Role And Mechanisms Of Different Types Of Exercise To Alleviate Depression-like Behaviors In CUMS Mice

Objectives: Increasing social stress has prompted the increase in the prevalence of depression,and the economic burden of depression as one of the major factors of the global disease burden is also unimaginable,so how to effectively treat the depression becomes crucial.Recent studies have found that neuronal injury,apoptosis,and ER stress are closely related to the occurrence of depression.Exercise,as a low-cost depression intervention,has attracted much attention in clinical treatment.This paper aims to explore the role and related mechanisms of different types of exercise in reducing depression-like behavior in Chronic unpredictable mild stress（CUMS）mice,and to provide theoretical support for exercise intervention in depression as a clinical treatment mode.Study method: choose 65 male 5 weeks old SPF mice randomly divided into 2 groups,respectively model group（n = 58）,normal group（N,n = 7）,model group after 7 weeks CUMS stimulation depression model,and using sucrose preference experiment,forced swimming experiment test model is successful,then successful mice into model group（M group,n = 7）,aerobic exercise group（E group,n = 7）,resistance exercise group（R group,n =7）.Groups N and M mice were fed normally without formal intervention;Group E and R mice underwent one week of adaptive training,during which mice increased exercise（from 6m /min to 10 m / min,from 10 min to 40 min to 1 cm for 3 days,1 group,with 5 repeats on the first day,7 and 9 on the next day.After adaptive training,group E mice underwent 4 weeks of running exercise intervention,10 m / min,exercise frequency 5 times per week,40 min / time;Group R mice underwent 4 weeks of resistance exercise training on the ladder,25% in first week,50% in second week,75% in third week,100% in fourth week and 5 times per week,each group,9 replicates.At 24 hours after the last exercise intervention,experimental mice were killed and collected serum,hippocampus and cortical tissue samples,HE staining,neuronal damage,TUNEL staining nerve cell apoptosis,immunofluorescence,serum inflammatory cytokines,transmission electron microscopy,protein immunoblot（western blots）method to detect the expression of hippocampus and cortical proteins.Study results:1.Depression-like performance changes:1）Body weight: Compared with group N mice,group M mice lost weight significantly（p <0.05）,and after 4 weeks of exercise,the mice in group E and group mice in group M increased significantly（p <0.05）.2)Sucrose preference: The sucrose preference index of group M mice was significantly reduced compared with group N mice,and the difference was statistically significant（p<0.05）.After the exercise intervention,the sugar water preference index of group E mice and group R mice compared with group M mice was significantly higher,and the difference was statistically significant（p <0.05）.3)Forced swimming: Compared with mice in group N,mice in group M were longer,statistically significant（p <0.05）,after exercise treatment,mice in group E and R mice decreased,statistically significant（p <0.05）.4)Water maze: compared with group N mice,group M mice escape latency time increased,through the platform,the difference is statistically significant（p <0.05）,and after 4weeks of exercise treatment,compared with group M mice,group E and R mice escape latency time shortened,through the platform,the difference is statistically significant（p<0.05）.2.Morphological and structural changes of neural tissue in the hippocampus and cortex,as follows:1)HE staining: compared with mice in group N,nerve cells in CA1 area of hippocampus in group M were evacuated,with small numbers,nucleus sequestration,different staining shades,cytosolic eosinophilic,compared with mice in group M,mice in group E and R hippocampus neurons arranged orderly and improved cell body damage.2)Nissl staining: Compared with mice in group N,mice in group M reduced the number of neurons in the CA1 area,scattered arrangement,reduced the number of cytosolic bodies,obvious nuclei,enlarged intercellular space and nucleolysis.After 4 weeks of exercise therapy,the number of neuronal cells increased in CA1 and cytosolic bodies in E and R,and intact nuclear membrane.3)TUNEL staining: compared with N mice,the number of apoptosis in group M mice increased（p <0.05）,compared with group mice after 4 weeks（p <0.05）.4)Neuroimmunostaining: Compared with N mice,the distribution of GFAP and Nestin expression in hippocampus and cortex was decreased,statistically significant（p <0.05）;after exercise intervention,mice in group E and R（p <0.05）.5)ELISA: Compared with group N mice,inflammatory cytokine IL-1 and TNF-were increased in M mice（p <0.05）,and IL-1 and TNF-in serum（p <0.05）.6)TEM: Compared with group N mice,M group mice showed ER swelling,fewer synapse number,wider synaptic gap,and thinner postsynaptic membrane density thickness;after 4 weeks of exercise intervention,group E and R group mice showed improved ER swelling,synaptic gap thinning and increased,statistically significant（p <0.05）.3.Western blot analysis:1)Expression level of apoptosis-related proteins: compared with group N mice,The expression of the proapoptotic proteins Bax and cleaved caspase-3 was increased significantly in the hippocampus and cortex of group M mice（p <0.05）,However,the expression level of the antiapoptotic protein Bcl-2 was slightly reduced;After 4 weeks of exercise intervention,The expression of mice in group E and R expressed pro-apoptotic proteins Bax and cleaved caspase-3 in the hippocampus and cortex compared with mice in group M（p <0.05）,The expression of the anti-apoptotic protein Bcl-2 was significantly increased（p <0.05）.2)Expression level of ER stress-related proteins: compared with group N mice,The expression levels of ER stress-related protein proteins GRP78,p-PERK / PERK,CHOP,caspase-12 and p-el F2 / el F2 increased significantly in the hippocampus and cortical tissues of group M mice（p <0.05）;After 4 weeks of the exercise intervention,In comparison with the mice in group M,Protein expression of GRP78,PERK,p-PERK,el F2,p-el F2,CHOP and caspase-12 was significantly reduced in the hippocampus and cortical tissues of group E mice and group R mice（p <0.05）.3)Neurogenesis-related protein expression level: Compared with group N mice,Nestin and GAP43 protein expression were significantly decreased in hippocampus and cortical tissues in group M mice（p <0.05）,while after 4 weeks of exercise intervention,Nestin and GAP43 protein expression were significantly increased in group E mice and group M mice（p<0.05）.4)Expression level of synaptic plasticity: compared with group N mice,PSD95 and SYN protein expression in hippocampus and cortical tissues of group M mice decreased significantly（p <0.05）;after 4 weeks of exercise intervention,PSD95 and SYN protein expression were significantly increased in group E mice and group R mice（p <0.05）.5)Expression level of inflammatory-related proteins: Compared with that of mice in group N,FAK and Ras protein expression in the hippocampus and cortex tissues were significantly increased in group M mice（p <0.05）;after 4 weeks of exercise intervention,FAK and Ras protein expression in hippocampus and cortex tissues in group E and R（p<0.05）.Conclusion: Aerobic exercise and resistance exercise can reduce neuronal damage,reduce apoptosis,promote neurogenesis,enhance synaptic plasticity,and finally improve the depression-like performance of CUMS mice.There is no significant difference between the two types of exercise.