Single‐Cell RNA Sequencing and Spatial Transcriptomics Reveal a Novel Mechanism of Oligodendrocyte–Neuron Interaction in Cognitive Decline After High‐Altitude Cerebral Edema

ABSTRACT Background High‐altitude cerebral edema (HACE) leads to cognitive decline, but the underlying cellular and molecular mechanisms remain unclear. Methods We established a mouse model of HACE under hypobaric hypoxia (simulating at an altitude of 6000 m) and analyzed hippocampal changes using single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics (ST) at 3 days and 7 days post‐exposure. Results Hypobaric hypoxia induced HACE and cognitive decline by altering the transcriptomic profiles and interactions of oligodendrocytes (MOL and MOL2) and neurons (ExN‐L6‐CT‐2). Early upregulation of PI3K/mTOR in oligodendrocytes mitigated Rps29‐bax‐mediated ribosomal stress and oxidative phosphorylation, promoting survival and myelin repair. Prolonged hypoxia suppressed PI3K/mTOR, triggering apoptosis/autophagy via oxidative phosphorylation and ribosomal stress. Enhanced Tnfrsf21‐App interactions between MOL2 and ExN‐L6‐CT‐2 exacerbated neuroinflammation and cognitive decline. Conclusions Our study reveals that HACE‐induced cognitive impairment is closely associated with dysregulated ribosomal stress and oxidative phosphorylation and impaired neuroactive ligand‐receptor interactions. Furthermore, we identify PI3K/mTOR dynamics, Rps29‐bax‐axis, and Tnfrsf21‐App as novel regulators, offering potential therapeutic targets.