Experimental neurology · 2026
Chronic Intermittent Hypoxia Induces Hippocampal Cellular Remodeling through microglial polarization imbalance and neural functional disconnection.
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Ye Yuxin, Li Chaonan, Huang Xinxing, Sun Guojing, Zhang Yunyan, Rao Peitong, Gao Xiangyu, Gao Jin, Zhang Cantang
Аннотация
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.
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.