Adolescent alcohol exposure is a well-known, major public health problem affecting a large number of youths during a particularly critical moment of cognitive and psychological development. Characterizing its effects and potentially reversing any damage caused is therefore of significant clinical interest.
“Adolescent binge drinking is dangerous and has long-term epigenetic effects on the brain,” notes Dr. Subhash Pandey, director of the UIC Center for Alcohol Research in Epigenetics and senior scientist at the Jesse Brown VA Medical Center. “Understanding this mechanism helps us get one step closer to understanding how those effects happen and how we can potentially undo that damage.”
His team’s recently published study sheds some light on this epigenetic mechanism, using adolescent rats and advanced molecular biology methods to provide clarity on how heavy drinking during adolescence affects gene expression over the course of a lifetime.
From previous UIC research, Dr. Pandey was already aware that heavy alcohol consumption during adolescence correlated with epigenetic alterations to a brain protein called BDNF, which can hinder brain development.
But what specific molecular mechanisms are at play? The answer to this question opens the door for potential intervention, while also explaining how lasting changes to gene expression could be made without the genetic code itself being directly altered.
While several types of epigenetic regulation mechanisms exist, Dr. Pandey chose to focus on the function of microRNA (miRNA). These small, noncoding pieces of RNA have recently emerged as playing a critical role in altering RNA levels—and thus affecting gene expression without changing the genetic sequence itself. In turn, miRNA expression itself can be regulated epigenetically, such as through DNA methylation and histone modification.
microRNA-137 (miR-137) is known to be important for normal neurodevelopment, directly affecting epigenetic enzymes like lysine-specific demethylase 1 (LSD1). Previous studies had implicated this miRNA in adolescent intermittent ethanol (AIE) exposure-induced anxiety as well as epigenetic changes in adult amygdalas. It followed, then, that Dr. Pandey and his team should examine the effects of adolescent binge drinking on miR-137 levels.
Adolescent rates were given either ethanol or saline solutions at fixed doses for two days on, two days off. Once they became adults, the researchers compared the rats’ behavior, miRNA expression, and epigenetic changes in amygdala tissue samples. Across the samples from the rats who had “binge-drank alcohol” in their adolescence, researchers found increased levels of miR-137 and decreased expression of Lsd1 target genes in the amygdalas. They also noted higher anxiety-like behavior akin to AIE anxiety and susceptibility to ongoing high alcohol consumption.
“By altering microRNA-137 levels, binge drinking actually rewires the brain,” says Dr. Pandey. Fortunately, the researchers’ findings didn’t stop there, at characterization of miR-137 levels and their effects on anxiety and alcohol consumption. The team went on to start laying the groundwork for potential intervention.
Researchers were then able to rescue rats from these changes—or effectively undo them—by infusing these rats with a small, synthetic miR-137 called antagomir, which is complementary to the miRNA and interferes with its activity. This antagomir was successful and Lsd1 expression was restored, along with healthy downstream effects. This finding is significant because it means that miR-137 could be used as a molecular therapeutic target to reverse some negative effects of adolescent binge drinking; and even though the adolescent epigenetic changes leading to the altered adult behavior persistent over time, they are by no means fixed and permanent.
Further characterization of miR-137 levels is needed, particularly in humans, before the development and testing of interventions can begin. But in individuals known to have consumed large amounts of alcohol as an adolescent, miR-137 could potentially be bound up using some sort of molecular intervention and its harmful downstream effects—from molecular through behavioral changes—could thus be stopped.
Source: Pandey S et. al. (2019) MicroRNA-137 Drives Epigenetic Reprogramming in the Adult Amygdala and Behavioral Changes after Adolescent Alcohol Exposure eNeuro 6:6
Reference: University of Illinois at Chicago “Mechanism connects early binge drinking to adult behaviors.” UIC Today. 18 Nov. 2019