Mesoscale Recovery of Microglial and Neuronal Dynamics After Craniotomy Across Wide Cortex in Transgenic Mice

ABSTRACT Craniotomy is commonly used to access the brain for neurosurgical procedures or neural probe implantation. However, the dynamic structural and functional changes in microglia and neurons during postoperative recovery remain poorly understood. Here, we utilize mesoscale fluorescence imaging and multiple transgenic mouse models (Cx3cr1‐GFP, Thy1‐YFP, and Rasgrf2‐2A‐dCre/Ai148D) to longitudinally record the dynamic recovery of microglia and neurons across the wide cortex over 50 days after craniotomy. Our findings reveal that both neuronal and microglial structures and functions are significantly altered after surgery, yet their recovery to the first day after craniotomy follow distinct temporal patterns. Microglia exhibit the most rapid structural changes, reaching peak inflammatory response within approximately 10 days. Subsequently, neuronal structural fluorescence intensity peaks around 14 days post‐surgery, showing a strong positive correlation with microglial changes. Finally, neuronal functional dynamics are assessed using drifting grating visual stimulation, with functional modularity indices to quantify network integrity. We observe that functional modularity undergoes significant disruption, reaching its peak disruption at approximately 21 days post‐surgery. These findings provide new insights into the dynamic process following craniotomy and offer a novel perspective on neuroimmune interactions in traumatic conditions.