Antidepressant-likeeffectsandcognitiveenhancementofSchisandrach inensisinchronicunpredictablemildstressmiceanditsrelated mechanism五味子对慢性不可预见性轻度应激小鼠的抗抑郁样作用和认知增强作用及其相关机制TingxuYan1,Bosai He2,ShutongWan1,MengjieXu1,HuilinYang1,FengXiao3,Kaishu nBi2&YingJia3AbstractTheaimofthisstudywastoevaluatewh etherSchisandrachinensisextract(SCE)administrationinfluence schronicunpredictablemildstress(CUMS)-induceddepressionand cognitiveimpairment,andexploresunderlyingmechanisms.Sucros epreferencetest(SPT)andforcedswimmingtest(FST)wereused forassessingdepressivesymptoms,andY-maze,Morriswatermaze wereusedforevaluatingcognitionprocesses.Theresultsshowed thatCUMS(4weeks)waseffectiveinproducingbothdepressionan dmemorydeficitsinmice.Additionally,CUMSexposuresignifican tlydecreasedbrainderivedneurotrophicfactor(BDNF)levelsin hippocampusasindicatedbyELISA,immunohistochemistryandimmun ofluorescenceassays,accompaniedbydown-regulatedtyrosinekina sereceptorB(TrkB)/cAMP-responseelementbindingprotein(CREB) /extracellularsignal-regulatedkinase(ERK)andphosphatidylinos itol3kinase(PI3K)/proteinkinaseB(AKT)/glycogensynthasek inase-3β(GSK-3β)signalingpathways.ChronicadministrationofS CE(600or1200?mg/kg,i.g.)significantlypreventedalltheseCU MS-inducedbehavioralandbiochemicalalterations.Itsuggestedt hatSCEcouldimprovethedepression-likeemotionalstatusandas sociatedcognitivedeficitsinCUMSmice,whichmightbemediated byregulationofBDNFlevelsinhippocampus,aswellasup-regul atingofTrkB/CREB/ERKandPI3K/AKT/GSK-3βpathways.本研究的目的是评估五味子提 取物(SCE)的施用是否影响慢性不可预见性轻微刺激(CUMS)诱导的抑郁和认知障碍,并且探索其潜在机制。蔗糖偏好测验(SPT)和强 迫游泳实验(FST)被用来评估抑郁症状,Y型迷宫和Morris水迷宫被用来评估认知过程。结果显示,CUMS(4星期)对小鼠的抑郁症 状和记忆缺损有作用。此外,在酶联免疫吸附测定(ELISA)、免疫组织化学和免疫荧光检测的显示下,CUMS作用显著减少了海马体中脑源 性神经营养因子(BDNF)的水平,同时伴随着酪氨酸激酶受体B(TrkB)/cAMP应答元件结合蛋白(CREB)/细胞外信号调节激酶 (ERK)和磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(AKT)/糖原合成酶激酶-3β(GSK-3β)信号通路的一系列下调。慢性控制 下的SCE(600or1200?mg/kg,i.g.)明显抑制了这些CUMS诱导的行为和生化变化。综合表明,SCE能够改善C UMS小鼠的抑郁样情感状态并且和认知缺陷有关联,可能是受海马体BDNF水平的调节和TrkB/CREB/ERK和PI3K/AKT/G SK-3β通路的上调所影响。IntroductionDepressionisacommonillnessworldwid e,withanestimated350millionpeopleofallagesafectedaccor dingtoareportofWHOin20141,itisalsotheleadingcauseof disabilityandisamajorcontributortotheoverallglobalburd enofdisease.Depressionisaheterogeneoussyndromeandmayres ultinpoorerwell-being.Atitsworst,depressioncanleadtosu icide2.Ingeneral,mostclinicalsymptomsofmajordepressivedi sorder,suchasdelusions,anxiety,irritabilityorinsomnia,can beefectivelytreatedbycurrentpsychopharmacologicaltreatment s.Nevertheless,cognitivedefcits(likeadiminishedabilityto thinkorconcentrate,orindecisiveness),whichrepresentcorede fcitsofdepression3,maypersistinpatientsevenwhendepressiv esymptomshaveabatedordisappearedandsignificantlyaffectth eindividual’ssocialandoccupationalfunction.Indeed,meta-ana lyseshaveshownthatcognitivedefcitsarestillpresentinremi ttedpatients4.Forthisreason,cognitiveimpairmentemergesas apotentialtargetforbothpharmacologicalandpsychosocialtrea tments,withthefinalgoalofimprovingfunctioning.