Dataset Information

DNA methylation associated with future risky ethanol use.

ABSTRACT: Alcohol use disorder (AUD) is a highly prevalent, complex, multifactorial and heterogeneous disorder, with 11% and 30% of adults meeting criteria for past-year and lifetime AUD, respectively. Identification of the molecular mechanisms underlying risk for AUD would facilitate effective deployment of personalized interventions. Studies using rhesus monkeys and rats, have demonstrated that individuals with low cognitive flexibility and a predisposition towards habitual behaviors show an increased risk for future heavy drinking. Further, low cognitive flexibility is associated with reduced dorsolateral prefrontal cortex (dlPFC) function in rhesus monkeys. To explore the underlying unique molecular signatures that increase risk for chronic heavy drinking, a genome-wide DNA methylation (DNAm) analysis of the alcohol-naïve dlPFC-A46 biopsy prior to chronic alcohol self-administration was conducted. The DNAm profile provides a molecular snapshot of the alcohol-naïve dlPFC, with mapped genes and associated signaling pathways that vary across individuals. The analysis identified 1,463 differentially methylated regions (DMRs) related to unique genes that were strongly associated with average ethanol intake consumed over 6 months of voluntary self-administration. These findings translate behavioral phenotypes into neural markers of risk for AUD, and hold promise for parallel discoveries in risk for other disorders involving impaired cognitive flexibility.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE293587 | GEO | 2025/04/02

REPOSITORIES: GEO

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Project description:Introduction: There is a high co-occurrence between trauma and stress-related diseases, such the formerly named post-traumatic stress disorder, and alcohol use disorder (AUD). This necessitates an understanding of the physiological and genetic factors contributing to this relationship. Binge drinking is the most common method of alcohol consumption among adolescent males and significantly increases the risk of developing comorbid stressor-related disorders and AUD. In experiments modeling the effects of a single binge-like alcohol exposure in male adolescent mice, we observed a clear deficit in context extinction learning. This exposure led to a significant initial increase in subsequent voluntary drinking on day one, as measured by the every-other-day (EOD) two-bottle choice drinking assay, which normalized thereafter. Methods: For this study we performed an mRNASeq analysis of mice nucleus accumbens (NAc), a region intricately involved in regulating both aversive contextual fear responses and reward, after EOD to profile the differential expression of mRNAs within this region. We also used immunohistochemistry of coronal brain slices to characterize expression of proteins associated with stress-related disorders and molecular alcohol tolerance, such as FKBP5, GSK3ß, and ß-catenin, within the striatum, nucleus accumbens (NAc), hippocampus, and basolateral amygdala (BLA). Results: Comparative mRNA profile analysis reveals significant long-term changes in gene expression induced by binge-like alcohol exposure, even 30 days after the initial exposure. Immunohistochemistry showed a full recovery of previously observed altered levels of target proteins prior to EOD. Conclusions: These findings suggest that the temporal activation of specific gene subsets plays a crucial role in the comorbidity of AUD and stressor-related diseases. Understanding these mechanisms can help develop more effective, integrated treatment approaches to improve outcomes for affected individuals. B13:AD13