| Background:In 2017,a global health estimates report released by the World Health Organization（WHO）showed that the normal lives of at least 300 million people around the world were seriously affected by depression.Especially at present,under the influence of the global New Coronavirus pneumonia（COVID-19）epidemic,people of all ages are faced with the threat posed by this high-risk disease.Peroxisome proliferator-activated receptorγcoactivator-1α（PGC-1α）can increase the level of brain-derived neurotrophic factor（BDNF）by stimulating downstream regulators,and then play an antidepressant role.Studies have shown that PGC-1αcan promote neuronal survival and play a key role in the expression regulation of hippocampus through the dependent mechanism of FNDC5 gene and BDNF.This may be related to neurodevelopmental abnormalities and synaptic transmission disorders in the pathological process of depression.However,the specific mechanism of PGC-1αin the occurrence and development of depression is still unclear.Previous studies have shown that simplified acute tryptophan depletion（SATD）can induce depressive behavior.As one of the non-drug interventions,exercise preconditioning can effectively alleviate the occurrence and development of depression,but there is still no systematic research to clarify its internal mechanism.Therefore,this study explored the mechanism of PGC-1αand its related signaling pathway mediated exercise preconditioning to alleviate depressive behavior,and provided new ideas and directions for further improving the exercise intervention mechanism of depression.Objective:This study aims to explore the effects of simplified acute tryptophan depletion and exercise preconditioning on depressive behavior in mice,and reveal the expression changes of PGC-1αand its related signaling pathway and synaptic plasticity related proteins in the specific brain region in the simplified acute tryptophan depletion model.On this basis,we further explore the mechanism of PGC-1αmediated exercise preconditioning in alleviating depressive behavior.Methods:In this experiment,91 healthy male mice of SPF grade C57BL/6 line,aged4-5 weeks and weighing 18-20g,were selected.They were randomly divided into 8groups:（1）NC group（n=11）,i.e.blank control group,which was fed normally for 8weeks;（2）SATD group（n=12）,that is,the simplified acute tryptophan depletion group,the experimental mice received the simplified acute tryptophan depletion model after 8weeks of normal feeding;（3）SATD+Saline group（SS,n=12）,the experimental mice were injected with normal saline after 8 weeks of normal feeding,and then received the simplified acute tryptophan depletion model;（4）SATD+PGC-1α+group（SP+-Sedentary,n=12）,the experimental mice were injected with PGC-1αactivator after 8weeks of normal feeding,and then received the simplified acute tryptophan depletion model;（5）SATD+PGC-1α-group（SP--Sedentary,n=12）,the experimental mice were injected with PGC-1αinhibitor after 8 weeks of normal feeding,and then received the simplified acute tryptophan depletion model;（6）SATD+Saline-Exercise group（SSE,n=10）,the experimental mice were injected with normal saline after 8 weeks of treadmill exercise,and then received the simplified acute tryptophan depletion model;（7）SATD+PGC-1α+-Exercise group（SP+-Exercise,n=11）,the experimental mice were injected with PGC-1αactivator after 8 weeks of treadmill exercise,and then received the simplified acute tryptophan depletion model;（8）SATD+PGC-1α--Exercise group（SP--Exercise,n=11）,the experimental mice were injected with PGC-1αinhibitor after8 weeks of treadmill exercise,and then received the simplified acute tryptophan depletion model.After the experimental intervention,all groups of mice received behavioral tests,including forced swim test（FST）and tail suspension test（TST）.Then the mice were killed and the serum,gastrocnemius muscle,hippocampus and whole brain were taken.Serum 5-hydroxytryptamine（5-HT）concentration was detected by Elisa kit.The m RNA relative expression levels of PGC-1α,FNDC5,BDNF in gastrocnemius muscle and PGC-1α,CREB,PRKaca and BDNF in hippocampus were examined by Real-time PCR.Simple western technique was used to detect the protein levels of PGC-1α,BDNF in gastrocnemius muscle and PGC-1α,CREB,p-CREB and BDNF in hippocampus.Immunofluorescence technique was used to examine the expression of synaptic plasticity related proteins such as GFAP,SYN and GAP-43 in the dorsal and ventral hippocampus CA1 region.Results:（1）The results of depression behavior experiments and ELISA showed that compared with NC group,the immobility time was increased significantly（P<0.05）and the struggling time was significantly decreased（P<0.01）in FST of SATD group mice,the immobility time was significantly increased（P<0.05）in TST and there was no significant difference in struggling time,the level of serum 5-HT was significantly decreased（P<0.05）.Compared with SS group,the immobility time of SSE group mice in FST was significantly decreased（P<0.01）,the struggling time was significantly increased in both FST（P<0.01）and TST（P<0.05）,and the level of serum 5-HT was significantly increased（P<0.05）.Compared with SS group,the immobility time in FST of SP+-Exercise group mice was significantly decreased（P<0.05）.Compared with SS group,the immobility time was significantly decreased（P<0.05）and the struggling time was significantly increased（P<0.05）in TST of SP--Exercise group mice.