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Cholinergic Interneurons Use Orbitofrontal Input to Track Beliefs about Current State

When conditions change, organisms need to learn about the changed conditions without interfering with what they already know. To do so, they can assign the new learning to a new “state” and the old learning to a previous state. This state assignment is fundamental to behavioral flexibility. Cholinergic interneurons (CINs) in the dorsomedial striatum (DMS) are necessary for associative information to be compartmentalized in this way, but the mechanism by which they do so is unknown. Here we addressed this question by recording putative CINs from the DMS in rats performing a task consisting of a series of trial blocks, or states, that required the recall and application of contradictory associative information. We found that individual CINs in the DMS represented the current state throughout each trial. These state correlates were not observed in dorsolateral striatal CINs recorded in the same rats. Notably, DMS CIN ensembles tracked rats' beliefs about the current state such that, when states were miscoded, rats tended to make suboptimal choices reflecting the miscoding. State information held by the DMS CINs also depended completely on the orbitofrontal cortex, an area that has been proposed to signal environmental states. These results suggest that CINs set the stage for recalling associative information relevant to the current environment by maintaining a real-time representation of the current state. Such a role has novel implications for understanding the neural basis of a variety of psychiatric diseases, such as addiction or anxiety disorders, in which patients generalize inappropriately (or fail to generalize) between different environments. SIGNIFICANCE STATEMENT Striatal cholinergic interneurons (CINs) are thought to be identical to tonically active neurons. These neurons have long been thought to have an important influence on striatal processing during reward-related learning. Recently, a more specific function for striatal CINs has been suggested, which is that they are necessary for striatal learning to be compartmentalized into different states as the state of the environment changes. Here we report that putative CINs appear to track rats' beliefs about which environmental state is current. We further show that this property of CINs depends on orbitofrontal cortex input and is correlated with choices made by rats. These findings could provide new insight into neuropsychiatric diseases that involve improper generalization between different contexts.