Disappointment alters brain chemistry and behavior

From work meetings to first dates, it’s essential to adjust our behavior for success. In certain situations, it can even be a matter of life or death. So how do we switch our behavior when situations change? Published in Nature Communications, neuroscientists from the Okinawa Institute of Science and Technology (OIST) describe the neural basis of behavioral flexibility in mice, with insights which may help us understand a wide variety of diseases and disorders, from addiction to obsessive compulsive disorder (OCD) to Parkinson’s disease. 

“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,” explains co-author Professor Jeffery Wickens, head of the Neurobiology Research Unit at OIST. “Previous work has indicated that cholinergic interneurons—brain cells that release a neurotransmitter called acetylcholine—are involved 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 chemical signals of disappointment 

In their investigations, the researchers trained mice in a virtual maze, teaching them the correct route to receive a reward. They then switched the route, leading to an unexpected loss of reward for the mice, and observed the effects of this disappointing change using two-photon microscopy. 

“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,” says Dr. Gideon Sarpong, first author on the study. “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 confirm their findings, the researchers inhibited acetylcholine production. They saw a significant drop in lose-shift behavior, proving the essential role of this neurotransmitter in behavioral adaptation. 

Whilst the majority of cholinergic interneurons produced more acetylcholine, some small regions of cells showed a decrease or no change. The researchers believe this could be a method to preserve previous information on the correct pathways. “This indicates that the mice may not necessarily forget the previous pathway to reward, but retain this information in case the situation changes again,” says Dr. Sarpong. 

Understanding neurological disorders 

Whilst the study presents a leap forward in understanding behavioral flexibility, the researchers emphasize that this research is just one part of a wider picture. Other brain regions, cells and neurotransmitters are involved in a complex multi-component system. “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,” emphasizes Prof. Wickens. 

Beyond fundamental understanding of the neuroscience of behavior, the researchers hope these findings can inform medicine and healthcare. “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,” says Prof. Wickens. “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.”