Single-Nucleus Transcriptomics Reveals Microglial State Transitions and Astrocytic Trajectory Divergence During Glial...

The foreign body response to intracortical electrodes, characterized by chronic neuroinflammation and glial scar formation, remains a primary cause of long-term functional failure. However, neurons and glial cells' heterogeneity and intercellular signaling mechanisms following electrode implantation remain poorly resolved, which is responsible for direct dysfunction. Here, we applied single-nucleus RNA sequencing (snRNA-seq) to profile the peri-implant microenvironment in rat motor cortex tissue at 3, 25, and 50 days post-electrode implantation. Integrated bioinformatic analyses, including clustering, pseudotemporal trajectory reconstruction, and cell-cell communication inference, revealed a coordinated cellular response. We identified a pathologic microglial subpopulation (marked by Gpnmb, SPP1, and CD63) and a scar-associated astrocytic subtype (characterized by Mctp1 and Lrrc7) that progressively dominate the peri-implant niche. Crucially, we reveal that neurons orchestrate these processes via CX3CL1-CX3CR1 signaling, modulating microglial polarization and PTN-ALK/Ptpprz1 interaction, promoting astrogliosis and scar formation. These findings define the dynamic neuron-glia signaling landscape surrounding chronically implanted electrodes and provide mechanistic insight into how modulating cell-cell communication may improve the long-term biocompatibility of neural interfaces.