Microglia Stimulate Zebrafish Brain Repair Via a Specific Inflammatory Cascade

The adult zebrafish brain, unlike mammals, has a remarkable regenerative capacity. Although inflammation inhibits regeneration in mammals, it is necessary for zebrafish brain repair. Microglia are resident brain immune cells that regulate the inflammatory response. To explore the microglial role in repair, we used liposomal clodronate and colony stimulating factor-1 receptor (csf1r) inhibition to suppress microglia during brain injury. We found that microglial ablation inhibited injury-induced neurogenesis and regeneration. Microglial suppression specifically attenuated cell proliferation at the progenitor cell amplification stage of neurogenesis. Notably, the loss of microglia impaired phospho-stat3 (signal transducer and activator of transcription 3) and beta-catenin signaling by altering tumor necrosis factor-a expression after injury, and the ectopic activation of stat3 and beta-catenin rescued neurogenesis defects caused by microglial loss. Leukocytes also accumulated after microglial ablation, potentially hindering the resolution of inflammation. These findings reveal specific roles of microglia and inflammatory signaling during zebrafish telencephalic regeneration that should provide strategies to improve mammalian brain repair.