Exposure to chronic hypoxia is considered to be a risk factor for deficits in brain function in adults, but the underlying mechanisms remain largely unknown. Since active myelinogenesis persists in the adult central nervous system, here we aimed to investigate the impact of chronic hypoxia on myelination and the related functional consequences in adult mice. Using a transgenic approach to label newly-generated myelin sheaths (NG2-CreER^TM; Tau-mGFP), we found that myelinogenesis was highly active in most brain regions, such as the motor cortex and corpus callosum. After exposure to hypoxia (10% oxygen) 12 h per day for 4 weeks, myelinogenesis was largely inhibited in the 4-month old brain and the mice displayed motor coordination deficits revealed by the beam-walking test. To determine the relationship between the inhibited myelination and functional impairment, we induced oligodendroglia-specific deletion of the transcription factor Olig2 by tamoxifen (NG2-CreER^TM; Tau-mGFP; Olig2 fl/fl) in adult mice to mimic the decreased myelinogenesis caused by hypoxia. The deletion of Olig2 inhibited myelinogenesis and consequently impaired motor coordination, suggesting that myelinogenesis is required for motor function in adult mice. To understand whether enhancing myelination could protect brain functions against hypoxia, we treated hypoxic mice with the myelination-enhancing drug-clemastine, which resulted in enhanced myelogenesis and improved motor coordination. Taken together, our data indicate that chronic hypoxia inhibits myelinogenesis and causes functional deficits in the brain and that enhancing myelinogenesis protects brain functions against hypoxia-related deficits.

慢性缺氧被认为是成人脑功能缺陷的危险因素，但其潜在机制仍然很大程度上未知。由于活跃的髓鞘形成持续存在于成年中枢神经系统中，因此我们的目的是研究慢性缺氧对成年小鼠髓鞘形成的影响以及相关的功能后果。使用转基因方法标记新生成的髓鞘（NG2-CreER ^TM；Tau-mGFP），我们发现髓鞘生成在大多数大脑区域（例如运动皮层和胼胝体）高度活跃。在每天 12 小时处于缺氧（10% 氧气）环境中 4 周后，4 个月大的大脑中髓鞘质生成在很大程度上受到抑制，并且通过平衡木行走测试发现，小鼠表现出运动协调缺陷。为了确定髓鞘形成受抑制与功能障碍之间的关系，我们通过他莫昔芬（ NG2-CreER ^TM；Tau-mGFP；Olig2 fl/fl ）在成年小鼠中诱导少突神经胶质细胞特异性删除转录因子 Olig2，以模拟少突胶质细胞引起的髓鞘形成减少。缺氧。Olig2 的缺失会抑制髓鞘质生成，从而损害运动协调性，这表明髓鞘质生成是成年小鼠运动功能所必需的。为了了解增强髓鞘形成是否可以保护大脑功能免受缺氧影响，我们用增强髓鞘形成药物氯马斯汀治疗缺氧小鼠，从而增强了骨髓生成并改善了运动协调性。综上所述，我们的数据表明，慢性缺氧会抑制髓鞘质生成并导致大脑功能缺陷，而增强髓鞘质生成可以保护大脑功能免受缺氧相关缺陷的影响。