Gene editing resets rat brains to cure anxiety disorders and alcoholism

Watching Fear and Loathing in Las Vegas (now streaming on Peacock) with its frenetic pace, bizarre performances, and twisted cinematography is a visual experience akin to falling into a drug binge, and that’s by design. The movie is constructed to give the feeling of living inside the minds of its two protagonists as they consume every illicit substance known to humanity, while supposedly on a work trip in Las Vegas. The result is an anxiety-laden two hours capturing a glimpse inside the mind of author Hunter S. Thompson.

While the movie has a certain amount of humor at the expense of its characters, driven mostly by the bombastic performances of Johnny Depp and Benicio del Toro, real-world substance dependence offers little to laugh about.

Long-term exposure to substances like alcohol, especially during adolescence — not to mention the hard stuff found in the fictional Thompson’s drug stash — causes epigenetic changes to a person’s brain chemistry which leads to dependence and anxiety disorders. According to a new study, gene editing by way of a modified version of CRISPR Cas9, might be able to reverse those changes in the brain.

Subhas Pandey from the Center for Alcohol Research in Epigenetics at the University of Illinois was the senior author of the study, now published in the journal Science Advances, which sought to reverse the negative effects of alcohol dependence in the brains of rats and, hopefully someday, in humans.

“Adolescent binge drinking is a major public health concern, and it produces long lasting impacts on brain chemistry. So, it’s really important to catch the disease early and cure it before someone predisposes to substance abuse disorder, anxiety, and depression,” Pandey told SYFY WIRE.

The research targeted the enhancer region of the activity-regulated cytoskeleton-associated protein, ARC for short, which is suppressed when individuals are exposed to chronic alcohol use in adolescence. According to Pandey, ARC is important for making connections between neurons so they can communicate with one another, and plays an important role in synaptic plasticity, learning, and memory. When it’s suppressed, alcohol consumption and anxiety behaviors increase.

Researchers used a modified version of CRISPER Cas9, known as dCAS9, which causes a functional change in a target gene without clipping it out. In this case, that meant researchers were able to increase ARC expression to undo the epigenetic damage caused by alcohol exposure.

In tests, rats were given alcohol between the 27^th and 41^st days of life, the equivalent of ages 10 to 18 in humans, which led to anxiety and increased alcohol consumption when the rats grew to adulthood. Then, they injected dCas9 into the amygdala to increase ARC expression. The process takes two weeks to go into full effect, but the results were impressive. Symptoms of anxiety as well as alcohol consumption decreased. The evidence suggests the relationship between gene expression and alcoholism or anxiety also holds for adults without early exposure to alcohol.

“In a previous study, we found that chronic alcohol exposure in adulthood also leads to a reduction in the expression of this gene and causes anxiety-like behavior. In adult control animals, who are normal, if we do gene editing to suppress the expression of the ARC gene, they become anxious and start drinking more. So, it looks like this phenomenon is also important in adults,” Pandey said.

Understanding the genetic and epigenetic drivers of anxiety and alcohol disorders, as well as gene editing strategies to address them, could lead researchers to novel therapies.

“There are drugs which can manipulate this gene, but they may also affect several places in the brain, so we might get side effects because other genes are affected. Targeted manipulation of the gene, I personally feel, is the future of the medicine,” Pandey said.

Hunter S. Thompson somehow straddled the line between brilliance and complete collapse, at least for a while. He was one of a kind, it’s unlikely there will ever be another like him. Especially now that gene editing can flip the off switch on our inner demons.