| Background:In 2017,World Health Organization reported that the total number of people living with depression in the world is 322 million,It was estimated that 4.2%of the China population suffer from depressive disorder.Depressive disorders led to China for a total of over 8.9 million Years Lived with Disability(YLD)in 2015.Both fluoxetine and exercise can improve depression-like behaviors,but the mechanisms underlying its effects still remain unknown.FGF9 is a member of fibroblast growth factor family,playing a critical role in CNS development via neuronal fate determination,maintenance of cell survival and differentiation.FGF9 has been found dysregulated in postmortem brain tissue from individuals with major depressive disorder.In 2015,a study published in PNAS reported that FGF9 as an endogenous molecule promoted negative affect and might play a role in vulnerability to major depression.While another study recently found that bred low responders(bLRs)animals had significantly lower FGF9 expression in the dentate gyrus and the CA1 subfields of the ventral hippocampus.Therefore,the role of FGF9 in depression is yet unclear.Previous studies indicated that FGF signaling might cross-talk with GSK3?/?-catenin signaling pathway,whether this interactive mechanism is underlying the antidepressant effects of fluoxetine and exercise needs to be further understood.Objective:The current study aims to investigate the expression of FGF9 and related signaling proteins in the brain of chronic unpredictable mild stress mouse model.On this basis,we will further explore and compare the mechanism of exercise and fluoxetine in the treatment of depression.Methods:A total of 50 male C57/BL6 mice(18-20g,4-5weeks old),were randomly divided into five groups:Con,Control;CUMS,The experimental mice experienced 7 weeks of chronic unpredictable mild stress;CUMS+Saline,fourth weeks of CUMS began to inject saline;CUMS+Flu,fourth weeks of CUMS began to inject fluoxetine;CUMS+Swim,fourth weeks of CUMS began to swimming exercise.After 7 weeks of experimental treatment,behavioral tests were performed.Mice were decapitated;Blood was taken and then separateed the serum and blood cells.Serum corticosterone concentrations were determined using a commercially Elisa kit.The hippocampus and prefrontal cortex were rapidly and carefully extracted.Real-time PCR were used to examine the mRNA levels of FGF9,FGF2,FGFR1,FGFR2,and FGFR3.Western blotting were used to examine the protein levels of FGF9,Akt,pAkt(Ser473),GSK3?,pGSK3?(Ser9),pGSK3?(Tyr216),and ?-catenin.Results:(1)CUMS exposure induced depression-like behaviors,including reduced sucrose preference,reduced number of poking into holes in OFT,decreased weight gain,increased immobility time in FST and TST,as well as increased serum CORT level compared to the control.Fluoxetine could ameliorates depression-like behaviors induced by CUMS,including increased sucrose preference,increased number of poking into holes in OFT,decreased immobility time in FST and TST,compared to the CUMS+Saline group.Swimming exercise could ameliorates depression-like behaviors induced by CUMS,including increased number of poking into holes in OFT,decreased immobility time in FST and TST,compared to the CUMS group.(2)CUMS exposure significantly decreased the mRNA levels of FGF9,FGF2,and FGFR3 in hippocampus,as well as FGFR3 in prefrontal cortex,compared to the control.Fluoxetine significantly increased the mRNA levels of FGF9,FGF2,and FGFR2 in HPC,compared to the CUMS+Saline group.Swimming exercise significantly increased the mRNA levels of FGF9,FGF2,FGFR1,FGFR2,and FGFR3 in HPC,as well as FGFR3 in PFC,compared to the CUMS group.The correlation analysis showed that the mRNA level of FGF9 in HPC was inversely correlated with serum CORT level,and immobility time in TST,and a positive correlation with poking number in OFT.The mRNA level of FGF9 in PFC was in positive correlation with poking number in OFT.Moreover,The mRNA level of FGF9 was positively correlated with FGF2,FGFR1,FGFR2,and FGFR3 in HPC,The mRNA level of FGF9 was positively correlated with FGF2,FGFR2,and FGFR3 in PFC.(3)CUMS exposure significantly decreased the protein levels of FGF9,Akt,pAkt(Ser473),GSK3?,pGSK3?(Ser9),and ?-catenin in HPC,compared to the control.Fluoxetine significantly increased the protein level of Akt,pAkt(Ser473),and P-catenin in HPC,compared to the CUMS+Saline group.Swimming exercise significantly increased the protein level of Akt,pAkt(Ser473),GSK3P,pGSK3?(Ser9),and ?-catenin in HPC,compared to the CUMS group.The correlation analysis showed that the protein level of FGF9 was positively correlated with pAkt(Ser473),the protein level of pAkt(Ser473)was positively correlated with pGSK3?(Ser9),the protein level of pGSK3?(Ser9)was positively correlated with pGSK3P(Ser9).Conclusion:(1)Fluoxetine and exercise can enhance the tolerance of CUMS exposure and control the pathological process of depression.(2)Stress-induced depression is associated with decreased hippocampal FGF9 expression,Fluoxetine and exercise ameliorated depression-like behaviors are associated with increased hippocampal FGF9 expression.(3)Stress-induced depression is associated with the dysfunction of FGF9/Akt/GSK3?/?-catenin signaling pathway,and exercise ameliorated depression-like behaviors may associate with reversing the dysfunction of GSK3(3/?-catenin signaling pathway,and that fluoxetine ameliorats depression-like behaviors may be independent with GSK3?/?-catenin signaling pathway.Significance:This study unmasks a previously unidentified functional role of FGF9 in exercise and fluoxetine alleviating depression-like behaviors.To our knowledge,this is the first report showing that FGF9 may be an essential factor that mediates the antidepressant effects of exercise on the brain by FGF9-mediated activation of GSK3?/?-catenin signaling pathway.Our results reveal a possible mechanism by which exercise controls the pathological process of depression and also suggest a promising therapeutic treatment for depression. |
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