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Rewiring Dynamics of Functional Connectome in Motor Cortex during Motor Skill Learning

The brain’s connectome continually rewires throughout the life of an organism. In this study, we sought to elucidate the operational principles of such rewiring by analyzing the functional connectomes in mouse primary motor cortex (M1) during a 14-session (day) lever-press task learning in response to an auditory cue. Specifically, we employed Calcium imaging recordings of L2/3 and L5 of M1 in awake mice to reconstruct and analyze functional connectomes across learning sessions. Our results show that functional connectomes in L2/3 and L5 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 higher 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. Significance Statement Connectomes in the motor cortex rewire during motor skill learning, but the operational principle behind this rewiring is yet to be determined. Here, we characterized the rewiring dynamics of functional connectomes in L2/3 and L5 of M1 in mice engaging in a lever-press learning, using two-photon fluorescence microscopy data. We identified a universal biphasic rewiring trajectory across animals and layers in the motor cortex that reflects two objectives: an exploratory phase that increases functional connectivity and optimizes motor performance, and a pruning phase that brings connectivity back to a homeostatic level while maintaining motor performance. We found further that connectome rewiring during motor skill learning concentrates around a core set of highly interconnected neurons in L2/3 that reliably encode movements.