抑郁症是一种全球广泛的常 见疾病,据WHO报道称至2014年估计有3.5亿各年龄段的人深受其害,而且它也是造成残疾的主要因素和全球疾病负担的一大主力贡献者。 抑郁症是一种病情复杂的综合症状,可能会导致较差的健康。更糟糕的是,抑郁症会导致自杀的发生。一般来说,大多数重度抑郁症的临床表现有妄 想、焦虑、烦躁或失眠,可以被现在的精神药物治疗有效地解决。然而,认知功能障碍(如思考能力减弱或集中或犹豫不决),作为抑郁症核心障碍 的体现,即使当抑郁综合征状减少或者消失,它可能仍然存留在病人身上,明显地影响到个体的社会功能和职业能力。事实上,荟萃分析显示,认知 障碍仍然出现在已经被治疗的病人身上。因此,认知损伤恢复成为药理治疗和心理治疗的潜在目标,改善健康是最终的目标。BDNFisa memberofthenervegrowthfactorfamilyandisexpressedinthe adultmammaliancentralandperipheralnervoussystem,particular lyinthehippocampusandcortex5.Thevastmajorityoftheliter aturelinkingneurotrophinstomooddisordersdealswithBDNF,ot herneurotrophinsshowingonlyveryminorrole6-8.Inaddition,c linicalstudieshaveshownthatserumBDNFlevelsandhippocampal volumereductionsinelderlyindividualsarecloselycorrelated withmemoryloss9,10,andBDNFmayrescuecognitiveimpairments andlearningdeficitsinAlzheimer’sdisease11,12.Previousrepo rtsindicatedthatchangesinBDNFlevelareimplicatedinthepa thophysiologyofcognitivedeclineindepressionandneurodegener ativedisorders13.BDNFexertsitspro-survivaleffectsbybindin gitshighaffinityreceptorTrkB,toactivateBDNF-TrkBsignalin g14.Behavioralresponsestoantidepressantshavebeenabolished inanimalsinwhichBDNF-TrkBsignalingisinhibited15.Itisals oinvolvedinpropofol-inducedlearningandmemoryimpairments16. Tus,theseresultssuggestthatBDNF-TrkBsignalingplaysacrit icalroleinthemolecularmechanismsofantidepressantsandcogn itionenhancement.BDNF-TrkBdownstreamsignaling,includingERK/ CREBandPI3K/AKT/GSK-3βpathways,canmodulateneurotransmitter release,cellviability,apoptosisandpostsynapticresponses,an dthesefunctionsarecloselyassociatedwithdepression17,18an dlearningability19.BDNF是神经生长因子家族的一员,在成年哺乳动物中枢和周围神经系统中被表达,特别是在海马 体和皮层中。大多数文献指出神经营养因子与情绪混乱之间是通过BNDF联系的,其他的神经营养因子则几乎无作用。此外,临床研究显示,在老 年个体中血清BDNF水平下降和海马体体积减小是和失忆紧密联系的,并且对于老年痴呆症,BDNF也许能挽救认知障碍和学习缺陷的症状。以 前的研究表明BDNF水平的改变被牵涉进抑郁症人群的认知能力下降和神经退行性疾病的病理生理学研究中。BDNF通过结合它的高亲和力受体 TrkB,启动BDNF-TrkB信号通路来发挥它的促存活作用。当BDNF-TrkB信号通路被抑制时,动物对抗抑郁药物的行为反应会丧 失。它也参与异丙酚诱导的学习和记忆损伤。因此,这些结果显示BDNF-TrkB信号在抗抑郁药和认知增强的分子机制研究中具有很关键的作 用。BDNF-TrkB下游信号,包括ERK/CREB和PI3K/AKT/GSK-3β通路,可以调节神经递质的释放、细胞活力、细胞凋 亡和突触后效应,并且这些作用与抑郁症和学习能力有着紧密的联系。