Functionally distinct NPAS4-expressing somatostatin interneuron ensembles critical for motor skill learning

During motor learning, dendritic spines on pyramidal neurons (PNs) in the primary motor cortex (M1) undergo reorganization. Intriguingly, the inhibition from local somatostatin-expressing inhibitory neurons (SST-INs) plays an important role in regulating the PN plasticity and thus new motor skill acquisition. However, the molecular mechanisms underlying this process remain unclear. Here, we identified that the early-response transcription factor, NPAS4, is selectively expressed in SST-INs during motor learning. By utilizing in vivo two-photon imaging in mice, we found that cell-type-specific deletion of Npas4 in M1 disrupted learning-induced spine reorganization among PNs and impaired motor learning. In addition, NPAS4-expressing SST-INs exhibited lower neuronal activity during task-related movements, and chemogenetically increasing the activity of NPAS4-expressing ensembles was sufficient to mimic the effects of Npas4 deletion. Together, our results reveal an instructive role of NPAS4-expressing SST-INs in modulating the inhibition to downstream task-related PNs to allow proper spine reorganization that is critical for motor learning. •Motor learning selectively induces NPAS4 expression in SST-INs in M1•Cell-type specific KO of Npas4 in SST-INs of M1 in mice impairs motor learning•NPAS4+ SST-INs exhibited lower activity during task-related movements•NPAS4 re-expression maintains the functionally distinct SST-INs throughout learning Utilizing in vivo two-photon imaging in behaving mice, Yang et al. reveal that motor learning triggers an emergence of an NPAS4-expressing SST-IN ensemble that regulates the spine remodeling of downstream PNs through disinhibition. Moreover, NPAS4 re-expression is critical in maintaining the functionally distinct SST-IN ensemble throughout the course of learning.