The Study Of The Effects Of Intermittent Hypoxic Preconditioning On Post-Traumatic Stress Disorder And Its Possible Mechanism

Background: Intermittent hypoxia(IH)has preventive and therapeutic effects on the various disease models,like hypertension,acute myocardial infarction,cerebral ischemia and depression et al.Its potential impact on the post-traumatic stress disorder(PTSD)is unknown.Objective: To explore the effect of intermittent hypoxic preconditioning(3000 m,4 h/d,14 d)on the behavior of fear and anxiety in PTSD mice model.In addition,the possible mechanisms are also investigated.Methods: The physiological indexes of the mice were evaluated by body weight,respiration,blood routine and other indicators.The anxiety and fear behavior were evaluated by fear conditioning,open field and elevated plus maze(EPM)tests.The learning and memory function was evaluated by novel object recognition test.The serum levels of corticosterone(CORT)and adrenocorticotropic hormone(ACTH)were evaluated by Enzyme linked immune sorbent assay(ELISA).The number of Fos positive neurons in the hippocampus,amygdala and medial prefrontal cortex(m PFC)was detected by Immunohistochemistry(IHC);the protein levels of HIF-1?,VEGF and BDNF in these brain areas were detected by western blot(WB).Results:(1)The effect of IH on physiological indexes.IH had no effect on the basic physiological indexes of body weight,respiratory rate,heart rate and oxygen saturation,and also had no effect on white blood cell and platelet parameters in blood routine,but could increase the number of red blood cells and hemoglobin of mice.(2)Establishment of PTSD model mice.Compared with the mice in the control group,the weight of the PTSD mice model was significantly reduced.The freezing time and the number of fecal pellets in the fear conditioning test were significantly increased,the distance of movement and the time,number and distance of activities in the central area were significantly reduced in the OFT,“OE%” and “OT%” in the EPM test were significantly reduced.There was no difference between the two groups in the “Recognition index” in the novel object recognition test.There was also no difference between the two groups in the serum levels of CORT and ACTH hormones.The expression of HIF-1? was significantly reduced in the hippocampus and amygdala after one day inescapable electric shock.(3)Effect of IH preconditioning on PTSD model mice.IH preconditioning significantly reduced the freezing time and the number of fecal pellets in the fear conditioning test in PTSD mice model,and it significantly increased OE% in EPM test.Moreover,IH preconditioning reduced the number of Fos positive neurons in the hippocampus,amygdala and m PFC of PTSD model mice,and increased the expression levels of HIF-1?,VEGF and BDNF proteins in these brain regions.Conclusion:IH preconditioning can relieve the fear and anxiety behavior of PTSD mice,which maybe related to the reduction of neuronal over-excitation in the hippocampus,amygdala and m PFC.At the molecular levels,the protective effect of IH is associated with increased expression of HIF-1?,VEGF and BDNF proteins.