Neuroscientists at the Okinawa Institute of Science and Technology (OIST) have identified neural mechanisms involved in behavioral flexibility in mice, according to a study published in Nature Communications. The research may contribute to understanding conditions such as addiction, obsessive-compulsive disorder (OCD), and Parkinson's disease.
Professor Jeffery Wickens, head of the Neurobiology Research Unit at OIST and co-author of the study, explained, "The brain mechanisms behind changing behaviors have remained elusive, because adapting to a given scenario is very neurologically complex. It requires interconnected activity across multiple areas of the brain." He added that earlier studies had suggested cholinergic interneurons—brain cells that release acetylcholine—play a role in enabling behavioral flexibility. "Here, we were able to use advanced imaging techniques to see neurotransmitter release in real time and delve into the fundamental mechanisms behind behavioral flexibility."
The team trained mice to navigate a virtual maze for rewards. After switching the correct route unexpectedly, they observed how the mice responded using two-photon microscopy. Dr. Gideon Sarpong, first author on the study, said: "Neurally, we saw a significant increase in acetylcholine release in certain areas of the brain. And behaviorally, we saw more mice displaying what's known as 'lose-shift' behavior-changing their choices in the maze after non-reward. The greater the increase in acetylcholine the more likely the mice were to change their future choices. Our results demonstrated the importance of acetylcholine in breaking habits and enabling new choices to be made."
To test these findings further, researchers inhibited acetylcholine production and noted a drop in lose-shift behavior among mice. This supported their conclusion about acetylcholine's essential role in adaptation.
While most cholinergic interneurons increased acetylcholine production during these tasks, some regions showed little or no change. Dr. Sarpong commented: "This indicates that the mice may not necessarily forget the previous pathway to reward, but retain this information in case the situation changes again."
Professor Wickens noted that while this research provides important insight into one aspect of behavioral flexibility—specifically within striatal cholinergic interneurons—it is part of a broader network involving various brain regions and neurotransmitters. "But it's an important piece of the puzzle, as the activity of the striatum, where these cholinergic interneurons are held, is a central component of this system," he said.
Looking ahead, researchers hope these findings will inform approaches for treating neuropsychiatric disorders where habit-breaking is impaired or neurotransmitter levels are altered. Professor Wickens stated: "Acetylcholine levels are often altered in treatments for neuropsychiatric disorders like Parkinson's disease or schizophrenia, so understanding the function of this neurotransmitter is essential in treating many neuropsychiatric disorders. In particular, with conditions such as addiction and obsessive-compulsive disorder we see a difficulty in breaking habits and shifting behavior. So, understanding the mechanics of behavioral flexibility may one day help us develop better treatments."
