UNCOVERING MICROGLIAL MECHANISMS ORCHESTRATING CORTICAL REORGANIZATION AFTER PARALYSIS

Paralysis induces profound functional and structural reorganization of cortical circuits. This cortical plasticity is essential for restoring movement upon motor recovery, however the cellular and molecular mechanisms orchestrating these adaptive changes remain poorly understood. Microglia, the resident immune cells of the CNS, have emerged as key regulators of synaptic remodeling and experience-dependent plasticity, yet their contribution to cortical reorganization after paralysis remains largely unexplored. Here, we investigate the role of microglia in cortical plasticity using a mouse model of painless, transient hindlimb paralysis based on botulinum toxin A injection (Botox-Induced Paralysis, or BIP mouse model). A detailed characterization of the primary motor (M1) and somatosensory (S1) cortices in the BIP model show a reduction in microglial density, altered microglial morphology, and a loss of excitatory and inhibitory synaptic markers, together with disrupted propagation of cortical activity from S1 to M1 (via voltage-sensitive dye imaging), 7 days post paralysis induction. Importantly, pharmacological depletion of microglia via PLX3397 chow administration significantly delays motor recovery induced by a standardized rotarod training every other day, indicating that microglia are required for efficient, timely rehabilitation-driven improvement. Building on these findings, we are exploring how microglia actively support cortical reorganization after paralysis by dynamically interacting with neurons during recovery. To test this, we combine longitudinal two-photon imaging of microglial process motility and neuronal calcium signaling at multiple time points following paralysis and training. Overall, our work defines microglia as critical cellular mediators of cortical plasticity after paralysis, potentially indicating novel targets to improve rehabilitation outcomes.