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Stress and emotional memorReviewStressandemotionalmemory:amatteroftimingMarianJoe虉ls1,GuillenFernandez2andBennoRoozendaal31DepartmentNeuroscienceandPharmacology,DivisionofNeuroscience,UMCUtrecht,RudolfMagnusInstitute,Utrecht,TheNetherlands2DepartmentforCognitiveNeuroscience,DondersInst...

Stress and emotional memor
ReviewStressandemotionalmemory:amatteroftimingMarianJoe虉ls1,GuillenFernandez2andBennoRoozendaal31DepartmentNeuroscienceandPharmacology,DivisionofNeuroscience,UMCUtrecht,RudolfMagnusInstitute,Utrecht,TheNetherlands2DepartmentforCognitiveNeuroscience,DondersInstituteforBrain,CognitionandBehavior,RadboudUniversityNijmegenMedicalCenter,Nijmegen,TheNetherlands3DepartmentNeuroscience,SectionAnatomy,UniversityMedicalCenterGroningen,UniversityofGroningen,Groningen,TheNetherlandsGlossaryCorticosteroidhormones:steroidhormonesproducedinthecortexoftheadrenalglands.Themaincorticosteroidhormoneinhumansiscortisolwhereascorticosteroneprevailsinmostrodents.Corticosteroidsbindtotwotypesofintracellularreceptors:themineralocorticoidandtheglucocorticoidreceptor.Onbindingofthehormone,thesereceptorstranslocatetothenucleuswheretheyeitherbindasdimerstospecificrecognitionsitesintheDNA(glucocorticoidresponseelements)orviaprotein鈥損roteininteractionsinfluencetranscriptionfactorsthatinteractwiththeDNA.Asmallfractionofthereceptorsisthoughttomovetotheplasmamembraneratherthanthenucleus.Genomiceffects:corticosteroidreceptorsactastranscriptionalregulators:theyalterthetranscriptionofasetofresponsivegenes(anestimated1鈥�%ofallgenes).Eventuallythisleadstochangesinthelevelsoftheproteinforwhichtheresponsivegeneencodes.Theprocessoftranscription,translationandinsomecasespost-translationalmodificationisthoughttotakeatleastonehourtobeaccomplished.Nongenomiceffects:neurotransmitters(e.g.glutamateornoradrenaline)generallyactthroughG-protein-coupledreceptorsorligand-gatedionchannels.Thisisafast-actingmechanismthatdoesnotinvolvegenetranscription:nongenomic.Recentlyithasbecomeevidentthatcorticosteroidhormonescanalsoactthroughsignalingpathwaysthatbypassgenetranscriptionandthuschangeneuronalactivityoverthecourseofminutesratherthanhours.Noradrenaline:catecholaminethatisenzymaticallyderivedfromdopamineandcanbeconvertedintoadrenaline.Noradrenalineisproducedtoalargeextentinthelocuscoeruleus,withadditionalproductionsitesinthebrainstem.Noradrenalinebindstoa-andb-adrenoceptorswhichthroughG-proteinsandsecondmessengersinducechangesinmembranepotentialatatimescaleofStressfuleventsactivatetheamygdalaandanetworkofassociatedbrainregions.Studiesinbothhumansandrodentsindicatethatnoradrenalinehasaprominentroleinthisactivation.Noradrenalineinducesahypervigilantstatethathelpstoremembertheevent.Thismnemoniceffectisenhancedwhenthesituationissostressfulthatsubstantialamountsofcorticosteroidsarereleasedandreachtheamygdala.Thecombinationofthetwohor-monesleadstooptimalstrengtheningofcontactsandthusmemory.Yet,risesincorticosteroidlevelsthatarenotpreciselysynchronizedwithnoradrenalinereleasedonotactsynergisticallybutratherpreventorsuppresstheeffectofnoradrenaline.Thisdynamicinteractionillustratestheadaptiveandpotentiallyprotectivecapac-ityofcorticosteroidsregardingtraumaticmemories.Timingisessential:themodelIndailylifepeoplegothroughmanysituationsthatpoten-tiallyimposeaphysicalorpsychologicalthreat.Thesub-jectiveexperienceofthesethreatsiscalledstress.Forstresstooccur,thethreateningsituationsdonothavetobefactual;veryoften,anticipationoftheeventissufficienttoinitiateabiologicalresponsemeanttoadapttotheconditions[1,2].Oneofthekeyfeaturesofsuccessfuladaptationisrememberingtheimportant(oftenemotion-allychallenging)aspectsofthestressfulsituationforfutureuse.Limbicareas,inparticulartheamygdala,playanimportantroleinestablishingsuchmemories.Thestressresponseishighlyconservedamongverte-brates(Box1).Aspartoftheresponse,neurons鈥�includingprincipalcellsintheamygdala鈥�receiveastrongnorad-renergicinputfromthelocuscoeruleus[3].Studiesinrodentsrevealedthatthiswaveofnoradrenaline(seeGlossary)isrelativelyshortlived(lastinglessthan30min-utes)[4].Thesameneuronsalsoreceivehighlevelsoftheadrenocorticalhormonecorticosterone(inmostrodentspecies;cortisolinhumans).Thekineticpropertiesofcorticosteroidexposureareslowerthanthoseofnoradren-aline;peakcorticosteroidlevelsinbrainareprobablynotreachedearlierthan20minutesafterstressonset,andnormalizationtakesplaceonlyafter1鈥�hrs[5].Neverthe-less,thereseemstobeawindowintimeduringwhichCorrespondingauthor:Joe虉ls,M.(m.joels@umcutrecht.nl).2801364-6613/$鈥�seefrontmatter2011ElsevierLtd.Allrightsreservelimbiccellsareexposedtoelevatedlevelsofbothnoradren-alineandcorticosteroidhormones(Figure1).Itshouldbeemphasizedthatalthoughnoradrenalineandcorticoster-oidsarekeyelementsinthestressresponse,theyaccom-plishtheirfulleffectinconcertwithseveralothertransmittersandhormones(Box1).Thepartiallyoverlappingpresence鈥�intimeandspace鈥�ofnoradrenalineandcorticosteroidssetsthestageforinteractions,providedthatsignalstransducedbyrecep-torsoftheseligandsactinthesametimeframe[6].NoradrenalinesignalsaremediatedviaG-protein-cou-pledmembranereceptorsthat,onactivation,changeneu-ronalfunctionwithinseconds.Activityisterminatedwhenligandconcentrationsdropbelowthelevelsneces-saryforsubstantialbinding.Althoughreceptoractivationcansecondarilygiverisetotranscriptionalchanges,thisisnotthemainpathwaythroughwhichnoradrenalineisthoughttoact.Corticosteroids,bycontrast,bindtoseconds.Downstreameffectormoleculescansecondarilychangegenetranscriptioninducingslowchangesinneuronalfunction.d.doi:10.1016/j.tics.2011.04.004TrendsinCognitiveSciences,June2011,Vol.15,No.6[()TD$FIG]NoradrenalineCorticosteroidsHormonelevelsintheBLAStressRapidanddelayednoradrenalineeffectsRapidanddelayedcorticosteroideffectsPotentialwindowsforfunctionalinteractionsCORT:SuppressiveCORT:SynergisticEncodingupCORT:NormalizationCognitivecontrolup(delayed)Quickreset(rapid)123hrsTRENDSinCognitiveSciencesFigure1.Shortlyafterstress,noradrenalinelevels(yellow)intheBLAaretransientlyelevated.Corticosteroids(blue)reachthesameareasomewhatlaterandremainelevatedforapproximately1鈥�hrs.ForarestrictedperiodoftimeBLAneuronsareexposedtohighlevelsofbothhormones(upperpanel).NoradrenalineprimarilyworksthrougharapidG-proteincoupledpathway(paleyellow)butsecondarygenomiceffectsrequiringgenetranscriptionmightdevelop(brightyellow).Bycontrast,effectsofcorticosteroidhormonesaremostlyaccomplishedvianuclearreceptorsthatmediateslowandpersistentactions(brightblue),althoughrapidnongenomicactionshavealsobeendescribedintheBLA(paleblue).Thelowerpanelreflectsthewindowsintimeduringwhichthetwohormonesmightfunctionallyinteract(green).Shortlyafterstress,corticosteroidsarethoughttopromoteeffectsofnoradrenaline(upwardarrow)enablingencodingofinformation.Lateron,corticosteroidhormonesnormalizeBLAactivity(delayedeffectviaGR),aphaseinwhichhighercognitivecontrolsseemtoberestored.Whencorticosteroidsaregivenoutofsyncwithnoradrenalinetheygenerallyworksuppressive.ThisisreflectedbythequickresetofBLAactivity(nongenomicGReffects)bycorticosteroneinorganismswitharecenthistoryofstressexposure.Itisalsoevidentfromexperimentsinwhichcorticosteroidsweregivenseveralhoursinadvanceofstressexposureornoradrenalineadministrationandexertedsuppressiveeffects.Thelatterisapharmacologicalsituationbutcouldpotentiallyservetherapeuticgoals.ReviewTrendsinCognitiveSciencesJune2011,Vol.15,No.6discretelylocalizednuclearreceptorsthatactastran-scriptionalregulators(Box1).Untilrecentlyitwasthoughtthatcorticosteroidsgenerallychangebrainfunc-tionthroughthesenuclearreceptors,viaaprocessthatisveryslowinonsetyetlonglasting[2].Ifso,corticosteroidswouldactatatimewhennoradrenergiceffectshavealreadysubsided.However,overthepastdecadeithasbecomeevidentthatcorticosteroidhormonescanalsoquicklychangeneuronalcellfunctioninanongenomicmanner[6,7].Thisresultsinapictureinwhichshortlyafterstressnoradrenalinereacheslimbiccellsandexertsitsrapidactionsthataftersomeminutesarepotentiallymodulatedbycorticosteroidhormones(Figure1).Simul-taneously,agene-mediatedcascadeisstarted鈥�primarilybycorticosteroidsbutpossiblyalsobymonoaminesorneuropeptidesreleasedafterstress鈥�thatseveralhourslaternormalizestheactivityoftheseneurons.Thispor-traystheneuronalstressresponseasafine-tunedhor-monalinterplayinwhichtimeisoftheessence.Belowwewillsummarizethecurrentevidencefromneurophysiological,animalbehaviorandhumanneuroim-agingstudiesthatthisfine-tunedschemeofhormoneexposureindeedresultsinoptimalfunctioningoftheamygdalainresponsetostress,ensuringthatstress-relat-edinformationisretainedverywell,particularlythoseaspectswithastrongemotionalload.Inthismodel,allhormoneexposurethatoccursoutofsyncisexpectedtoattenuatethefunctionaloutcome.AMPARsignaling:acommontargetfornoradrenalineandcorticosteroidsSeminalworkbyLeDouxandcoworkershasestablishedthatthebasolateralnucleusoftheamygdala(BLA)isanessentialhubintheformationofemotionalmemory[8],particularlymemoriesrelatedtofearfuloremotionallyarousingsituationsthatareassociatedwiththereleaseofnoradrenalineand(ifsufficientlyarousing)corticoster-oidhormones[9].Theamygdalaiscoretoalargernetworkofbrainregionsthatontheonehandareinvolvedinbetterconsolidationofinformationinefferentbrainregions,in-cludingthehippocampusandneocorticalareas[10],andontheotherhandincognitivecontrol,forexamplethemedialprefrontalcortex(mPFC)[8,11].Noradrenalineandcorticosteroidhormonesmightin-teractatseveral(sub)cellularendpointsinthissystem,includingcalcium-dependentpotassiumchannels[2,12],281Box1.Stress-inducedreleaseofnoradrenalineandcorticosteroidsThevariousaspectsofastressfulevent鈥�e.g.visual,auditoryandnociceptivestimuli鈥�areprocessedinthecorrespondingareasinthebrainandeventuallythisinformationisprojectedtotheparaven-tricularnucleusofthehypothalamus(forreviewssee[1,2]).Fromthere,neuronsinthebrainstemareactivatedthatquicklygiverisetoactivationofthesympatheticnervoussystem.Themostprominentconsequenceisaquickreleaseofadrenalinefromtheadrenalmedullathatallowstheorganismtoliberateenergysourcesforimmediateaction.Noradrenalineisreleasedinthebrainviathevagalnerveandstimulationofthenucleustractussolitarius[34].Therealsoseemstobeadirectstress-inducedshiftinthefiringpatternoflocuscoeruleusnoradrenergicneuronsthatinvolvescorticotrophinreleas-inghormone(CRH)andopioids[69].Asaconsequenceofthesepathways,amygdalaneuronsareexposedtohighlevelsofnora-drenalineshortlyafterstress[4].ActivationofadifferentsetofcellsintheparaventricularnucleuscausesreleaseofCRHthatviaportalvesselsleadstosecretionofadrenocorticotropinhormone(ACTH)inthecirculation.Intheadrenalcortex,exposuretoACTHincreasessynthesisandreleaseofcorticosterone(inmostrodents)orcortisol(inhumans).Intheperiphery,corticosteroidshelptheorganismtorestorefromstressexposure,forexamplebyreplenishingenergyresources.Corticoster-oidsalsofeedbackonthepituitaryglandandparaventricularnucleus,therebysuppressingthehypothalamo鈥損ituitary鈥揳drenalaxis.Thecombinationofslowreleaseofcorticosteroidsfromtheadrenalglandswiththeirnegativefeedbackgivesrisetoaninherentoscillatingpatternofcorticosteroidrelease,withultradianpulsesapproximatelyonceperhour,ontopofwhichsurgesofcorticosteroidhormonesarereleasedafterstress[70].Corticosteroidhormoneseasilyenterthebrainandbindtohigh-affinityMRsandsomewhatlower-affinityGRs(forreviewssee[1,2[).MRsareenrichedinallprincipalcellsofthehippocampus,thelateralseptumandtoalesserextentotherlimbicregions,forexamplethecentralamygdalaandanteriorcingulatecortex.Lowconcentrationsofcorticosteroids,correspondingtolevelscirculatingduringthenadirofthepulses,sufficetotranslocatethesereceptorstothenucleuswheretheyactastranscriptionalregulators.GRsaremuchmorewidespreadinbrainbothinneuronsandglialcells.ThesereceptorsrequirestresslevelsofcorticosteroidstobecomefullyoccupiedandtranslocatetothenucleuswheretheytransientlybindtoresponseelementsintheDNA.OverthepastyearsithasbecomeevidentthatbothMRandGRcanalsoresideinorclosetotheplasmamembranewheretheymediaterapidnongenomicactions[6,7].Theserapideffects(alsoviaMRs)seemtobeevokedwithcorticosteroidconcentrationsthatareonlyachievedduringstressconditions.Inadditiontothetwocompoundsdiscussedinthisviewpoint,thatisnoradrenalineandcorticosteroidhormones,manymoretransmit-tersandhormonesplayaroleinthecentralresponsetostress,forexampleCRH,acetylcholine,GABAandendogenousopioids[6].However,forthesecompoundsaspectsoftiminghavehardlybeeninvestigatedsotheywillnotbediscussedhere.Box2.QuestionsforfutureresearchTowhatextentdonoradrenalineandcorticosteroneinteractonAMPARsignalingwhentestedinthesameBLAcell(orthesamecellinanotherbrainregion)?Howdovariousconcentrationsofcorticosteronegivenapproxi-mately20minutesafterapulseofnoradrenaline(i.e.thenaturallyoccurringtimeframeofbothcompoundsafterstress)affectsignaltransductionintheBLA?WhatistheeffectoftimedcorticosteroneandnoradrenalineadministrationintotheBLAonthevariousphasesofmemory?DoesmetaplasticityofBLAfunction(i.e.aswitchinresponseafterasecondstressor)alsohappenatthenetworkandbehaviorallevel?ExactlyhowdoendocannabinoidsaffectBLAfunctionafterstress?Aretheeffectsofcorticosteroidadministrationseveralhoursbeforenoradrenalineonanimalbehaviorcomparabletothoseindicatedbytheelectrophysiologicalstudiesand,ifso,aretheyvalence-dependentasinhumansubjects?Aresomeofthediscrepantfindingsexplainedbythefactthatmoderateconcentrationsofthetwohormonesinteractdifferentlyfromhighdoses?WhatarethetimedeffectsofACTHandCRHonamygdalatissueinindividualsthatarestressedorreceivecorticosteroidssystemi-cally?Areindividualdifferencesinprocessescontrollingamygdalaresponsivenesscrucialfordifferencesinstresssensitivityandresilience?Bywhichmechanismsdoadverseenvironmentalfactorschangehumanamygdalasensitivity?ReviewTrendsinCognitiveSciencesJune2011,Vol.15,No.6remodelingofnuclearchromatin[13]andthefunctionofa-amino-3-hydroxy-5-methyl-4-isoxazolepropionaterecep-tors(AMPARs).Hereweelaborateonthelatter.Gluta-matetransmissionintheBLAandotherlimbicregions,specificallyviaAMPARs,iscrucialforestablishingemo-tionalmemories[14].AMPARsarecomposedofvariouscombinationsofsubunits,ofwhichtheGluA1andGluA2subunitsaretightlylinkedtomemoryformation[15].Itisthoughtthatonexposuretoemotionallyarousingsitua-tions,locallyreleasedneurotransmitterscausephosphor-ylationofseveralserineresiduesoftheGluA1subunitbyproteinkinaseA(PKA)orCamKII/proteinkinaseC[16].Consequently,GluA1istransportedtothepostsynapticdensity,aprocessthatisnecessaryandsufficienttoinducelong-termpotentiation(LTP)ofthesynapses[12,16].Pos-sibly(asseeninthehippocampus),GluA1subunitsareinternalizedatalaterstageandreplacedbyGluA2sub-units[15],thusestablishingstablecontacts,enablingthedownstreamformationofmemories.Noradrenalineisoneofthetransmittersthattriggerthiscascade[16].TheexactmechanismstillneedstoberesolvedintheamygdalabutitmightresemblethatinthemPFCwhereb2-adrenoceptorsformacomplexwithGluA1subunits,PKAandotherproteins[17].Activationofb2-adrenoceptorsleadstophosphorylationofGluA1subunitsandincreasestheamplitudeofAMPAR-mediatedminia-turepostsynapticcurrents(mEPSCs),i.e.currentscausedbyspontaneousreleaseofoneglutamate-containingsyn-apticvesicle[17].CorticosteronealsotargetstheAMPAsignalingpath-way[18,19].Initsslow,genomicmodeitenhancessurfaceexpressionofGluA2and,withahigherconcentration,GluA1subunitsinthehippocampus,viathelower-affinityglucocorticoidreceptor(GR).Moreover,corticosteroneslowlyincreasestheamplitudeofhippocampalmEPSCs[19,20],similartotherapideffectsbynoradrenaline.282EnhancedAMPARsurfaceexpressionandmEPSCampli-tudebycorticosteroneandstresswerealsoobservedinthemPFC[21].Thiscouldpointtoageneralizedslowenhance-mentinmEPSCamplitudebycorticosterone,includingintheamygdala(Box2).Yet,corticosteronecanalso鈥榬apidly鈥�nongenomicallychangeAMPARsignalingviathemineralocorticoidrecep-tor(MR).Thehormonequicklypromoteslateraldiffusion[()TD$FIG]0204060801001201401601802000510152025303540455055606570758085Time(inmin)Response(%ofbaseline)2.01.51.00.50.01stAmygdalaBLA鈭�鈭�鈭�2ndFrequency(Hz)ISOCORTpreincubatedAfterrestraintstress100nMCORTCORTpreincubatedbeforeISO(a)(c)(b)2.076543210-505101520Time(min)1.51.00.50.01stHippocampusCA1鈭�鈭�2ndFrequency(Hz)Frequency(Hz)TRENDSinCognitiveSciencesFigure2.Corticosteroneadministrationseveralhoursafterorbeforestress/noradrenalinetreatmentattenuatesthefunctionaloutcome.Inthepresenceofcorticosterone(gray/greenbarsin(a)mEPSCfrequencyinthehippocampusisincreased.Asimilarresponseisseenafterasecondpulseofcorticosterone.IntheBLA,however,thefirstpulselastinglyincreasesmEPSCfrequencythatisquicklyresetbyasecondpulse.Alsoafterrestraintstress(b),corticosteronesuppressesmEPSCfrequency.Basedon[23].