Monocyte-Derived Microglia in Development and after Neonatal Brain Injury

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PROJECT SUMMARY (Abstract) Microglia were once thought derived exclusively from the early yolk sac progenitors, but recent studies raised the possibility of monocyte-derived microglia in normal development and particularly after neonatal brain injury, including stroke, hypoxia-ischemia (HI), and inflammation/LPS-sensitized HI (LPS/HI). However, the extent of monocyte-derived microglia in normal development is unknown, and the roles of monocyte-derived pathologic microglia partially defined. Better understanding of these issues may shed mechanistic insights and suggest potential treatments of neonatal brain injury. We will address these issues in three specific aims. In Aim 1, we will use CCR2-Cre mice crossed with R26R-EGFP mice to determine the extent and distributions of CCR2+ monocyte-derived microglia in the brain. In Aim 2, we will use PF-04136309 (IP) to inhibit the MCP1/CCR2-mediated chemoattraction or clodronate liposomes (IV) to ablate the blood-borne monocytes to assess their potential benefits against the neonatal LPS/HI brain injury. In Aim 3, we will use tamoxifen-dosed CCR2-CreER; R26R-EGFP mice to isolate monocyte-derived microglia- like cells in LPS/HI-injured brains for single-cell RNA-Seq to search for the potential effectors responsible for delayed neurotoxicity and damage to the synaptic network.