CIRBP mediates hypoxia-induced mitochondrial metabolic reprogramming in microglia to regulate polarization and anxiety-like behavior.

Exposure to high-altitude hypoxia can lead to anxiety-like behaviors, social issues, and other dysfunctions of the central nervous system (CNS), but the molecular mechanisms behind these effects are not fully understood. Microglial M1 polarization and changes in mitochondrial metabolism are crucial in hypoxic brain injury. The cold-inducible RNA-binding protein (CIRBP) is known to regulate mitochondrial balance and inflammatory responses. However, its role in hypoxia-induced microglial metabolic changes, polarization issues, and anxiety-like behaviors is still unclear. This study established an in vivo mouse model of high-altitude hypoxia, an in vitro hypoxic injury model of BV2 microglia, and an in vitro neuronal intervention model with microglia-derived conditioned medium. Integrating in vivo and in vitro experimental designs, we further systematically elucidated the potential molecular mechanisms underlying hypoxic brain injury. Findings indicated that high-altitude hypoxic exposure led to anxiety-like behaviors, social dysfunction, and neuronal and synaptic damage in the hippocampal CA1 region of mice. Hypoxia first triggered mitochondrial metabolic reprogramming in microglia, characterized by inhibition of oxidative phosphorylation, decreased ATP production, and accumulation of reactive oxygen species (ROS) and lactate, which subsequently drove the conversion to the M1 pro-inflammatory phenotype. Inhibition of microglial activation by minocycline significantly reversed hypoxia-induced synaptic damage. At the molecular level, hypoxia downregulated CIRBP expression in microglia. Overexpression of CIRBP in microglia ameliorated mitochondrial metabolic dysfunction and regulated microglial polarization, while knockdown of CIRBP in microglia exacerbated these abnormalities. Targeted overexpression of CIRBP in microglia within the hippocampal CA1 region significantly attenuated hypoxia-induced neuronal damage and behavioral abnormalities. This study elucidates a novel mechanism by which CIRBP in microglia mediates hypoxic brain injury, offering a potential therapeutic target for neuropsychiatric disorders associated with high-altitude hypoxia.