For the first time researchers demonstrate in an animal how heavy alcohol use leads to long-term behavioral issues by damaging brain circuits critical for decision-making.
Rats exposed to high amounts of alcohol exhibited poor decision-making during a complex task even after a monthslong withdrawal period. Key areas of their brains had undergone dramatic functional changes compared to healthy rats.
The findings, published today in Science Advances, provide a new explanation of alcohol's long-term effects on cognition.
"We now have a new model for the unfortunate cognitive changes that humans with alcohol use disorder show," said author Patricia Janak , a Johns Hopkins University neuroscientist who studies the biology of addiction. "We know that humans who are addicted to alcohol can show deficits in learning and decision-making that may contribute to their poor decisions related to alcohol use. We needed an animal model to better understand how chronic alcohol abuse affects the brain. Knowing what is happening in the brain of an animal when they are having these decision-making difficulties will tell us what is happening in humans."
In experiments led by first author Yifeng Cheng, a research scientist in Janak's lab who studies alcohol's effects on the brain, rats recieved very high alcohol exposure for a month. Then after a withdrawal period of nearly three months, the rats were given a reward-based decision-making test along with a control group of rats that had not been exposed to alcohol.
To get a reward, rats were given a choice of two levers. Pressing one lever led to a higher likelihood of reward than pressing the other lever. Rats easily learn which lever results in the most reward, so the researchers complicated things by every few minutes switching which lever had the highest reward likelihood. To get the most reward, a rat should rapidly change its behavior every time it figures out that the reward likelihood has changed.
It was a difficult task that required memory and strategy. The alcohol-exposed rats performed considerably worse.
Previous experiments in animals weren't comparable to humans with alcohol use disorder because the animals didn't demonstrate deficits in rapid decision-making. The team believes this was because tasks in earlier experiments were too easy.
"Our experiment was quite challenging and the alcohol-exposed rats just couldn't do it as well," Janak said. "When the right answer was constantly changing, the control rats made the best decisions faster. They were more strategic. And when we looked at their brains, the control rats' decision-related neural signals were stronger."
The team linked the behavioral difficulties to dramatic functional transformations in the dorsomedial striatum, a part of the brain critical for decision-making. The alcohol had damaged neural circuits causing alcohol-exposed rats to process information less effectively.
One surprise was how long alcohol dependence impairs cognition and neural function, even after withdrawal.
"This may give us insight into why relapse rates for people addicted to alcohol are so high," Janak said. "Alcohol-induced neural deficits may contribute to decisions to drink even after going to rehab. We can clearly demonstrate these deficits can be long-lasting."
The team only found the behavioral and neural impairments only in male rats. The team does not believe this suggests female rats are immune from the effects of alcohol, but that there could be sex-related sensitivities in long-term alcohol effects on brain function.
The researchers next hope to explore how alcoholism affects other areas of the brain that interact with the dorsomedial striatum, and what might be causing the differences between males and females.
Additional authors include Robin Magnard, a postdoctoral fellow at Johns Hopkins; Angela J. Langdon of the National Institutes of Health; and Daeyeol Lee, a Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences at Johns Hopkins.
