Summary: A network connecting the medial prefrontal cortex and the brainstem plays a central role in the development and expression of compulsive drinking. Activity in this circuit can predict which individuals will progress from binge drinking to compulsive alcohol use.
Source: Vanderbilt University
Overview: Occasional binge drinking is common, yet a substantial subset of people—roughly 30 percent of adults exposed to alcohol—go on to display compulsive drinking despite harmful consequences, a defining feature of alcohol use disorder.
For decades, scientists have asked why alcohol affects people so differently: why can some individuals drink throughout their lives without developing compulsive habits while others rapidly transition to problematic drinking? A new collaborative study by neuroscientists at Vanderbilt University and The Salk Institute provides important answers and a powerful experimental approach to study the shift from moderate to compulsive alcohol consumption.
The study appears in the journal Science.
“Our lab focuses on the neuroscience of addiction and how specific neural activity patterns produce compulsive drug and alcohol use,” said Cody Siciliano, assistant professor of pharmacology and an author on the study. “We began by asking how binge drinking alters the brain to promote compulsive alcohol consumption. Unexpectedly, we found that neural activity recorded during an animal’s first drinking session could predict whether it would later develop compulsive drinking behavior.”
Using a mouse behavioral paradigm the researchers call a “binge-induced compulsion task,” the team recreated a drinking scenario that reveals how predisposition and experience interact to generate compulsive intake. Even when mice received identical access to alcohol, they separated into distinct drinking phenotypes: light drinkers, heavy drinkers, and compulsive binge drinkers—those who continued to consume alcohol despite negative consequences.
The investigators monitored neuronal activity at cellular resolution using calcium imaging with miniature microscopes during each animal’s initial exposure to alcohol. They observed that some cortical neurons projecting to the brainstem became highly active during that first drinking episode, while in other mice these same neurons quieted. Mice whose cortical-brainstem neurons showed stronger activation during the first drinking experience were less likely to develop compulsive drinking later. By contrast, animals with reduced neural activity in this circuit during their first exposure were more likely to become compulsive drinkers.
Crucially, these neural signatures appeared during the very first drinking session—well before compulsive behavior emerged—allowing the team to predict which subjects would later display problematic drinking patterns. Those early activity patterns functioned as a biomarker for vulnerability.
Beyond prediction, the researchers tested causality by manipulating activity in the identified cortical-to-brainstem circuit. Reproducing the activity patterns associated with resilience or vulnerability was sufficient to bidirectionally modulate alcohol consumption, supporting the idea that this specific circuit both forecasts and governs compulsive drinking behavior.
From these results the authors developed a novel behavioral model to chart the progression from binge drinking to compulsive use, and they identified a cortical-brainstem circuit as a cellular platform that underlies that progression. Siciliano and colleagues note that while the model was developed for alcohol use disorder, the framework could extend to other substances and forms of compulsive use.
“We developed this model to study the path to alcohol use disorder, but we plan to apply a similar framework to advance our understanding of compulsive use of other substances.”
Implications: The study provides mechanistic insight into individual variation in vulnerability to compulsive alcohol drinking and suggests a potential neural biomarker for identifying risk. Identifying the neural circuits that both predict and control compulsive drinking opens new avenues for research into targeted interventions and for understanding compulsive behaviors across different substances.
Funding: The research was supported by the National Institutes of Health (F32 MH111216 and RO1-MH102441), the National Institute on Drug Abuse (K99 DA045103), the JPB Foundation, New York Stem Cell Foundation, the NIH Director’s New Innovator Award (DP2-DK102256) and Pioneer Award (DP1-AT009925).
Source:
Vanderbilt University
Media Contacts:
Spencer Turney – Vanderbilt University
Image Source:
The image is credited to Vanderbilt University.
Original Research: Closed access
“A cortical-brainstem circuit predicts and governs compulsive alcohol drinking”. Cody Siciliano et al., Science. doi: 10.1126/science.aay1186.
Abstract (concise): The transition from casual to compulsive alcohol consumption is poorly understood. Longitudinal monitoring in male mice revealed that binge drinking exposes latent individual differences in consumption and propensity for compulsive use. Distinct activity patterns in cortical neurons projecting to the brainstem, present before binge drinking, predicted later compulsivity. Recreating those activity patterns bidirectionally altered drinking behavior. These findings provide a circuit-level mechanism for individual differences in vulnerability to compulsive alcohol drinking.