Throughout the decades after birth when the brain develops and matures, it is highly sensitive and responsive to the external environment. Binge drinking during adolescence reprograms brain chemistry and increases the likelihood of mental health issues later in life.

Specifically, alcohol exposure during adolescence reprograms the epigenome at an enhancer region called SARE (synaptic activity response element) that regulates the expression of a gene called Arc (activity-regulated cytoskeleton-associated protein). This decreases Arc expression in both rodent and human amygdala, a region of the brain important in regulating emotional behaviors. How epigenomic changes at Arc SARE, upon adolescent exposure to alcohol, results in anxiety and drinking disorders in adulthood is unclear.

A new study on animal models by researchers from the University of Illinois Chicago published in the journal Science Advances (“Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure“) suggests gene editing may treat anxiety and alcohol use disorder in adults who were exposed to binge drinking in their adolescence.

Subhash Pandey, PhD, a professor of psychiatry and director of the alcohol research center at the University of Illinois, is the senior author of the study.

The team, led by Subhash Pandey, PhD, a professor of psychiatry and director of the alcohol research center at the University of Illinois, has been investigating the effects of early-life binge drinking on health later in life. In earlier work they found that binge drinking in adolescence alters epigenetic programming at the enhancer region of the Arc gene and decreases Arc expression in the amygdala in rodents and humans, predisposing them to anxiety and alcohol use disorder in adulthood.

In the current study, the researchers showed that this epigenetic reprogramming due to alcohol exposure in adolescence, which persists throughout life, can be reversed using CRISPR/Cas9 mediated gene editing in rat models.

Pandey said, “Early binge drinking can have long-lasting and significant effects on the brain. 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.”

Pandey’s team used CRISPR-dCas9 to manipulate the histone acetylation and methylation processes at the Arc gene in rats, to increase or decrease Arc gene expression, respectively. The use of the dCas9 system avoids off-target effects since DNA is not cut and therefore is not subject to error-prone nonhomologous recombination.

Targeted acetylation of histone proteins at Arc SARE using dCas9-P300, the investigators showed, increases Arc expression to normal levels and prevents adulthood anxiety and alcohol abuse in a rat model exposed to alcohol during adolescence.

The researchers studied adult rats with intermittent alcohol exposure in their adolescence, corresponding to about age 10 to 18 in human years. They observed when dCas9 was used to promote acetylation, a process that loosens chromatin and allows transcription factors to bind to the DNA, Arc gene expression normalized, and indicators of anxiety and alcohol consumption decreased in adulthood.

On the other hand, targeted increases in repressive histone methylation at the ArcSARE using dCas9-KRAB decreases Arc expression in the amygdala in normal control rats without early alcohol exposure. Methylation tightens chromatin and prevents transcription factors from binding to DNA, thereby decreasing gene expression. Decreased Arc expression increases anxiety and alcohol drinking behavior in the control rats.

The authors concluded, “Epigenomic editing in the amygdala can ameliorate adult psychopathology after adolescent alcohol exposure.”

“Adolescent binge drinking is a serious public health issue. 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.”

Increased anxiety was measured through decreased exploratory activity of rats 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 bottles containing tap water, sugar water, and varying concentrations of alcohol.

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