(c)Isoproterenoladministration(horizontalbar)causesLTPinresponsetoweaktetanicstimulation(arrow)thatbyitselfdoesnotinduceLTP(notshown).Pretreatmentwithcorticosterone1鈥�hoursbeforeisoproterenolapplication,ineffectivebyitself,attenuatesthepotentialoftheb-agonisttoinduceLTP.Adapted,withpermission,from[25].ReviewTrendsinCognitiveSciencesJune2011,Vol.15,No.6ofGluA2subunitsinculturedhippocampalcells[18]andincreasesmEPSCfrequencyratherthanamplitude[22].Interestingly,intheBLArapidMR-dependentincreasesinmEPSCfrequencydevelopintolong-lastingchangesthroughaslowprocessrequiringproteinsynthesis[23].ThisaltersthestateofBLAneuronssuchthatafteronesurgeofcorticosterone,forexampleafterexperiencingstress,theyrespondtorenewedexposureofcorticosteronewithaquickdecreaseinmEPSCfrequency,resettingtheBLAcellactivity(Figure2);thisinvolvesGRsandendo-cannabinoidsignaling.Whatdoesthismeanforthecombinedeffectsofnor-adrenalineandcorticosteroneonlimbiccellfunction(Figure1)?Initsrapidmode,corticosteroneseemstotargetGluA2subunitswhereasnoradrenalineseemsmoreeffectiveonGluA1subunits,althoughstudiesdi-rectlyaddressingthisissuearelackingsofar(Box2).Ifso,effectsofthetwohormonesmightbeadditiveratherthansynergistic.Electrophysiologicaldatasupportthistosomeextent.Inthedentategyruscorticosteroneaccel-eratedtheeffectofco-administeredisoproterenol(ab-adrenoceptoragonist)onLTP[24].Yet,corticosteronedidnotrapidlyfacilitateisoproterenoleffectsintheBLA,neitherwithrespecttoLTPnorAMPARsignaling[25,26].Nevertheless,giventhequickbutparticularlylong-lastingincreaseinamygdalamEPSCfrequencybycorticosterone[23],thishormonecouldindirectlyenableeffectsofnoradrenalineandprolongthewindowduringwhichstress-relatedmemoryisencoded.Theenablingeffectsofcorticosteroneintheshorttermcontrastwithitsslowgenomiceffects.CorticosteronewasshowntograduallynormalizetheresponseofBLAneuronsearlierraisedbynoradrenaline[25],potentiallyallowingamoreprominenthighercognitivecontrolintheaftermathofstress.Simultaneously,corticosteroneslowlychangesthestateofBLAneuronssuchthattheirresponsetoanewstressorisdifferent,aphenomenonreminiscentofcellularmetaplasticity[23].ThismightcurtailtheactivityofBLAneuronsonreactivationofthecircuit.Whencorticosteroneisgivenseveralhoursinadvanceofisoproterenol鈥�aconditionthatwillnottakeplacephysiologicallybutmightbeexploitedtherapeutically鈥�itreducestheefficacyoftheb-adrenoceptoragonisttofacilitateLTPandevokedresponsesviaAMPARs,bothinthedentategyrusandBLA[24鈥�6](Figure2),possiblyduetoconvergenceofthetwohormonesonthesamesignalingpathways.Inthismodecorticosteronecouldpreventtheformationofemo-tionalmemories.283[()TD$FIG]TrainingtrialA1A2A3BInterval?DayHabituationTrainingRetentionWith-habituationWith-habituationWithout-habituationWithout-habituationVehicle******Key:Cort0.3mg/kgCort3.0mg/kgCort1.0mg/kgPropranolol(3.0mg/kg)Yohimbine(0.3mg/kg)50Discriminationindex(%)Discriminationindex(%)403020100-106050403020100-10123456789Corticosterone(sc)TRENDSinCognitiveSciencesRetentiontrialFigure3.Glucocorticoideffectsonmemoryconsolidationforobjectrecognitiontrainingrequirearousal-inducednoradrenergicactivation.Ratswereeitherhabituatedtothetrainingcontextornotforsevendays.Onday8,theyweregivena3-minutetrainingtrialduringwhichtheycouldfreelyexplore2identicalobjects(top)followedbysystemicdrugadministration.Retentionwastested24hourslaterbyplacingtheratsbackintotheapparatusfor3minutesinwhichoneobjectwassimilartothatexploredduringtrainingwhereastheotherobjectwasnovel.Corticosteroneinjectionselectivelyenhancedmemoryconsolidationincontext-na谋虉veratsthatshowedagreateremotionalarousalresponseduringtraining(bottomleft).Systemicpost-trainingadministrationoftheb-adrenoceptorantagonistpropranololblockedthiscorticosterone-inducedenhancementofobjectrecognitionmemoryinna谋虉ve(emotionallyaroused)rats.Coadministrationofthea2-adrenoceptorantagonistyohim
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