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The brain’s functional connectome continually rewires throughout an organism’s life. In this study, we sought to elucidate the operational principles of such rewiring in mouse primary motor cortex (M1) by analyzing calcium imaging of layer 2/3 (L2/3) and layer 5 (L5) neuronal activity in M1 of awake mice during a lever-press task learning. Our results show that L2/3 and L5 functional connectomes follow a similar learning-induced rewiring trajectory. More specifically, the connectomes rewire in a biphasic manner, where functional connectivity increases over the first few learning sessions, and then, it is gradually pruned to return to a homeostatic level of network density. We demonstrated that the increase of network connectivity in L2/3 connectomes, but not in L5, generates neuronal co-firing activity that correlates with improved motor performance (shorter cue-to-reward time), while motor performance remains relatively stable throughout the pruning phase. The results show a biphasic rewiring principle that involves the maximization of reward/performance and maintenance of network density. Finally, we demonstrated that the connectome rewiring in L2/3 is clustered around a core set of movement-associated neurons that form a highly interconnected hub in the connectomes, and that the activity of these core neurons stably encodes movement throughout learning. 

Experience-dependent gene expression reshapes neural circuits, permitting the learning of knowledge and skills. Most learning involves repetitive experiences during which neurons undergo multiple stages of functional and structural plasticity. Currently, the diversity of transcriptional responses underlying dynamic plasticity during repetition-based learning is poorly understood. To close this gap, we analyzed single-nucleus transcriptomes of L2/3 glutamatergic neurons of the primary motor cortex after 3 d motor skill training or home cage control in water-restricted male mice. “Train” and “control” neurons could be discriminated with high accuracy based on expression patterns of many genes, indicating that recent experience leaves a widespread transcriptional signature across L2/3 neurons. These discriminating genes exhibited divergent modes of coregulation, differentiating neurons into discrete clusters of transcriptional states. Several states showed gene expressions associated with activity-dependent plasticity. Some of these states were also prominent in the previously published reference, suggesting that they represent both spontaneous and task-related plasticity events. Markedly, however, two states were unique to our dataset. The first state, further enriched by motor training, showed gene expression suggestive of late-stage plasticity with repeated activation, which is suitable for expected emergent neuronal ensembles that stably retain motor learning. The second state, equally found in both train and control mice, showed elevated levels of metabolic pathways and norepinephrine sensitivity, suggesting a response to common experiences specific to our experimental conditions, such as water restriction or circadian rhythm. Together, we uncovered divergent transcriptional responses across L2/3 neurons, each potentially linked with distinct features of repetition-based motor learning such as plasticity, memory, and motivation.