Researchers led by teams at the Salk Institute and Massachusetts Institute of Technology, have discovered a brain circuit that controls alcohol-drinking behavior in mice. Their studies identified a biomarker that predicted the development of compulsive drinking in the animals, and which could, if the findings translate to humans, become a therapeutic target for alcohol use disorders (AUDs). “I hope this will be a landmark study, as we’ve found (for the first time) a brain circuit that can accurately predict which mice will develop compulsive alcohol drinking weeks before the behavior starts,” said Kay Tye, PhD, a Salk Institute professor in the Systems Neurobiology Laboratory and holder of the Wylie Vale Chair. “This research bridges the gap between circuit analysis and alcohol/addiction research, and provides a first glimpse at how representations of compulsive alcohol drinking develop across time in the brain.”

Tye and colleagues reported their findings in Science, in a paper titled, “A cortical-brainstem circuit predicts and governs compulsive alcohol drinking.”

More than 80% of adults are exposed to alcohol during their lifetime, the authors wrote. While fewer than 30% of people will develop an alcohol use disorder, alcohol is the most commonly abused substance. Excessive alcohol use is linked to more than 200 diseases and is a leading cause of preventable death.

The National Institutes of Health defines alcohol use disorder as a chronic brain disease in which an individual drinks compulsively, often with accompanying negative emotions. “Compulsive alcohol drinking, defined as continued drinking in the face of a negative consequence, is a distinguishing feature of AUDs,” the authors explained, but what isn’t understood is why some people who drink to excess lose the ability to control their alcohol use, despite significant negative health and personal consequences, while others can retain a level of control. Previous research has focused on examining the brain after a drinking disorder develops, but Tye’s team aimed to identify brain circuits that might underpin a predisposition for compulsive drinking, and this hasn’t previously been studied.

Prior research has suggested that changes in the prefrontal cortex (PFC) may contribute to compulsive substance use. “Both preexisting and alcohol-induced changes in PFC function can contribute to maladaptive behaviors including compulsive drinking,” the authors stated. However, studies to date have failed to account for the variety of outcomes that are apparent in the development of compulsive drinking behavior among individuals who drink.

Tye and colleagues developed a binge-induced compulsion task (BICT) to assess how predisposition interacts with experience to produce compulsive drinking in mice. The BICT allowed the researchers to examine alcohol consumption as well as consumption with negative consequences (or punishment), such as a bitter taste added to the alcohol. “The BICT allows for longitudinal assessment of two behavioral outcomes associated with diagnostic criteria for AUDs: alcohol consumption and continued consumption despite negative outcomes,” the investigators stated. Through this series of tests, they observed that the mice could be sorted into three groups: low drinkers (with or without the negative consequence), high drinkers (these animals showed high levels of alcohol drinking, but were sensitive to punishment), and compulsive drinkers with high levels of drinking that persisted even through punishment.

The researchers then used an imaging technique called microendoscopic single-cell resolution calcium imaging to chart the cells and brain regions of interest prior to drinking, during drinking, and after drinking alcohol. They focused on neuronal activity in two regions involved in behavioral control and responding to adverse events: the medial prefrontal cortex and the periaqueductal gray (PAG) matter, respectively. Their imaging studies indicated that the development of compulsive alcohol drinking was related to neural communication patterns between the two brain regions, and that this was a biomarker for predicting future compulsive drinking.

Kay Tye, PhD [Salk Institute]

“Although there were no detectable differences among groups in behavioral performance during initial alcohol exposure, the neural response during initial exposure predicted the future development of compulsive drinking,” the scientists noted. “The proportion of excitatory to inhibitory responses of individual mPFC-dPAG neurons for each animal did not correlate with behavior during pre-binge or binge drinking, but did correlate with post-binge behavior >2 weeks after the neural recordings during initial exposure were collected.” By using optogenetics to switch this brain circuit on and off, the researchers were able to either increase compulsive alcohol drinking or reduce it.

“We identified a cortical-brainstem circuit that serves as both a biomarker and a circuit-specific cellular substrate for the development of compulsive drinking,” they concluded. “We initially sought to understand how the brain is altered by binge drinking to drive compulsive alcohol consumption,” said Cody Siciliano, PhD, assistant professor in the department of pharmacology at Vanderbilt University, and first and co-corresponding author of the Science paper. “In the process, we stumbled across a surprising finding where we were actually able to predict which animals would become compulsive based on neural activity during the very first time they drank.”

This is the “first time we’ve been able to longitudinally image neurons from the beginning of initial alcohol exposure all the way through the development of compulsive binge-drinking patterns,” said Tye. “Now, we can look into the brain and find activity patterns that predict if mice will become compulsive drinkers in the future, before the compulsion develops. We do not know if this brain circuit is specific to alcohol or if the same circuit is involved in multiple different compulsive behaviors such as those related to other substances of abuse or natural rewards, so that is something we need to investigate.”

The scientists plan to sequence these cortical-brainstem neurons with the goal of identifying targets that could be used for therapeutics.

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