Intermittent Ethanol during Adolescence Leads to Lasting Behavioral Changes in Adulthood and Alters Gene Expression and Histone Methylation in the PFC

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.

Binge-Like, Naloxone-Sensitive, Voluntary Ethanol Intake at Adolescence Is Greater Than at Adulthood, but Does Not Exacerbate Subsequent Two-Bottle Choice Drinking

“…Repeated ethanol administration (2.0-4.0 g/kg, once daily for a total of 7-8 administrations) has been shown to impair cognitive performance in the NOR test in rats (Marszalek-Grabska et al, 2018) and in mice (Wolstenholme et al, 2017). Moreover, Marco et al (2017) reported performance deficits in the NOR test, in male and female Wistar rats that selfadministered ethanol (20% in drinking water) four times a week during PDs 28-52.…”

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism

“…Furthermore, using genomic profiling of transcripts in the PFC, a recent study showed that binge EtOH reduced myelin‐related gene expression and altered chromatin modifying genes involved in histone demethylation at H3K9 and H3K36. Thus, EtOH may regulate histone methylation as a switch for regulation of myelin . These are the potential pathways that EtOH exposure during critical periods of development can have long‐lasting effects on neurobehavioral function and could, in part, explain the deficits noted in FASDs, as well as persistent cognitive and behavioral problems related to adolescent binge alcohol exposure.…”

A Novel Neighbor Housing Environment Enhances Social Interaction and Rescues Cognitive Deficits from Social Isolation in Adolescence

“…We used the novel object recognition task to measure prefrontal cortex (PFC)-mediated recognition memory, as previously described [30]. Novel object recognition involved a training and a test phase, separated by a 5-min delay.…”

“…The light-dark (LD) box conflict model for anxiety-like behavior was conducted using a standard commercial open field activity box divided into two equally sized light and dark zones (25.4 × 12.7 × 20.3 cm). Tracking software (Fusion v5.3; Omnitech Electronics Inc.) was used to record movement, as described [30]. Animal position and locomotor activity was monitored by infrared photobeam breaks.…”