About30%ofpatientssufferingfr omamajordepressivedisorderdonotrespondsufficientlytoest ablishpharmacological,psychotherapeutic,orsomatictreatments2 0.Inaddition,differentstudiesconcludethatonly30–40%ofpa tientsthatareoptimallytreatedwithfirstlineantidepressants achieveremissionandmorethanonethirdofpatientswithdepre ssionareclassifiedastreatment-resistantdepression(TRD)21.I nordertodealwiththementionedlimitationsshownbycurrenta ntidepressantdrugs,traditionalChinesemedicine(TCM)isattrac tingincreasingattentionasamethodformeetingthedemandsfor higherremissionrate,fasteronset,persistentantidepressanta ction,andfeweradverseeffects22-24.Schisandrachinensis(Truc z.)Bail.isafamoustraditionalChinesemedicinewhichisusual lyusedintheclinicwiththefunctionsofinducingastringency, replenishingandpromotingtheproductionofbodyfluidandtoni fyingthekidneystorelievementalstrain25.Dibenzo[a,c]cycloo ctadienelignansarethemainchemicalcomponentsinSchisandrac hinensisextract(SCE),andtheseareshowingvariouspharmacolog icalactivities,ofwhichtheirantioxidative,neuroprotective,a nti-cancer,vasorelaxantandcytoprotectivepropertiesareamong themoststudiedones26-28.OurgrouppreviousreportedthatSCE couldproduceantidepressant-likeeffectsindifferentdepressed models29,30,andamelioratecognitiondeficits31.However,thepot entialneuroprotectiveeffectsofSCEagainsttheCUMS-inducedde pressionandcognitivedeficits,aswellasthemechanismsremain tobeclarified.Thus,inthisstudy,weusedtheCUMSmodelto investigatetheantidepressant-likeactivityandcognitiveimpair menteffectsofSCE,moreover,theBDNF/TrkB/ERK/CREBandPI3K/AK T/GSK-3βsignalingpathwaysweredeterminedtoillustratetheact ionmechanismofSCE.大约30%的病人患有重度抑郁症,用建立药理学治疗、心理学治疗和体细胞治疗的方式尚不足以 治愈该疾病。此外,不同的研究总结得出,只有30-40%的用一线抗抑郁药治疗的患者达到缓解效果,超过三分之一的抑郁症患者被列为耐药性 抑郁症(TRD)。为了应对目前抗抑郁药所表现出来的局限性,中医药学(TCM)作为一种满足高缓解率、更快见效、持续抗抑郁和更少副作用 需求的一种治疗方式,正在引起越来越多的关注。五味子(防风属),是一味著名的中药,经常被用于诊所中,具有诱导止血、补充和促进体液生产 以及滋补肾脏来缓解精神紧张的作用。二苯并[a,c]环辛二烯木脂素是五味子提取物(SCE)的主要化学成分,它们具有各种药理学作用,其 抗氧化,神经保护,抗癌,血管舒张和细胞保护能力是被研究最多的。我们团队曾报道过SCE可以在不同的抑郁模型中产生抗抑郁效果和改善认知 障碍。然而,SCE对CUMS诱导的抑郁症和认知障碍的潜在神经保护作用以及机制仍有待澄清。因此,在这篇论文,我们采用CUMS模型来研 究SCE的抗抑郁作用和认知损伤效果,并确定BDNF/TrkB/ERK/CREB和PI3K/AKT/GSK-3β的信号通路来建立S CE的作用机制。DiscussionNumerousneuropsychologicalstudieshaveexamin edtheroleofcognitioninpsychopathology,revealingthatmost psychiatricdisordersareassociatedwithsomedegreeofcognitiv eimpairment32.WeusedCUMSproceduretomimicthesymptomofde pressionconfirmedbySPTandFSTinmiceinourbehavioralstudi es,whichisconsistentwithpreviousreports33.Further,CUMSal soimpairedthecognitivefunctionofmiceaccordingtotheperfo rmancesofYmazeandMWMtest,whicharetwoclassicalmethodst oassesstheabilityoflearningandmemory.Theseresultsarewe llcoincidentwithpreviousstudies34,35.However,withthetreat mentofSCE,theanhedonia-likebehaviorinsucrosepreferencete standimmobilitytimeinforcedswimtestwhichbothinducedby