More than 15 million people worldwide struggle with alcohol use disorder, a chronic relapsing condition that can have severe consequences on a person’s physical, emotional, and mental wellbeing. Despite its prevalence, few effective medications to treat alcohol addiction exist, and the risk of relapse after seeking treatment can be up to 90 percent within four years.
Now, a May 4 Science Advances study finds that editing epigenetic markers on a noncoding, regulatory region of the genome diminished both alcohol-seeking and anxious behaviors in rats exposed to binge drinking early in life. While the technology is far from being able to treat alcohol use disorder in people, the University of Illinois at Chicago researchers say the discovery could pave the way for future therapies.
“The paper is awesome,” Elizabeth Heller, an addiction neuroscientist at the University of Pennsylvania who was not involved in the study, tells The Scientist. “It is clearly exciting for everyone because this implies that we could have some sort of therapeutic for alcohol addiction.”
Targeting the alcoholic epigenome
Studies have found that binge drinking in adolescence can increase the likelihood of alcohol addiction, anxiety, depression, and a host of other debilitating mental health issues in adulthood. Researchers have also linked chronic alcohol exposure during brain development to profound, long-term epigenetic changes in the brain, providing a possible mechanistic explanation for lasting behavioral effects of early alcohol abuse.
In previous work, the authors of the new study found that binge drinking in adolescence alters the epigenome, specifically at an enhancer region for the gene Arc (activity-regulated cytoskeleton-associated protein), which amplifies production of the Arc gene. The Arc gene codes for the Arc protein, a key regulator of synaptic plasticity.
“Arc plays a very important role in the regulation of dendritic spines and synapses . . . [and] synaptic communication,” says study coauthor Subhash Pandey, a neuroscientist at the University of Illinois. Previously, he and his coauthors associated decreased Arc expression with a predisposition for alcohol use disorder and anxiety in adulthood.
The team had found that alcohol use early in life caused modifications to the gene’s enhancer region that led to reduced Arc expression in the amygdala—the emotion-processing center of the brain—of rats. They'd also found reduced Arc expression in post-mortem samples of brain tissue taken from people with alcohol use disorder who began drinking at an early age.
The researchers wanted to test if they could reverse these changes using epigenomic editing. So, they employed the CRISPR-dCas9 system. Like its widely used sister system CRISPR-Cas9, CRISPR-dCas9 targets a single gene, but instead of snipping and modifying the DNA sequence, it modifies how tightly chromatin is condensed at a particular gene region by acetylating histones and other transcription-related proteins, changing the ease with which transcription-boosting activator proteins can access the genetic sequence.
In one experiment, the researchers exposed some rats to alcohol intermittently from the 27th to 41st days of their lives (ages that roughly correspond to 10- to 18-year-old humans). Typically, rats with this degree of alcohol exposure display increased alcohol use in adulthood. After a period of abstinence, the study authors delivered CRISPR gene editing therapy via a viral vector to the rats’ amygdalas. Finally, they tested the rats, as well as age-matched controls, that weren’t exposed to alchohol for alcohol dependence by measuring how often rats drank alcohol instead of water when given the choice. They also tested the rats’ anxiety levels by placing them in a maze, half of which was shrouded in darkness, and measuring the total time they spent in the light. More anxious rats tend to prefer the perceived safety of the dark side, Pandey says, and explore less.
After treatment, the researchers observed that Arc expression levels returned to pre-alcohol exposure baselines. But even more strikingly, says Pandey, the adult rats showed less anxiety-like behavior and their alcohol consumption decreased. Conversely, when the researchers injected mice with no history of alcohol consumption with an epigenome-altering system that increased histone methylation and reduced Arc expression, the animals exhibited an increase in both anxiety-like behaviors and alcohol consumption.
“When we saw the effect on the behavioral phenotype, that was the exciting moment for us,” he says.
“Epigenetics is a hot topic right now,” in addiction research, says Elena Martin Garcia, a neuroscientist at the University of Pompeau Fabra in Barcelona who studies food addiction and wasn’t involved in the current work. She says that a lot of studies have shown that epigenetics are involved in addiction, but “not a lot of studies show a mechanism that they validate,” as this study does.
Pandey and colleagues acknowledge that the exact pathways by which epigenetic regulation of Arc affects addiction-related behaviors remain mysterious. Arc is an immediate early gene, they explain, meaning its expression or lack thereof affects the expression of other genes, so further research is needed to untangle and describe its cascading effects to more precisely identify the molecular underpinnings of addiction behaviors.
Heller says that while a lot of work needs to be done before a CRISPR-based treatment could be approved for people, citing hurdles such as therapy delivery and potential off target effects of epigenetic therapies. The fact that the authors delivered the CRISPR-based treatment in adulthood is particularly encouraging, given the fact that most people that struggle with chronic alcohol addiction starting in adolescence seek treatment as adults, and few treatment options exist. “It’s incredible how little investment there is, and how few [therapies] are in the pipeline,” she says.
While potential therapeutics are developed, she adds, “we need to destigmatize [addiction].”