A burst of the neurotransmitter acetylcholine in a key brain region helped mice abandon a previously rewarded choice after an expected reward failed to appear, according to a study that mapped chemical signals in the striatum during reversal learning.
Researchers at the Okinawa Institute of Science and Technology (OIST) trained mice to navigate a virtual-reality Y-maze in which choosing one arm produced a reward. When the reward contingency was reversed without warning, mice that selected the formerly rewarded arm experienced an unexpected non-reward—an outcome the team linked to a rise in acetylcholine activity across the dorsal striatum. Using a genetically encoded acetylcholine sensor and two-photon imaging, the researchers reported that rewarded outcomes were associated with brief decreases in acetylcholine signals, while unexpected non-reward after the reversal produced broader increases. The magnitude of these increases predicted whether mice would adopt a “lose-shift” strategy—switching to the alternative arm after not receiving the expected reward. When the team inhibited striatal cholinergic interneurons, the mice showed fewer lose-shift responses, indicating a causal role for acetylcholine signaling in this form of behavioral flexibility. Jeffery R. Wickens, the study’s senior author, and colleagues said the results help clarify how striatal acetylcholine dynamics contribute to changing behavior when circumstances shift. The authors also argued that the findings offer a mechanistic framework for understanding rigid, habitual behaviors that feature in disorders such as addiction and obsessive-compulsive rituals. The study was published in Nature Communications on December 17, 2025.