CUMSweresignificantincreased,respectively.Ontheotheraspec t,thespontaneousalternationinYmaze,timeinthetargetquad rantandescapelatencyintrainingofSCEmicewereremarkablei mprovedcomparedtotheCUMSmice.AndNosignificantdifferences ofthetotaltraveldistanceinthelocomotoractivitytestand numberofarmentriesinYmazewhichcouldexcludethefalsepos itiveresultscausedbythemobilityofmiceduringallthebehav ioraltests.Moreover,wefoundasignificantcorrelationbetween thesucrosepreferencevs.spontaneousalternation,thesucrose preferencevs.timeinthetargetquadrant,immobilitytimevs.s pontaneousalternationandimmobilitytimevs.timeinthetarget quadrantwhenlinearregressionwasdetermined(Fig.10).Integra tedwiththeresultsofH.E.staining,wefoundthatSCEindeedh astheabilitytoimprovethedepressivesymptomsandtheassocia tedcognitivedeficitseffectively.许多神经心理学研究已经论证了认知在精神病理学中的作用,揭示了 大多数精神失调与一定程度的认知障碍有关。我们使用CUMS程序来模拟我们在行为研究中已被SPT和FST小鼠证实的抑郁症状,这和之前的 研究是一致的。此外,根据Y迷宫和MWM这两种评估学习和记忆能力的经典方法的测试结果显示,CUMS也会损害小鼠的认知功能。这些结果与 以前的研究是符合的。然而,在SCE的治疗下,由CUMS诱导的蔗糖偏好测试和固定时间的强迫游泳测试中,快感缺失行为分别显著得到改善。 另一方面,与CUMS小鼠相比,SCE小鼠的Y迷宫自发交替、到达目标象限的时间和训练的逃生潜伏期得到显著改善。并且在运动行为测试中的 总奔跑路程和在Y迷宫测试中的进臂次数没有明显的差异,可以排除小鼠在所有行为测试中的不定性造成的假阳性结果。此外,当在确定线性回归时 ,我们发现在蔗糖偏好和自发交替、蔗糖偏好和目标象限时间、不动时间和自发交替以及不动时间和目标象限时间之间存在着明显的相干性(图10 )。整合HE染色的结果,我们发现SCE确实具有有效改善抑郁症状和相关认知缺陷的能力。Figure10.Pearson’sco rrelationbetweenthesucrosepreferencevs.spontaneousalternat ion(A),thesucrosepreferencevs.timeinthetargetquadrant( B),immobilitytimevs.spontaneousalternation(C)andimmobilit ytimevs.timeinthetargetquadrant(D).图10:在蔗糖偏好与自发交替之间的皮尔森相关 性(A),蔗糖偏好与目标象限中时间的比较(B),不动时间与自发交替的比较(C)和不动时间与目标象限时间的比较(D)。Theint errelationshipbetweendepressionandcognitiveimpairmentiscom plexandstillnotwellunderstood.Inthebrain,BDNFhasbeeni mplicatedindevelopment,neuralregeneration,synaptictransmiss ion,synapticplasticityandneurogenesis36.AlternationinBDNF levelshavebeenimplicatedinpsychiatricdisorders,includingd epressionandsubstanceabuse,aswellasneurodegenerativedisor ders,suchasAlzheimer’s,Parkinson’sandHuntington’sdiseases3 7.WefoundthatinthehippocampusofCUMS-inducedmice,BDNFle velsweresignificantlydecreased,andtheresultsofY-mazeand MWMtestwereshownthatthecognitionimpairmentalongwiththe depressionsymptoms.AftertreatmentwithSCE,theBDNFlevelswe reupregulated,andthedepressionsymptomsandcognitiondecline werealleviatedatthesametimeaccordingtothebehavioralres ults.BesidestheresultsofimmunohistochemistryanalysisandIm munofluorescenceassay,theaboveallillustratedthatBDNFhasp layedavitalrolebothindepressionandthelearningobstaclet riggeredbyit,whichinlinewiththepreviousreports38.抑郁症和认知障 碍之间的相互关系是复杂的,且尚未弄清楚。在大脑中,BDNF涉及神经发育、神经再生、突触传递、突触可塑性和神经发生。BDNF水平的变 化涉及到精神障碍,包括抑郁症和药物滥用,以及神经退行性疾病如阿尔兹海默症、帕金森症和亨廷顿病。