Unique Cortical-Brainstem Activity Underlies Compulsive Alcohol Drinking

Post by Lincoln Tracy

What's the science?

A key feature of alcohol use disorders is compulsive drinking—defined as continued drinking regardless of the resulting negative consequences. While most people drink alcohol at some point during their adult life, less than a third develop an alcohol use disorder. But what makes these individuals more vulnerable to compulsive drinking? Scientists currently have a poor understanding of the individual differences in behavior and neural circuitry that drive compulsion. Previous animal studies suggest that the prefrontal cortex, a brain region involved in planning and coordinating our thoughts and actions, plays a crucial role in compulsive behaviors. Prefrontal cortex activity is different in individuals who have consumed alcohol or who have a family history of alcohol use disorders. This week in Science, Siciliano, and colleagues investigated how individual differences in behavior and neural activity in the prefrontal cortex predict the development of compulsive drinking in mice.

How did they do it?

First, the authors took the mice and exposed them to a “binge-induced compulsive task” (BICT), a conditioning task comprising of three different periods. In the first period, the pre-binge, mice had been conditioned to drink from a bottle containing only alcohol. After three days, increasing amounts of the bitter-tasting quinine was added to the alcohol to act as a punishment—or negative consequence—of drinking. In the subsequent 14-day binge drinking period the mice had unlimited access to water and alcohol at certain times. Finally, the post-binge period ran similarly to the pre-binge period, where the mice were presented with alcohol alone for the first three days followed by the alcohol-quinine mix for the next four. Mice were sorted into groups based on their drinking behavior during the post-binge period. Second, the authors compared drinking behavior in the pre-binge period between the newly identified groups. Third, they used cellular-resolution calcium imaging as a proxy for neuronal activity during the BICT to examine whether the activity of the neural connections between the medial prefrontal cortex and the dorsal periaqueductal grey contributed to susceptibility of developing compulsive drinking behaviors. Fourth, they used two different light-sensitive proteins and optic fibers to determine whether mimicking endogenous neuronal activity in this cortical-brainstem pathway could alter drinking behavior. One of the light-sensitive proteins—halorhodopsin—can inhibit cellular activity, while the other light-sensitive protein—channelrhodopsin-2—helps activate cells.

What did they find?

Three groups of mice were identified based on post-binge period drinking behavior: low drinkers (low alcohol intake regardless of if quinine was present or absent), high drinkers (high alcohol intake that ceased when quinine was present), and compulsive drinkers (high alcohol intake even when quinine was present). Second, compulsive drinking mice drank more of the alcohol-quinine mix during the pre-binge drinking period compared to the other two groups. This compulsive drinking behavior was exacerbated after the binge drinking period. Third, the authors observed more inhibitory responses in the neurons connecting the medial prefrontal cortex and the dorsal periaqueductal grey in compulsive drinking mice compared to the low drinking mice. The low drinking mice also exhibited more excitatory neuronal activity between these two brain regions when consuming alcohol. Therefore, the neural response during initial alcohol exposure predicted the future development of compulsive drinking. Finally, they found that inhibiting neuronal activity between the medial prefrontal cortex and the dorsal periaqueductal grey increased quinine intake and that stimulating neuronal activity over the same neurons decreased alcohol intake. The authors concluded that light-induced inhibition prevented punishment signals being sent from the cortex to the brainstem, whereas light-induced stimulation enhanced the punishment.

What's the impact?

This study provides a mechanistic explanation for the individual variance in the susceptibility to compulsive alcohol drinking. These findings are particularly important as this newly discovered cortical-brainstem circuit may help guide efforts in drug discovery to prevent alcohol use disorders. Future research is needed to determine the specific mechanisms underlying the reactivity of this circuit to alcohol.

Siciliano et al. A cortical-brainstem circuit predicts and governs compulsive alcohol drinking. Science (2019). Access the original scientific publication here.