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Dr. Jun Wang in his lab

Researchers discover neural mechanism behind why chronic alcohol use impairs cognitive flexibility

Insights from this study provide a base for developing a therapeutic to improve cognitive flexibility in patients with alcohol use disorder

Excessive alcohol drinking and its related problems have become a grave issue in the United States. Alcohol use disorder (AUD) is a chronic brain disorder that is characterized by the inability to stop drinking despite adverse consequences.

This inability to stop drinking is associated with impaired cognitive flexibility in decision-making, which contributes to compulsive alcohol use. According to a survey conducted in 2019 by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), 14.5 million people ages 12 and older (5.3 percent of this age group) had AUD. Also, approximately 10.5 percent (7.5 million) of U.S. children ages 17 and younger live with a parent with AUD, according to a 2017 study.

Given the prevalence of AUD, researchers are working to understand its mechanisms and ultimately discover new therapeutic strategies to treat the disorder.

Using an animal model, Jun Wang, PhD, associate professor in the Department of Neuroscience and Experimental Therapeutics at the Texas A&M University School of Medicine, and members of his laboratory observed that chronic alcohol intake and withdrawal reduce individuals’ cognitive flexibility. This research was published in the Journal of Clinical Investigation (JCI).

Cognitive flexibility is the mental ability to shift or switch one’s attention and behavior in response to a change in task rules or demands. It’s critical for adaptive and flexible behavior and is an important strategy people use to overcome adversity. For instance, with cognitive flexibility, someone can refuse a drinking invitation before driving his or her car, as drinking and driving may cause serious accidents. Increasing evidence suggests that a brain region called the dorsomedial striatum is involved in cognitive flexibility. In this part of the brain, one type of cell, called a cholinergic interneuron, is a major source of acetylcholine, a chemical that controls cognitive flexibility in response to relevant stimuli. Another brain region, the thalamus, is the relay station in the brain that receives environmental signals and transmits them to other brain regions.

“This decreased behavioral flexibility is mainly due to the reduced thalamic inputs onto dorsomedial striatum cholinergic interneurons caused by chronic alcohol consumption,” Wang said. “By compromising the communication between the thalamus and striatum, chronic alcohol consumption impaired animals’ behavioral flexibility.” In other words, over time, alcohol exposure and withdrawal cause a long-lasting suppression of the communication between the thalamus and the striatum. This lack of communication then causes impaired cognitive flexibility, indicated by the lack of reversal of instrumental learning.

“More importantly, when we selectively increased the transmission between thalamus and dorsomedial striatum cholinergic interneurons using optogenetic tools, we were able to rescue alcohol-induced reversal learning deficits in animals,” Wang added.

Even though this optogenetic method is still far from clinical application, the insights gained from this study provide a base for developing new therapeutic strategies to enhance cognitive flexibility in patients with AUD. “With improved cognitive flexibility, AUD patients are in a better position to stop compulsive alcohol use and make wiser decisions when they are confronted with alcohol drinking and negative consequences,” Wang said.

Media contact: Dee Dee Grays, grays@tamu.edu, 979.436.0611

Gracie Blackwell

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