Study On Brain White Matter Nerve Myelin Injury And Repair Mechanism In A Mice Model Of Hypoxia/reoxygenation

ObjectivesWith the economic development,more and more people need to enter the plateau due to tourism or work.Hypobaric hypoxic exposure can induce white matter damage and the main pathological features are myelin changes.A lot of studies have shown that myelin damage can cause dysfunction including cognition,sensation and motor function.Our group used MRI technology to observe a decrease in white matter FA value by hypoxic exposure while a significant increase after reoxygenation for 2 months,but the molecular mechanism is still unclear.At present,the study on myelin injury and regeneration after hypoxia-reoxygenation mainly focuses on brain development while rarely reported.in adults.Therefore,in order to further clarify the influence of myelin when the body entering and leaving the plateau,we observed the process on damage and repair of myelin sheath after hypoxia-reoxygenation,then discussed its molecular mechanism.Materials and methodsPhysiological indicators and behavioral testing.Thirty-two 8-week-old male Kunming mice were randomly divided into four groups,8 in each group.The hypoxic group,the reoxygenation 3 weeks group and the reoxygenation 2 months group were placed in a low-pressure oxygen chamber for 15 days hypobaric hypoxia with an altitude of 4300m.We tested the heart rate,respiratory rate and oxygen saturation of the mice and carried out a new obj ect recognition experiment under hypoxic conditi ons.Then the mice are taken out and their physiological indexes such as feed,drinking water and body weight are immediately detected,and behavioral experiments such as the open field-test and the water maze are successively carried out.The reoxygenation 3 weeks group and the reoxygenation 2 month group continued to be reared in the normoxic environment to their respective time nodes,and the same test was performed under normal oxygen conditions.The changes of myelin structure and its possible mechanism.We used Western blotting to detect myelin and axon content.Morphological structure of myelin sheath in corpus callosum and hippocampal was tested by transmission electron microscopy.The differentiation and maturation of oligodendrocytes was tested by immunofluorescence and quantitative real-time PCR.ResultsHypobaric hypoxia mimic 4300m altitude for 15 days can invoke changes in physiological indexes,including daily average drinking water consumption,feed consumption,body weight gain and blood oxygen saturation reduction,while heart rate and respiratory rate increasing.It also induced spatial learning and memory impairment and anxiety in mice.The feed consumption and body weight indicators related to growth and development are fully restored in reoxygenation for 2 months while the remaining indicators can return to normal after 3 weeks of reoxygenation.Hypobaric hypoxia mimic 4300m altitude for 15 days can lead myelin damage in corpus callosum and dentate gyrus.The myelin content is reduced and the myelin thickness is thinning in both.But there is no significant change in axon content.Myelin changes in the corpus callosum did not fully recover after 3 weeks of reoxygenation until reoxygenation for 2 months.Hypobaric hypoxic exposure causes a decrease in the number of mature oligodendrocytes in corpus callosum.The transcriptional level of PDGFRa and NG2 in OPCs were significantly up-regulated,suggesting that the number of OPCs may increase.There was no change in the transcriptional level of the transcription factor Olig2 which was used to label oligodendrocytes.After the reoxygenation for 2 months,the above changes can be restored to normal.Conclusion1.Hypobaric hypoxic exposure at 4300m for 15 days can lead a increase in respiration and heart rate but a decrease in blood oxygen saturation,reoxygenation for 3 weeks can return to normal.2.Hypobaric hypoxic exposure at 4300m for 15 days can cause spatial learning and memory impairment and anxiety in adult mice,reoxygenation for 3 weeks can return to normal.3.Hypobaric hypoxic exposure at 4300m for 15 days can cause myelin loss and myelin thinning in corpus callosum and dentate gyrus,reoxygenation for 2 months can return to normal.4.It is preliminarily clarified that the molecular mechanism of hypoxia-reoxygenation in duced myelin inj ury and repair is to regulate the differentiation process of oligodendrocytes.