Muscarinic antagonists impair multiple aspects of operant discrimination learning and performance.

Acetylcholine signaling can strengthen associations between environmental cues and reward availability. Diverse subtypes (M1-M5) of the muscarinic acetylcholine receptor (mAChR) family may have distinct roles in different learning and memory processes, such as encoding cue-reward associations and consolidating these associations in long-term memory. Using an operant discrimination learning task in which mice are trained to nose poke during a tone to receive a food reward, we found that acquisition of the task requires mAChR signaling in the central nervous system. In addition, post-session injections of a broad mAChR antagonist, scopolamine impaired consolidation of the cue-reward memory. Further, after successful learning of a cue-reward contingency across multiple training sessions, mice that received a single pre-session injection of scopolamine were unable to use the learned cue association to receive rewards. Taken together, these data demonstrate distinct roles for muscarinic signaling in acquisition, consolidation and recall of the operant discrimination learning task. Understanding mechanisms underlying natural reward-related responding may provide insight into other maladaptive forms of reward learning such as addiction.

Acetylcholine is released in the basolateral amygdala in response to predictors of reward and enhances the learning of cue-reward contingency.

The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and nucleus basalis of Meynert (NBM) cholinergic terminal activity in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the cue-reward contingency. BLA CaMKIIα neuron activity followed reward retrieval and moved to the reward-predictive cue after task acquisition. Optical stimulation of cholinergic NBM-BLA terminal fibers led to a quicker acquisition of the cue-reward contingency. These results indicate BLA ACh signaling carries important information about salient events in cue-reward learning and provides a framework for understanding how ACh signaling contributes to shaping BLA responses to emotional stimuli.