Chronic Exposure to Hypoxia Inhibits Myelinogenesis and Causes Motor Coordination Deficits in Adult Mice

Abstract 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.