Postpartum Brain Reveals Repopulating Process and Long‐Lasting Proteomic Changes of Microglia

The maternal brain undergoes significant structural and functional neuroplastic changes, yet the cellular and molecular effects of parturition-and the role of microglia in the postpartum brain-remain poorly understood. Here, we investigated microglial dynamics in the peripartum and postpartum mouse brain, focusing on changes in microglial number, origin, and proteomic profile. To determine whether postpartum microglial replenishment arises from resident proliferation or peripheral monocyte infiltration, we assessed both sources. For proteomic profiling, CD11b⁺ microglia were isolated from postpartum brain tissue using MACS and analyzed by LC-MS/MS. We found that hippocampal microglia significantly declined after parturition, followed by gradual repopulation via resident microglial proliferation rather than peripheral infiltration. Notably, microglia isolated from 50 days postpartum (PP50) exhibited a reduced aging-associated inflammatory profile compared to age-matched, nonparous controls. Subregional proteomic analysis revealed the most pronounced changes in the hippocampus. The proteomic signature of hippocampal microglia at PP50 closely resembled that of repopulating microglia and was distinct from microglial profiles associated with neurodegeneration, including microglial neurodegenerative phenotypes (MGnD), disease-associated microglia (DAM), or lipid-droplet accumulating microglia (LDAM). This study provides a unique resource characterizing microglial dynamics in the maternal brain and suggests that parturition induces long-lasting, region-specific alterations in the microglial proteome.