Myelin sheath, generated by oligodendrocytes, plays a vital role in ensheathing axons for efficient neural communication. Degeneration of myelin sheath is associated with several neurodegenerative diseases and aging. When myelin sheaths are damaged or degenerated, the resulting debris needs to be efficiently cleared to allow for regeneration and remyelination. The causes of myelin degeneration in various diseases vary, but the inability to effectively remove the myelin debris contributes to disease development and prevents tissue healing. Microglia are highly specialized phagocytic cells capable of recognizing and engulfing myelin debris. The Cx3cr1 gene, which is primarily expressed on microglial cells, plays a significant role in the process of debris clearance. To investigate the role of Cx3cr1 on clearance of single dying oligodendrocytes, we used a technique called 2Phatal. Longitudinal in vivo imaging revealed that microglia lacking the CX3CR1 receptor took on average 3 days longer to clear the targeted oligodendrocytes compared to controls. This suggests that Cx3cr1 plays a critical role in facilitating the rapid and efficient removal of dying oligodendrocytes.https://digitalcommons.dartmouth.edu/wetterhahn_2023/1000/thumbnail.jp