我们发现在CUMS诱导的小鼠的海马体 中,BDNF水平显著减少,并且Y迷宫和MWM测试的结果显示认知功能障碍伴随着抑郁症状。经SCE治疗后,BDNF水平得到上调,同时在 行为测试结果中发现抑郁症状和认知功能障碍得到缓解。除了免疫组织化学分析和免疫荧光检测的结果,以上所有结果都说明BDNF在抑郁和学习 障碍中扮演了至关重要的角色,这也符合以前的报导。Tropomyosin-relatedkinaseB(TrkB),ap roteintyrosinekinasereceptorandamemberofthelargerfamily ofTrkreceptors,whichwasexpressedathighlevelsinthebrai n,wasidentifiedastheprimarysignaltransductionreceptorfor BDNF.MultiplelinesofevidencelinkBDNF-TrkBsignalingtothe pathophysiologyofMDD,aswellasthetherapeuticmechanismsof antidepressants39,40.Furthermore,extensiveexperimentaleviden cesupportsthatBDNFmitigatesdepressivesymptomsmainlybybin dingtoTrkB,leadingtoautophosphorylationofTrkBtyrosineres idues,andactivationofdownstreamsignalingmolecules,includin gtheextracellularsignal-regulatedkinase1/2(ERK1/2)knownto phosphorylatecAMPresponseelementbindingprotein(CREB)41.It hasbeenreportedthatthefull-lengthTrkBautophosphorylation regulateERKonactivationbyBDNF,whichmayincreasecAMPanda ctivateCREB-regulatedgenetranscription,andthismechanismfur therpromotestranscriptionofBDNF42.Inagreementwithprevious studies,weobservedthatCUMS-induceddepressivesymptomsandc onsequentBDNF/TrkB/CREB/ERK1/2signalingdown-regulationreverse dbySCEtreatment,whichindicatedthatSCEcouldincreaseBDNF expressionbyaffectingTrkB/CREB/ERK1/2pathwaytoexertantidep ressant-likeeffect.Additionally,interactionofBDNFwithTrkB triggersreceptordimerization,transphosphorylationofintracell ulartyrosineresidues,andsubsequentactivationofthethreema jorsignalingpathwaysinvolvingMAPK/CREB/ERK,phosphatidylinosi tol3kinase(PI3K)/AKT,andphospholipaseC-γ43.PI3K/AKTandER KsignalingpathwaysarethemajorTrkB-mediatedsurvivalpathway sthatpromoteneuronalsurvivalandprotectagainstapoptosis.B DNF/TrkBsignalingcanpromotefurtherBDNFproductionthroughCR EBviaactivationofPI3K/AKTorERKsignaling,whichisemergin gasapositive-feedbackloop44.TrkB-inducedPI3Kactivityleads toAKTactivation,andonceactivated,AKTleadstoinactivation ofGSK-3βatSer-9.Morerecentfindingsshowedthatdisruptionof GSK-3phosphorylationbyAKTdecreasesanxietyandreducesprone nesstodepressioninmice45andintracellularsignaltransductio nsystemasAKT/GSK-3βpathwayhavebeenfoundtobealteredint hebrainofdepressivepatients46.Thisprovidescompellingevide ncethatthePI3K/AKT/GSK-3βsignalingpathwayisanimportantco ntributortodepression.HerewedemonstratedthattheSCEtreatm entwasabletoactivatePI3K/AKT/GSK-3βsignalingpathway,aswe lltopromoteincreasedphosphorylatedlevelsofrelatedproteins ,toimprovethedepressivesyndromesinCUMS-inducedmice.Taken allabovetogether,thesefindingsleadustosuggestthatSCEa ctingasanantidepressantincreasesBDNFlevelsbypromotingTrk B/CREB/ERKpathwayandactivatingPI3K/AKT/GSK-3βpathwaysimulta neously(Fig.?11).