Sometimes the brain takes a loss and changes course. A new study in mice suggests one chemical, the neurotransmitter acetylcholine, helps drive that switch.
The findings point to a role for acetylcholine in behavioral flexibility, and could help researchers better understand conditions linked to the neurotransmitter, including addiction, obsessive-compulsive disorder and schizophrenia.
“Acetylcholine levels are often altered in treatments for neuropsychiatric disorders like Parkinson’s disease or schizophrenia,” co-author and neurobiologist Jeffery Wickens from the Okinawa Institute of Science and Technology said. “So understanding the function of this neurotransmitter is essential in treating many neuropsychiatric disorders.”
The researchers examined how mice responded when a familiar path to a reward suddenly stopped working.
They trained mice to move through a virtual maze and gave them time to learn the route to rewards before changing it. When the mice repeated the strategy that had previously worked, they no longer got the reward they expected.
Using two-photon microscopy and a genetically encoded acetylcholine sensor, the researchers tracked brain activity before and after the switch.
“Neurally, we saw a significant increase in acetylcholine release in certain areas of the brain,” first author Gideon Sarpong, a neuroscientist at OIST, said. “And behaviorally, we saw more mice displaying what’s known as ‘lose-shift’ behavior, changing their choices in the maze after non-reward.”
The study found that the stronger the acetylcholine response, the more likely the mice were to try a different option next time.
“The greater the increase in acetylcholine, the more likely the mice were to change their future choices,” Sarpong said. “Our results demonstrated the importance of acetylcholine in breaking habits and enabling new choices.”
The team then inhibited acetylcholine production in some mice. Those mice showed more rigid behavior and were less likely to try new tactics after their usual approach failed.
Wickens said earlier research had already linked acetylcholine-releasing brain cells to flexible behavior.
“Previous work has indicated that cholinergic interneurons, brain cells that release a neurotransmitter called acetylcholine, are involved in enabling behavioral flexibility,” he said. “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 researchers also found the response was not uniform across all of those cells. While most of a mouse’s cholinergic interneurons increased acetylcholine release after the reward changed, some groups showed little reaction or reduced activity.
“This indicates the mice may not necessarily forget the previous pathway to reward, but retain this information in case the situation changes again,” Sarpong said.
The researchers said behavioral flexibility involves many interactions across brain regions and systems, and acetylcholine is only one part of that process.
“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,” Wickens said.
The study was published in Nature Communications.
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