Nos1+ neurons are critical for motor learning and post-stroke motor recovery.

Motor learning has strong significance for motor recovery after stroke. Although layer-specific patterns of circuit connectivity in the primary motor cortex (M1) are well established, cell type-specific responses to motor learning remain elusive. We discover that the neurons expressing neuronal nitric oxide synthase (nNOS; Nos1) in the male mouse M1 are mainly forelimb movement-related corticospinal neurons, selectively activated by and critical for motor learning. Activation of the male mouse M1 Nos1+ neurons enhances motor learning-associated dendritic spine reorganization, cortical oscillations, and regional cerebral blood flow and facilitates motor recovery from stroke. Moreover, the role of male mouse Nos1+ neurons in regulating motor learning depends on nNOS-derived nitric oxide (NO). Administration of NO donors during the repair phase is beneficial for motor memory recall and motor recovery. Together, M1 Nos1+ neurons are crucial for motor learning and post-stroke motor recovery, and NO donors may serve as a strategy for stroke recovery.