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Gene editing ‘factory reset’ the brain to treat anxiety and binge drinking

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A recent animal study showed that gene editing reverses the genetic reprogramming of the brain caused by binge drinking in adolescents.

Gene editing reverses the genetic reprogramming of the brain caused by binge eating in adolescents.

Gene editing may be a potential treatment for anxiety and alcohol use disorder in adults who were exposed to binge drinking as a teenager, according to the results of an animal study published May 4, 2022 in the journal. science progress.

This study was released by researchers from the University of Illinois at Chicago (UIC) who were studying the effects of binge drinking in early life on health later in life.

In previous research, the UIC team found that excessive alcohol intake in adolescence alters brain chemistry in an enhancer region of the Arc gene—the immediate early cytoskeletal associated protein activity-regulated gene—and reduces Arc expression in the amygdala of both rodents and humans. Epigenetic reprogramming of the Sagittarius gene in the emotion and memory center of the brain contributes to predisposition to anxiety and alcohol use disorder in adulthood.

In the new research, the scientists show that this epigenetic reprogramming, which continues throughout life, can in fact be reversed through gene editing.

“Excessive drinking early can have significant long-term effects on the brain, and the results of this study provide evidence that gene modification is a potential antidote to these effects, providing a kind of factory reset for the brain, if you will.” Study lead author Subhash Pandey, Professor of Psychiatry Joseph A. Flaherty and director of the Center for Alcohol Research in Epigenetics at the University of California.

Pandey and his team used a gene-editing tool called CRISPR-dCas9 in their experiments to manipulate histone acetylation and methylation processes in the Arch gene in adult mouse models. These processes make genes more or less operable.

First, the researchers studied adult mice with intermittent exposure to alcohol in their adolescence, which corresponds to about 10 to 18 years in human years. They note that when dCas9 is used to enhance acetylation, a process that loosens chromatin and allows transcription factors to bind to[{” attribute=””>DNA, Arc gene expression normalized. And, indicators of anxiety and alcohol consumption decreased.

Anxiety was measured through behavioral testing, such as 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 consisting of options such as tap water, sugar water, and varying concentrations of alcohol (3%, 7%, and 9%).

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

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

“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, who is also a senior research career scientist at Jesse Brown VA Medical Center. “That this effect was seen bidirectionally validates the significance of the Arc enhancer gene in the amygdala in epigenetic reprogramming from adolescent binge drinking.”

Reference: “Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure” by John Peyton Bohnsack, Huaibo Zhang, Gabriela M. Wandling, Donghong He, Evan J. Kyzar, Amy W. Lasek and Subhash C. Pandey, 4 May 2022, Science Advances.
DOI: 10.1126/sciadv.abn2748

Co-authors of the study, “Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure,” are John Peyton Bohnsack, Huaibo Zhang, Gabriela Wandling, Donghong He, Evan Kyzar and Amy Lasek, all of 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.