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Motor control requires precise temporal and spatial encoding across distinct motor centers that is refined through the repetition of learning. The recruitment of motor regions requires modulatory input to shape circuit activity. Here, we identify a role for the baso-cortical cholinergic pathway in the acquisition of a coordinated motor skill in mice. Targeted depletion of basal forebrain cholinergic neurons results in significant impairments in training on the rotarod task of coordinated movement. Cholinergic neuromodulation is required during training sessions as chemogenetic inactivation of cholinergic neurons also impairs task acquisition. Rotarod learning is known to drive refinement of corticostriatal neurons arising in both medial prefrontal cortex (mPFC) and motor cortex, and we have found that cholinergic input to both motor regions is required for task acquisition. Critically, the effects of cholinergic neuromodulation are restricted to the acquisition stage, as depletion of basal forebrain cholinergic neurons after learning does not affect task execution. Our results indicate a critical role for cholinergic neuromodulation of distant cortical motor centers during coordinated motor learning. SIGNIFICANCE STATEMENT Acetylcholine release from basal forebrain cholinergic neuron terminals rapidly modulates neuronal excitability, circuit dynamics, and cortical coding; all processes required for processing complex sensory information, cognition, and attention. We found that depletion or transient silencing of cholinergic inputs to anatomically isolated motor areas, medial prefrontal cortex (mPFC) and motor cortex, selectively led to significant impairments on coordinated motor learning; disrupting this baso-cortical network after acquisition elicited no effect on task execution. Our results indicate a pivotal role for cholinergic neuromodulation of distant cortical motor centers during coordinated motor learning. These findings support the concept that cognitive components (such as attention) are indispensable in the adjustment of motor output and training-induced improvements in motor performance.

Basal Forebrain Cholinergic Neurons Selectively Drive Coordinated Motor Learning in Mice