Comparisons in microglial responses to ischemic–hypoxic brain injury in neonatal and adult mice analyzed by transcriptome integration and deconvolution technologies

JOURNAL/atin/04.03/02274269-202512000-00003/figure1/v/2025-10-03T110833Z/r/image-tiff Microglia play a key role in response to cerebral ischemic–hypoxic injury, but their responses differ between neonatal and adult stages. By integrating bulk and single-cell transcriptome datasets, this study systematically compared microglial responses in neonatal and adult mice under ischemic–hypoxic conditions. The study included the gene expression omnibus dataset of isolated samples of microglia from neonatal hypoxia–ischemia and adult middle cerebral artery occlusion models as of June 2024. Eleven pathways were consistently altered in both neonatal hypoxia–ischemia and adult middle cerebral artery occlusion models, defined as hypoxia–ischemia-related pathways. Single-cell analysis revealed dynamic responses, with a proliferative microglial subpopulation enriched in neonates. A time-dependent shift of microglial subpopulations was also observed, transitioning from pro-inflammatory activation in the acute phase to repair and regeneration in the subacute phase. While male and female microglia responded similarly during the acute phase of neonatal ischemic–hypoxic injury, sex differences emerged during the subacute phase, suggesting distinct adaptive strategies. Males exhibited more extensive reprogramming of microglial subpopulations, whereas females tended to maintain stable compositions with altered cell cycle and metabolic regulation. Key transcription factors with altered activities were identified in each model, and the subsequent drug-gene interaction analysis predicted potential therapeutics for further investigations. These findings provide deeper insights for understanding the developmental stage-specific dynamics of microglial responses to ischemic–hypoxic injury, laying the foundation for microglia-directed therapeutic interventions.