Dynamic Responses of Striatal Cholinergic Interneurons Control the Extinction and Updating of Goal-Directed Learning

Abstract

AbstractStriatal cholinergic interneurons (CINs) regulate behavioral flexibility, but their exact contribution to this process remains elusive. In this study, we report that extinction learning enhances acetylcholine (ACh) release. Mimicking this enhancement by optogenetically inducing CIN burst firing promotes extinction learning. CINs receive excitatory thalamic inputs, and we observed that extinction training augmented thalamic activity. Optogenetically stimulating these thalamic inputs caused CIN burst firing and enhanced ACh release, strengthening extinction learning. Notably, CIN burst firing is usually followed by a pause in firing. We found that disrupting this pause through continuous optogenetic stimulation reversibly impaired the updating of goal-directed behaviors. Furthermore, excessive alcohol consumption reduced thalamus-induced burst-pause firing in CINs and impaired the reversal of goal-directed learning. In summary, thalamic-driven CIN burst firing promotes extinction learning, while the pause is pivotal for reversing goal-directed behavior, a process impacted by excessive alcohol. These findings shed light on how CIN’s dynamic responses affect behavioral flexibility.HighlightsH1.Burstfiring of CINs promotes extinction learningH2. Thalamic-CINexcitationenhances extinction learningH3.Pauseof CIN is critical for the reversal of goal-directed learningH4. Chronic alcohol consumption reduces theburst-pauseofCINsand impairs the reversal of goal-directed learning.