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

Abstract

Striatal 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.

Spatially organized striatum-wide acetylcholine dynamics for the learning and extinction of Pavlovian cues and actions

“…Cholinergic interneurons (CINs) provide the main source of acetylcholine (ACh) to the striatum 1,2 . Selective manipulations in rodents have revealed potential roles for the CINs in different forms of behavioral flexibility, response suppression, and extinction, which vary by striatal subregion [3][4][5][6][7][8][9][10][11][12][13] . Measurements of CIN activity or ACh release in the striatum during behavior have focused extensively on dynamics to salient and reward associated sensory stimuli 14,15 .…”

“…Mechanistic studies in brain slices and anesthetized rodents have indicated that pauses in ACh release to conditioned cues which coincide with phasic DA release may promote associative learning by creating a permissive window for striatal synaptic plasticity on D1 receptor expressing striatal projection neurons [25][26][27] . Less is known about how endogenous ACh dynamics to cues or actions might support a role in behavioral flexibility, but there is some evidence that increases in ACh may weaken excitatory striatal synapses to facilitate extinction 9,13 . Functional heterogeneities in ACh signaling across striatal subregions have been difficult to assess due to the sparseness of CINs in the striatum (~3-5% of total population) and inherent limitations in spatial coverage of current optical and electrophysiological approaches.…”