Study Of Antidepressive Effect And Molecular Mechanisms Of Exercise

PurposeTo investigate effects of regular exercise,the selective serotonin reputake inhibitor, fluoxetine(Flu),and the combination of them on behavior,neuronal impairment,and the neurotrophic factor signal pathway in the chronic unpredictable stress(CUS)animal model of depression,and to elucidate possible molecular mechanisms of antidepressive-like effect of exercise and it's combination with fluoxetine.Methods65 Male SD rats were habitually housed for three days and then adaptively exercised on treadmill for one week.According to running performance and body weight 56 rats were balancedly grouped into seven groups:Control,CUS,Flu,low intensity treadmill running(LIR),moderate intensity treadmill running(MIR),Flu+LIR and Flu+MIR.CUS was exercted on all groups exception of the Control group for four weeks.The Flu,Flu+LIR,and Flu+MIR group,fluoxetine(10mg/kg/day,2ml/kg)was applied to rats before one hour of daily stress.Other groups were administrationed same volume of saline.The LIR,MIR,Flu+LIR,and Flu+MIR group were exercised different intensity of treadmill running.After four weeks of CUS,chocolate milk anhedonia test,open-field test,novelty-suppressed feeding and together with weekly body weight were determined. Morphological,cytoarchitectural and quantitative changes of hippocampal CA1 pyramidal neurons were detected using immunohistochemistry,MAP-2C expression was determined using western-blotting.The expression of hippocampal brain-derived neurotrophic factor(BDNF),extracellular signal regulated kinase(ERK),phosphor-ERK (pERK),VGF(a neuropeptide,nonacronymic)were determined using western-blotting.Results(1)Behavioral studiesCUS significantly decreased the chocolate milk preference and spontaneous activity, prolonged latency to feed,and concomitant treatment with Flu could reverse these changes.CUS concomitant with exercise hasthe same antidepressive-like effect as Flu.(2)Body weightCUS could significantly suppress the increase of body weight.Flu,Flu+MIR and Flu+LIR did not improve CUS-induced the suppression of body weight.LIR and MIR reversed the low increase of body weight and they did not have significant difference compared with that of CUS.(3)Neurobiological studiesâ‘ immmunohistochemistry stainingCUS destructed the normally hippocampal morphosis,reduced the number of hippocampal CA1 pyramidal neurons.Flu,MIR,Flu+LIR and Flu+MIR could antagonize the CUS-induced hippocampal impairement and the reduction of the number of hippocampal CA1 pyramidal neurons.The antagonistic effect of Flu on the reduced number of hippcampal CA1 pyramidal neurons was better than that of LIR and MIR,respectively.â‘¡western-blottingCUS down-regulated significantly the expression of MAP-2C,pERK,BDNF and VGF in hippocampus.Flu,MIR,Flu+LIR and Flu+MIR could improve these changes. Flu+LIR up-reguated the expression of hippocampal pERK and BDNF but the expression of hippocampal MAP-2C and VGF.The up-regulaed effect of MIR and Flu+LIR on the expression of hippocampal pERK was better than that of LIR.The up-regulated effect of Flu+MIR on the expression of hippocampal BDNF was better than that of Flu or MIR,respectively;Flu+LIR was better than LIR.Conclusion(1)We successfully duplicated the CUS animal model of depression,which simulated the depressive-like behaviors as following:significantly decreased in chocolate milk preference in and spontaneous activity,prolonged latency to feed,and slowed growth of body weight.(2)Exercise could significantly improve the reduction of chocolate milk preference and spontaneous activity,and the augmentation of latency to feed in CUS model.These behavioral changes were consistent with the effect of fluoxetine in CUS model.(3)The antidepressant mechanisms of exercise may be related to following: exercise can antagonize the chronic stress-induced hipocampal impairment via:â‘ protecting the morphology and cyto-architecture of hippocampal CA1 pyramidal neurons;â‘¡preventing reduction of the number of hippocampal CA1 pyramidal neurons;â‘¢up-regalting the expression of hippocampal MAP-2C in CUS model of depression;â‘£up-regalting the expression of hippocampal BDNF,pERK and VGF which were related to BDNF's signal pathway may be underlying the neurotrophic and neuroplastic effects of exercise.(4)The neuroprotective and neurotrophic effect of fluoxetine can be enhanced further by exercise.