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

Alcohol Clin Exp Res. 2020 Feb;44(2):470-478. doi: 10.1111/acer.14259. Epub 2020 Jan 25.


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.

Keywords: Brain Gene Expression; Cortex; Cynomolgus Macaque; EtOH.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Drinking / genetics*
  • Alcohol Drinking / metabolism*
  • Animals
  • Ethanol / administration & dosage*
  • Gene Expression
  • Gene Expression Profiling / methods*
  • Macaca fascicularis
  • Male
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiology*
  • Self Administration


  • Ethanol