（2）The results of Real-time PCR of related genes and Simple western experiment of related proteins in gastrocnemius tissue showed that compared with NC group,the m RNA level of PGC-1αin SATD group was decreased,but not significantly（P=0.0547）,the m RNA level of BDNF was significantly decreased（P<0.05）.Compared with SS group,the m RNA levels of PGC-1α（P<0.01）and FNDC5（P<0.05）in SSE group were significantly increased,and the m RNA level of BDNF was increased,but there was no significant difference,the protein level of BDNF in SSE group was very significantly increased（P<0.01）.The m RNA level of PGC-1α（P<0.05）and the protein level of BDNF（P<0.05）in SP+-Exercise group were significantly increased,compared to SS group.The results of Real-time PCR of related genes and Simple western experiment of related proteins in hippocampus showed that the m RNA levels of PGC-1α（P<0.05）and BDNF（P<0.05）in SATD group were significantly decreased,the m RNA level of FNDC5 was decreased,but not significantly（P=0.0572）.Compared with SS group,the m RNA level（P<0.05）and the protein level（P<0.01）of PGC-1αin SSE group were significantly increased,the m RNA level of FNDC5 was very significantly increased（P<0.01）.The m RNA levels of PGC-1α（P<0.01）and FNDC5（P<0.01）in SP+-Exercise group were significantly higher than those in SS group,and there was no significant difference in the m RNA level of BDNF between the two groups.（3）The results of Real-time PCR of genes related to FNDC5/CREB/BDNF signaling pathway in hippocampus showed that compared with NC group,the m RNA level of CREB in SATD group was decreased,but not significantly（P=0.2985）,and the m RNA levels of PRKaca（P<0.05）and BDNF（P<0.05）were significantly decreased.Compared with SS group,the m RNA levels of CREB（P<0.01）and PRKaca（P<0.05）in SSE group were significantly increased,and the m RNA level of BDNF increased,but not significantly（P=0.0502）.Compared with SS group,the m RNA level of CREB in SP+-Exercise group was significantly increased（P<0.05）,and there was no significant difference in the m RNA level of other genes.The Simple western experiment results of FNDC5/CREB/BDNF signaling pathway-related proteins in hippocampus showed that the protein levels of CREB,p-CREB and BDNF in SATD group（P<0.05）were significantly lower than those in NC group.Compared with SS group,the protein level of CREB in SSE group was significantly increased（P<0.05）,and the protein level of BDNF was increased,but not significantly（P=0.0860）.Compared with SS group,the protein level of CREB in SP--Exercise group was increased,but it was not significant（P=0.1355）.（4）The results of immunofluorescence experiment showed that compared with NC group,the expression of SYN in hippocampal CA1d region of SATD group was decreased,but not significantly（P=0.0513）,and the expression of GAP-43 was significantly decreased（P<0.01）;the expression of GFAP in hippocampal CA1v region of SATD group was significantly decreased（P<0.05）,and the expressions of SYN（P=0.0706）and GAP-43（P=0.0504）were decreased,but there were no significant difference.Compared with SS group,the expressions of SYN and GAP-43 in hippocampal CA1d region of SSE group were significantly increased（P<0.05）;the expressions of GFAP（P<0.05）and SYN（P<0.01）in hippocampal CA1v region were significantly increased.Compared with SS group,the expression of SYN in hippocampal CA1v region of SP+-Exercise group was significantly increased（P<0.01）.Conclusion:（1）Simplified acute tryptophan depletion can lead to depressive behavior in mice.Exercise preconditioning can effectively alleviate the depressive behavior induced by simplified acute tryptophan depletion.（2）Simplified acute tryptophan depletion induced depressive behavior is related to the down-regulation of the expression of PGC-1αand its downstream molecules in hippocampus.Exercise preconditioning may play a role in alleviating depressive behavior by enhancing the expression level of PGC-1αin skeletal muscle and hippocampus.（3）The depressive behavior induced by simplified acute tryptophan depletion may be related to the disorder of FNDC5/CREB/BDNF signaling pathway where PGC-1αis located.Exercise preconditioning may alleviate depressive behavior by activating this signaling pathway.（4）The alleviating effect of exercise preconditioning on depressive behavior induced by simplified acute tryptophan depletion is related to the up regulation of the expression of synaptic plasticity related proteins such as GFAP,SYN and GAP-43 in hippocampus.PGC-1αmay mediate the process of exercise preconditioning regulating synaptic plasticity to alleviate depressive behavior.Significance:In this study,simplified acute tryptophan depletion mice were used as animal models to explore whether simplified acute tryptophan depletion could lead to depressive behavior in mice.This is a new exploration and attempt of animal models of depression.On this basis,this paper focuses on the alleviating effect of exercise preconditioning on depressive behavior in mice,and the role of PGC-1αand FNDC5/CREB/BDNF signaling pathway in mediating the process of exercise preconditioning in alleviating depressive behavior,so as to provide new evidence for the study of exercise antidepressant theory in the future. |
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