Role Of MTOR-autophagy Signal And NLRP3 In Anxiety-depression-like Behavior Induced By Chronic Intermittent Hypoxia In Mice

Background: OSAHS is one of the major public health problems in the world.It is considered an independent risk factor for cardiovascular disease,neurological damage and impairment of metabolic function.Its neuropsychiatric symptoms are mainly anxiety,depression and Alzheimer’s disease.In addition,it can also cause cognitive impairment.CIH is the main clinical feature of OSAHS,and the emotional structure and cognitive function structure of the brain are vulnerable to hypoxia.Therefore,it is speculated that the emotional and cognitive impairment of OSAHS patients may be related to the molecular mechanism changes and structural damage of hippocampus or prefrontal cortex.Objective: This project will simulate the effects of OSAHS on cognitive function and anxiety and depression like behavior in mice through CIH,explore the changes of inflammatory corpuscle and autophagy level,and explore the relationship between CIH and cognitive impairment,anxiety and depression like behavior,and provide a theoretical basis for the prevention and treatment of anxiety and depression-like behavior and cognitive impairment in OSAHS patients.Methods: 7-week-old C57BL/6 male mice were randomly divided into control group（Ctrl group）and CIH group.The Ctrl group was fed routinely,and the CIH group was modeled by CIH.The depression like behavior of mice was detected by tail suspension test（TST）and forced swimming test（FST）;The anxiety like behavior of mice was detected by open field test（OFT）,elevated-plus maze（EPM）,light-dark transition test and the hole-board test;At the same time,Morris water maze was used to detect the cognitive functions of mice.Serum lipids and liver function were detected by test kit;The levels of autophagy related proteins and neuroinflammation in mouse hippocampus and prefrontal cortex were detected by Western blot;Immunofluorescence was used to detect related protein expression levels.Results: 1)After 8 weeks of CIH,7-week-old mice showed significant anxiety and depression like behavior,and there was no cognitive impairment related to spatial learning and memory;2)After 2 weeks of CIH,the mice showed the excited symptoms of "anti anxiety";After 4 weeks,there were significant anxiety and depression like behaviors;After that,with the extension of CIH time,the depression like behavior of mice gradually increased,but the anxiety like behavior did not increase significantly;After 8 weeks of CIH,the state of CIH was relieved for 2 weeks,and there was no significant remission of anxiety and depression like behavior in mice;3)After 8 weeks of CIH,the serum lipid level increased significantly,but there was no significant liver function injury;4)After 8 weeks of CIH,the levels of proinflammatory cytokines and NLRP3 in mouse hippocampus increased significantly,and microglia increased significantly;The level of pm TOR in hippocampus increased significantly,the level of p AMPK were not significantly changed,and the autophagy levels were significantly decreased;The above indexes had no significant changes in prefrontal cortex;5)After reoxygenation for 2 weeks,there was no significant decrease in NLRP3 inflammatory corpuscle and no significant increase in autophagy level in mouse hippocampus.Conclusion: CIH can activate inflammatory corpuscle,cause the release of inflammatory factors,and induce m TOR phosphorylation,so as to inhibit the level of autophagy.Finally,the decrease of autophagy level and the accumulation of inflammatory response jointly mediate the injury of neurons in hippocampus and cause anxiety and depression like behavior.After reoxygenation,the anxiety and depression like behavior of mice did not improve significantly in a short time.This study may provide a theoretical basis for finding new targets to reduce neuroinflammation and prevent anxiety and depression-like symptoms in patients with OSAHS.