Epigenomic editing in the cerebral amygdala may ameliorate adult psychopathology after adolescent alcohol exposure. It resets the brain and leaves it as fresh from the factory.
Gene editing may be a potential treatment for anxiety and alcohol use disorder in adults who were exposed to heavy drinking in their teens, according to results of an animal study published in the journal Science Advances.
The study, developed by researchers at the University of Illinois Chicago, has analyzed the effects that binge drinking during youth have on health in later life.
In earlier research, the UIC team found that binge drinking in adolescence alter brain chemistry in the enhancer region of the Arc gene: it decreases its gene expression in the amygdala, both in rodents and in humans.
The Arc gene codes for a protein that plays a vital role in synaptic plasticity, a biological process that allows the brain to change and adapt to new information.
Epigenetic reprogramming of the Arc gene in the amygdala, which is the center of emotions and memory in the brain, caused by excessive alcohol consumption in youth, contributes to a predisposition to anxiety and alcoholism in adulthood , as established by the previous investigation.
In the new study, the researchers show that this epigenetic reprogramming, which persists throughout life, actually can be reversed with gene editing.
Gene editing is a type of genetic engineering in which the direct manipulation, modification or alteration of a DNA sequence in the genome of a cell or organism is carried out, either by deleting, inserting or replacing some sequence of interest in its genotype.
“Early binge 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 reset so that the brain is fresh.” factory, so to speak,” explains the lead author of the study, Subhash Pandey.
Pandey and his team used a gene-editing tool called CRISPR-dCas9 in their experiments with adult rats to manipulate the acetylation and methylation processes of basic proteins called histones present in the Arc gene. These processes make genes more or less accessible for activation.
The researchers first studied adult rats with intermittent alcohol exposure in their teens, which roughly corresponds to the age of 10 to 18 years in humans.
They found 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. And that the indicators of anxiety and alcohol consumption decreased.
Anxiety was measured through behavioral tests, such as by documenting the exploratory activity of rats placed in maze tests.
Alcohol preference was measured by monitoring the amount of fluid consumed when rats were presented with a choice of two bottles, consisting 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 alcohol exposure. When the inhibitor dCas9 was used to promote methylation, which hardens chromatin and prevents transcription factors from binding to DNA, Arc expression decreased and indicators of anxiety and alcohol consumption increased.
“These results show that the epigenomic editing in the amygdala may ameliorate adult psychopathology after adolescent alcohol exposure,” the authors report.
“Adolescent binge drinkers represent a serious public health concern, and this study not only helps us better understand what happens in developing brains when 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,” says Pandey,
He concludes: “That this effect can be reversed validates the importance of the Arc enhancer gene in the amygdala for epigenetic reprogramming of excessive alcohol consumption in adolescents.”
Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure. John Peyton Bohnsack et al. Science Advances, 4 May 2022; Vol 8, Issue 18. DOI: 10.1126/sciadv.abn2748