Imagine being able to undo some of the bad mistakes we made in our youth, like drinking too much. It’s been well reported that excessive alcohol consumption in adolescents can lead to serious health problems later on in life. Anxiety and continued alcohol dependence are two issues that often result from underage alcohol exposure, and both are difficult to treat.
Now scientists in the field of epigenetics are finding that it may be possible to reverse some of the damage caused by underage alcohol abuse. Working with newer genetic editing techniques, like the CRISPR-Cas9 system, researchers from the University of Illinois Chicago (UIC) have demonstrated that epigenetic dysregulation, specifically histone acetylation and methylation, can be manipulated to alter certain mental disorders that arise from improper alcohol exposure in adolescence. Their findings are available online in the journal Science Advances.
“Early binge drinking can have long-lasting and significant effects on the brain, says senior author and UIC professor Subhash Pandey. “The results of this study offer evidence that gene editing is a potential antidote to these effects, offering a kind of factory reset for the brain.”
Several studies have shown that alcohol abuse alters brain chemistry during juvenile development. In particular, the Arc gene, a main regulator of synaptic plasticity in the amygdala, is sensitive to alcohol exposure during this development time.
In a prior investigation, the UIC researchers established that this gene undergoes repressive epigenetic remodeling at its enhancer region, SARE, after adolescent alcohol exposure. The amygdala is the emotion and memory center of the brain, and disruption in Arc expression increases adult predisposition to anxiety and alcohol use disorder (AUC).
In the current study, the team sought to modify the Arc-SARE site using a CRISPR-dCas9 strategy to target the epigenetic alterations at this distinct genomic location in the nucleus of the amygdala. Using rodent models similar in age to human adolescence (approx. 10 – 18), they directly altered the brain region’s histone acetylation and methylation levels, which are the mechanisms responsible for making a gene accessible for activation.
The first group examined were adult rats exposed to intermittent binge levels of alcohol during adolescence. Pandey and his team observed that when dCas9 was used to increase histone acetylation to promote accessibility, the expression of the Arc gene normalized. In addition, the behaviors indicating anxiety and alcohol abuse were decreased.
Anxiety and alcohol consumption were measured by monitoring and documenting the rats’ behavior in both maze and exploratory tests as well as their preference for alcohol.
Adult rats not exposed to early alcohol consumption were examined in a second group. Using an inhibiting version of dCas9, the team noted that histone methylation levels increased, which reduced DNA accessibility and thus lowered Arc expression.
As a result, the rats showed signs of increased anxiety and alcohol consumption.
The overall results of the study prove that epigenetic editing in the amygdala section of the brain can lessen adult psychopathology in an animal model after binge drinking episodes in adolescence. Because the CRISPR-Cas9 system is easier to use and more precise than other genomic editing techniques, the authors suggest that further studies using dCas9 could lead to better therapies for adult anxiety and alcohol abuse, as well as aid in our understanding of the epigenetic changes that occur from environmental exposure to alcohol during juvenal development.
“Adolescent binge drinking is a serious public health issue, and this study not only helps us better understand what happens in developing brains when they are exposed to high concentrations of alcohol but more importantly gives us hope that one day we will have effective treatments for the complex and multifaceted diseases of anxiety and alcohol use disorder,” said Pandey. “That this effect was seen bidirectionally validates the significance of the Arc enhancer gene in the amygdala in epigenetic reprogramming from adolescent binge drinking.”
Source: J. P. W. Bohnsack, et al. Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure. Science Advances, 2022; 8 (18).
Reference: A ‘factory reset’ for the brain cures anxiety, drinking behavior. University of Illinois Chicago, May 4, 2022.