Global and subtype-specific modulation of cortical inhibitory neurons regulated by acetylcholine during motor learning

Inhibitory neurons (INs) consist of distinct subtypes with unique functions. Previous studies on INs mainly focused on single brain regions, and thus it remains unclear whether the modulation of IN subtypes occurs globally across multiple regions. Here, we monitored the activity of different cortical IN subtypes at both macroscale and microscale in mice learning a lever-press task. Learning evoked a global modulation of IN subtypes throughout the cortex. The initial learning phase involved strong activation of vasoactive intestinal peptide-expressing INs (VIP-INs) and weak activation of somatostatin-expressing INs (SOM-INs). Inactivating VIP-INs increased SOM-IN activity and impaired initial learning. Concurrently, cortical cholinergic inputs from the basal forebrain were initially more active but became less engaged over learning. Manipulation of the cholinergic system impaired motor learning and differentially altered activity of IN subtypes. These results reveal that motor learning involves a global and subtype-specific modulation on cortical INs regulated by the cholinergic system.