Abstract
Adolescents primarily consume alcohol in binges, which can be particularly harmful to the developing frontal cortex and increase risk for an adult alcohol use disorder. We conducted a study investigating immediate and long lasting changes to the prefrontal cortex (PFC) transcriptome to determine the molecular mechanisms underlying adult ethanol behavioral sensitivity following binge ethanol in adolescence. DBA/2J mice were orally dosed with 4 g/kg ethanol intermittently from day 29 to 42. Adolescent mice were tested for anxiety-like behavior and ethanol sensitivity using the loss of righting reflex task. As adults, mice were tested for cognitive changes using the novel object recognition task, ethanol-induced anxiolysis and ethanol sensitivity. Adolescent binge ethanol altered ethanol sensitivity in young mice and led to lasting memory deficits in the object recognition test and greater ethanol sensitivity in adulthood. Using genomic profiling of transcripts in the PFC, we found that binge ethanol reduced myelin-related gene expression and altered chromatin modifying genes involved in histone demethylation at H3K9 and H3K36. We hypothesize that ethanol’s actions on histone methylation may be a switch for future transcriptional changes that underlie the behavioral changes lasting into adulthood.
Highlights
Alcohol is the most commonly abused intoxicant among adolescents with 8.7 million underage youth reporting consumption in the past month (Center for Behavioral Health Statistics Quality, 2014)
We investigated the molecular basis for these identified changes by performing genome-wide expression profiling of prefrontal cortex (PFC) during both adolescence and adulthood, and epigenetic studies on global histone methylation
We focus on behavioral responses to acute ethanol because an individual’s level of response to acute ethanol is a well-established predictor of risk for developing alcohol use disorders (AUD) (Schuckit and Smith, 1996)
Summary
Alcohol is the most commonly abused intoxicant among adolescents with 8.7 million underage youth reporting consumption in the past month (Center for Behavioral Health Statistics Quality, 2014). The PFC exerts important top-down or executive control over other brain regions that mediate approach and positively reinforce drug seeking, as well as regions that mediate aversion and negatively reinforce drug seeking (Peters et al, 2009; Koob and Volkow, 2010) Altered connectivity between these structures, or deficits in executive control may lead to loss of control over attention and emotion and can lead to increased engagement in risky behaviors such as binge drinking. Chronic intermittent ethanol during adolescence impaired recognition memory in adulthood (Pascual et al, 2007; Vetreno and Crews, 2015) Together, these data suggest that adolescent ethanol imparts long lasting changes in brain structure and function, regarding PFC and myelin. Our studies identified strikingly different immediate and long-lasting transcriptional responses to adolescent ethanol exposure and implicate alterations in histone methylation in the long-lasting behavioral responses to adolescent ethanol
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