原肌球蛋白相关激酶B(TrkB),一种酪氨酸蛋白激酶受体,作为Trk受体大家族的一员,在大脑中 被高水平地表达,现已被确认为BDNF的早期信号转导受体。多种证据将BDNF-TrkB信号通路和MDD的病理生理学、抗抑郁药的治疗机 制联系起来。而且,广泛实验证据支持BDNF主要通过结合TrkB使TrkB的酪氨酸残基磷酸化并激活下游信号分子,包括已知的磷酸化cA MP反应原件结合蛋白(CREB)和胞外信号调节激酶1/2(ERK1/2)来缓解抑郁症状。据报道,激活的磷酸化TrkB通过激活BD NF来调节ERK,可能会增加cAMP含量和激活CREB调节基因转录,并且这个过程进一步促进BDNF的转录。与以前的研究一致,我们观 察到CUMS诱导的抑郁症状和用SCE治疗后随之发生的BDNF/TrkB/CREB/ERK1/2信号下调得到逆转,这表明SCE可以通 过影响TrkB/CREB/ERK1/2通路来增加BDNF表达量以发挥抗抑郁作用。需要补充的是,BDNF和TrkB的相互作用触发了受 体二聚体化、细胞内氨基酸残基的转磷酸化和随后的三个主要信号通路的激活,包括MAPK/CREB/ERK、磷脂酰肌醇3激酶(PI3K) /AKT和磷脂酶C-γ。PI3K/AKT和ERK信号通路是主要的TrkB介导的促进神经元存活并防止细胞凋亡的自救途径。BDNF/T rkB信号通路可以通过CREB经过PI3K/AKT或ERK信号的激活能够进一步促进BDNF的生产,如此形成了一个正反馈环路。Tr kB诱导的PI3K激活导致AKT活化,并且一旦激活,AKT将使Ser-9处的GSK-3β处失活。更多最近的研究结果表明小鼠中AKT 对GSK-3磷酸化的终止减少了焦虑和降低了抑郁的倾向性,并且像AKT/GSK-3β类的细胞内信号转导系统已被发现在抑郁症患者的脑中 发生了改变。这也为PI3K/AKT/GSK-3β信号通路是抑郁症重要的效力者提供了令人信服的证据。这里我们展示了SCE治疗有可能激 活PI3K/AKT/GSK-3β信号通路,以及促进相关蛋白磷酸化水平的提高,以改善CUMS诱导小鼠的抑郁综合征。综上所述,这些研究 表明,SCE作为抗抑郁药是通过促进TrkB/CREB/ERK通路同时激活PI3K/AKT/GSK-3β通路来增加BDNF水平。Fi gure11.ProposedSCEantidepressant-likemechanismsfortheinte ractionamongBDNF,TrkB,CREB,ERK,PI3K,AKTandGSK-3β.SCEre gulatesTrkB/CREB/ERKpathwaytoincreasetheBDNFtoalleviatet hedepressionandcognitivedecline.Ontheotheraspect,BDNFup regulatesPI3K/AKT/GSK-3βpathwaytoamelioratethedepressives ymptomsandcognitiondisabilityinducedbyCUMS.图11:BDNF,TrkB,CR EB,ERK,PI3K,AKT和GSK-3β之间相互作用的模拟的SCE抗抑郁药物机制。SCE调节TrkB/CREB/ER K途径增加BDNF以减轻抑郁症和认知功能下降。另一方面,BDNF上调PI3K/AKT/GSK-3β途径,改善由CUMS引 起的抑郁症状和认知障碍。Basedontheformerresearch,depressioncanbeapsy chologicalreactiontocognitivedecline,andthusmayalsoappearasanearlysymptomindementingindividuals47.However,recentdatasuggestthatdepression,andinparticularlylate-lifedepression,canalsobeariskfactorforAlzheimer’sdisease48.Inourpresentstudy,weconfirmedthatSCEcouldtreatdepressionandshowadefiniteimprovementofcognition.Thefurtherandin-depthstudyontheinteractionsbetweendepressionanddementia,andtheseparate,simultaneouseffectsofSCEonthesetwokindsofdiseaseswouldbeperformedinthefuturestudy.基于之前的研究,抑郁可能是一种认知衰退的心理反应,因此也可能表现为痴呆症患者的早期症状。然而,最新的数据显示抑郁,特别是晚期抑郁症,有可能成为阿尔兹海默症的危险因素。在我们目前研究中,我们证实了SCE可以治疗抑郁症并且明显改善认知功能,今后研究将进一步深入研究抑郁与痴呆之间的相互作用,以及SCE对这两种疾病的单独和同时影响效果。Insummary,ourstudyshowsthattheantidepressant-likeeffectandcognitionimprovementabilityofSCEdependsonBDNFlevelsraisebyincreasingTrkB/CREB/ERKpathwayandPI3K/AKT/GSK-3βpathwayinthemeantime.OurfindingssuggestthatSCEmightbeapromisingtherapeuticagentofdepression,andfurtherresearchisworthtobeinvested.总之,我们的研究表明,SCE的抗抑郁效果和认知改善能力依赖于通过同时促进TrkB/CREB/ERK通路和PI3K/AKT/GSK-3β通路致使的BDNF水平的提高。我们的发现表明SCE也许会成为一种有前途的抑郁症治疗剂,并且对其进一步的研究是值得投入的。1 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