A ‘factory reset’ for the brain cures anxiety and drinking behavior

Newswise – Gene editing may be a potential treatment for anxiety and alcohol use disorders in adults who were exposed to heavy drinking as teenagers, according to findings from an animal study published in the journal Science Advances.

The study is published by researchers from the University of Illinois at Chicago who studied the effects of excessive alcohol consumption in early life on health later in life.

In previous research, the UIC team found that heavy drinking in adolescence alters brain chemistry at the Arc gene activator region – for the immediate early gene associated with activity-regulated cytoskeleton – and decreases Arc expression in rodent and human amygdala. This epigenetic reprogramming of the Arc gene in the brain’s emotion and memory center contributes to a predisposition to anxiety and alcohol use disorders in adulthood.

In the new study, the researchers show that this epigenetic reprogramming, which persists throughout life, can in fact be reversed through gene editing.

“Early heavy drinking can have long-lasting and significant effects on the brain and 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. brain, if you will,” said Subhash Pandey, the study’s lead author, an endowed Joseph A. Flaherty professor of psychiatry and director of the Center for Alcohol Research in Epigenetics at UIC.

Pandey and his team used a gene-editing tool called CRISPR-dCas9 in their experiments to manipulate histone acetylation and methylation processes at the Arc gene in adult rat models. These processes make genes more or less accessible for activation.

First, the researchers studied adult rats exposed to alcohol intermittently during their teenage years, corresponding to about 10 to 18 years of age in humans. They observed that when dCas9 was used to promote acetylation, a process that loosens chromatin and allows transcription factors to bind to DNA, Arc gene expression normalized. In addition, indicators of anxiety and alcohol consumption decreased.

Anxiety was measured by behavioral tests, for example by documenting the exploratory activity of rats placed in maze tests, and preference for alcohol was measured by monitoring the amount of liquid consumed when the rats were presented with a choice of two bottles made up of options such as tap water, sugar water and different concentrations of alcohol (3%, 7% and 9%).

In a second model, the researchers studied adult rats without early exposure to alcohol. When the inhibitor dCas9 was used to promote methylation, which constricts chromatin and prevents transcription factors from binding to DNA, Arc expression decreased and indicators of anxiety and alcohol consumption alcohol increased.

“These findings demonstrate that epigenomic editing in the amygdala can ameliorate adult psychopathology following adolescent alcohol exposure,” the authors report.

“Excessive alcohol consumption among adolescents is a serious public health problem, and this study not only helps us better understand what happens in developing brains when exposed to high concentrations of alcohol, but above all gives us hope that one day we will have effective treatments for the complex and multifaceted diseases of anxiety and alcohol use disorders,” said Pandey, who is also a principal investigator at the Jesse Brown VA Medical Center “The fact that this effect was observed bidirectionally validates the importance of the arc activator gene in the amygdala in the epigenetic reprogramming of heavy drinking in adolescents.”

Co-authors of the study, “Targeted epigenomic editing improves adult anxiety and binge drinking after alcohol exposure in adolescentsare John Peyton Bohnsack, Huaibo Zhang, Gabriela Wandling, Donghong He, Evan Kyzar and Amy Lasek, all from UIC.

The research was supported by the National Institute on Alcohol Abuse and Alcoholism (U01AA019971, U24AA024605, P50AA022538, and F32AA027410) and the Department of Veterans Affairs.

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