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Chronic Intermittent Hypoxia Induces Hippocampal Cellular Remodeling through microglial polarization imbalance and
Yuxin Ye1, Chaonan Li2, Xinxing Huang1
1Department of Neurobiology and Cellular Biology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Background:
Cognitive impairment in Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is primarily driven by chronic intermittent hypoxia (CIH), yet the systemic, dynamic responses of hippocampal cell types to CIH are unclear.
Methods:
Using single-cell RNA sequencing (scRNA-seq), we analyzed hippocampal tissues from mice under normoxia or after 2 or 6 weeks of CIH. Integrated analyses assessed cellular composition, pseudotemporal trajectories, intercellular communication, and cell-type-specific responses.
Results:
CIH induced time-dependent hippocampal reorganization, characterized by a biphasic microglial response (an initial increase followed by a subsequent decline), progressive neuronal loss, and late-stage oligodendrocyte expansion. Pseudotime analysis revealed a coherent cellular transition from a synaptic/functional state, through an adaptive metabolic state, toward a terminal inflammatory state, identifying early-response genes such as Ptgds, S100a8, and S100a9. The intercellular communication network was extensively rewired, marked by strengthened microglia-oligodendrocyte crosstalk yet drastically attenuated neuronal input signals, suggesting functional disconnection of neurons. Mechanistically, microglia were activated via HIF-1 and p53 pathways and exhibited a polarization imbalance toward pro-inflammatory and oxidative-stress phenotypes. Neurons showed enriched pathways for synaptic dysfunction and apoptosis, while oligodendrocytes displayed a signature of maturational arrest involving simultaneous activation of myelination and oxidative-stress programs.
Conclusion:
This study delineates a high-resolution, dynamic map of CIH-induced hippocampal disruption. Our findings suggest that CIH initiates a multicellular pathological program in which microglial polarization imbalance serves as a central regulatory node, linking hypoxia to neural dysfunction. These findings reveal novel cellular mechanisms in OSAHS-related cognitive impairment and highlight candidate pathways for future investigation.
