| Summary: | <p>Cholinergic interneurons (ChIs) of the striatum pause their firing in response to salient stimuli and conditioned stimuli after learning. Several different mechanisms for pause generation have been proposed but a unifying basis has not previously emerged. Here, using <i>in vivo</i> and <i>ex vivo</i> recordings in rat and mouse brain and a computational model, we show that ChI pauses are driven by withdrawal of excitatory inputs to striatum and result from a delayed-rectifier potassium current (I<sub>Kr</sub>) in concert with local neuromodulation. This delayed-rectifier I<sub>Kr</sub> is sensitive to K<sub>v</sub>7.2/7.3 blocker XE-991, and enables ChIs to report changes in input, to pause on excitatory input recession and to scale pauses with input strength, in keeping with pause acquisition during learning. We show also that although dopamine can hyperpolarize ChIs directly, its augmentation of pauses is best explained by strengthening excitatory inputs. These findings provide a basis to understand pause generation in striatal ChIs. </p>
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