study, a novel within‐subject design was used to examine the effects of voluntary EtOH consumption on prefrontal cortex (PFC) gene expression in a NHP model. Methods Two cohorts of cynomolgus macaques (n = 23) underwent a schedule‐induced polydipsia procedure to establish EtOH self‐administration followed by 6 months of daily open access to EtOH (4% w/v) and water. Individual daily EtOH intakes ranged from an average of 0.7 to 3.7 g/kg/d. Dorsal lateral PFC area 46 (A46) brain biopsies were collected in EtOH‐naïve and control monkeys; contralateral A46 biopsies were collected from the same monkeys following the 6 months of fluid consumption. Gene expression changes were assessed using RNA‐Seq paired analysis, which allowed for correction of individual baseline differences in gene expression. Results A total of 675 genes were significantly down‐regulated following EtOH consumption; these were functionally enriched for immune response, cell adhesion, plasma membrane, and extracellular matrix. A total of 567 genes that were up‐regulated following EtOH consumption were enriched in microRNA target sites and included target sites associated with Toll‐like receptor pathways. The differentially expressed genes were also significantly enriched in transcription factor binding sites. Conclusions The data presented here are the first to use a longitudinal biopsy strategy to examine how chronic EtOH consumption affects gene expression in the primate PFC. Prominent effects were seen in both cell adhesion and neuroimmune pathways; the latter contained both pro‐ and antiinflammatory genes. The data also indicate that changes in miRNAs and transcription factors may be important epigenetic regulators of EtOH consumption. Walter et al. used a unique within subject design to detect changes in the brain prefrontal cortex transcriptome associated with chronic ethanol exposure in non‐human primates. The data obtained showed that broad categories of genes were affected, especially those associated with neuro‐immune function, cell adhesion and the extracellular matrix. The data suggest that chronic ethanol exposure has marked functional and structural effects on the prefrontal cortex.