神经生物学：学习与记忆-微观2-4-3

Outline1.Thebasicconceptsoflearning&memory

classificationoflearning&memorybrainstructureshostinglearning&memorylearning&memoryinbehavioralstudylearning&memoryandneuralplasticity2.Themolecularbasisoflearning&memory

studiesinAplysiastudiesinmouse,LTP,LTDandlongtermmemoryAplysia：habituationsensitizationassociativelearningVertebrates:LTPandLTDMolecularmechanismofLTMInvertebrateNervousSystemsShowPlasticity-AplysiaHabituationinAplysia:Squirtsofwateronitssiphoncausesittoretractitsgill.Afterrepeatedsquirts,theanimalretractsthegillsless–ithaslearnedthatthewaterposesnodanger.atthesensorynerveendingsintheskin,makingthemlesssensitivetothesquirtofwater;atthemuscle,makingitlessresponsivetosynapticstimulationbythemotorneuron;atthesynapsebetweenthesensoryneuronandthemotorneuron.RepeatedelectricalstimulationofasensoryNeuronleadstoaprogressivelysmallerEPSPinthepostsynapticmotorneuron.Wherethechangeunderlyinghabituationoccur

Wheredoesthesynapticmodificationhappen?lessneurotransmitterreleasebythepresynapticaxon?

-therearefewerquantareleasedperactionpotentialafterhabituation.decreasedpostsynapticresponsivenesstothetransmitter?

-ThesensitivityofthepostsynapticcelltoneurotransmitterdidnotchangeHabituationofthegill-withdrawalreflexisassociatedwithapresynaptic

modification.Whyisneurotransmitterreleasereducedafterrepeatedstimulationofthesensorynerveterminal?

AcriticalstepistheentryofCa2+intotheterminal,whichismediatedbyvoltage-gatedcalciumchannels.Inthenerveterminalofthesensoryneuron,thesechannelsbecomeprogressivelyandpersistentlylesseffectivefollowinghabituation.Despitetheapparentsimplicityofthistypeoflearning,howthischangeoccursisstillunknown.SensitizationoftheGill-WithdrawalReflex

---abriefelectricalshockappliedtotheheadofAplysiaresultsinexaggeratedgillwithdrawalinresponsetostimulationofthesiphon.ThemolecularmechanismofsensitizationL29release5-HTinresponsetoheadshock5-HTbind5-HTreceptorandactivateG-proteincoupledadenylylcyclaseinsensoryaxonterminal.CyclicAMPproductionactivatesproteinkinaseA(PKA).PKAphosphorylatepotassiumchannel,causingittoclose(Cont’d)ClosureofK+channelsleadtoprolongationofpresynapticactionpotentialMoreCa2+entrythroughvoltagegatedcalciumchannelsandmorequantaofneurotransmittersarereleasedMorepostsynapticglutamatereceptorscanalsoaddtotheexplanationofsensitizationConditioningoccurredonlyiftheCSprecededtheUSby≤0.5second.

AssociativeLearninginAplysia

Classicalconditioning:US:astrongshocktothetail.CS:gentlestimulationofthesiphonthatdoesnotcausearesponse.Response:thewithdrawalofthegill.(a)TheUSaloneleadstoactivationofthemotorneuron(viaaninterneuron,notshown)andtosensitizationofthesensoryinput.(b)PairingtheCSandtheUScausesgreateractivationofadenylylcyclasethaneitherstimulusdoesbyitselfbecausetheCSadmitsCa2+intothepresynapticterminal.TheCa2+(byinteractingwithaproteincalledcalmodulin)increasestheresponseofadenylylcyclasetoG-proteins.Aplysia：Vertebrates:LTPandLTDMolecularmechanismofLTMsynapticplasticityincerebellarcortexAnatomyoftheCerebellarCortexLong-TermDepressionintheCerebellarCortexMechanismsofCerebellarLTDsynapticplasticityinhippocampusAnatomyoftheHippocampusPropertiesofLTPinCA1MechanismsofLTPinCA1

LearningandmemoryinvertebratesLong-TermDepressionintheCerebellarCortexLTD-afterpairingstimulationofparallelfiberandclimbingfiber,activationoftheparallelfibersaloneresultedinasmaller,long-lastingpostsynapticresponseinthePurkinjecellinferioroliveandmuscleproprioceptorsThestructureofthecerebellarcortexpontinenucleiandcerebralneocortexMechanismsofcerebellarLTDClimbingfiberactivationdepolarizesthePurkinjecelldendrite,andthenactivatevoltage-gatedcalciumchannelstoallowinfluxofCa2+ParallelfiberreleaseglutamatetoactivatepostsynapticAMPAreceptorandallowNa+influxinPurkinjecelldendriteThereispostsynapticmetabotropicglutamatereceptorthatiscoupledviaGproteintophospholipaseCwhichcanproduceDAGtoactivatePKCPKCphosphorylateGluR2,anddecreasepostsynapticAMPAreceptorsLTDiscausedwhenthreeintracellularsignalsoccuratthesametime:(1)arisein[Ca2]iduetoclimbingfiberactivation,(2)arisein[Na]iduetoAMPAreceptoractivation(3)activationofproteinkinaseCduetometabotropicreceptoractivation.LTDcertainlyinvolvesthephosphorylationofproteins,includinganAMPAreceptorsubunitcalledGluR2,byproteinkinaseC.TheendresultisadecreaseinthenumberofAMPAreceptorchannelsinthepostsynapticmembrane.LTPinHippocampalCircuitsLong-termpotentiation(LTP)–astableandenduringincreaseintheeffectivenessofsynapses.Somemicrocircuitsofthehippocampus.➀Informationflowsfromtheentorhinalcortexviatheperforantpathtothedentategyrus.➁ThedentategyrusgranulecellsemitaxonscalledmossyfibersthatsynapseonpyramidalneuronsinareaCA3.➂AxonsfromtheCA3neurons,calledSchaffercollaterals,synapseonpyramidalneuronsinareaCA1.LTPareperformedontheSchaffercollateralsynapsesontheCA1pyramidalneurons.Long-termpotentiationinCA1.TheresponseofaCA1neuronismonitoredastwoinputsarealternatelystimulated.LTPisinducedininput1bygivingthisinputatetanus.(b)Thegraphshowsarecordoftheexperiment.Thetetanustoinput1(arrow)yieldsapotentiatedresponsetostimulationofthisinput.(c)LTPisinputspecific,sothereisnochangeintheresponsetoinput2afteratetanustoinput1.InductionofLTPinCA1Usually,ateststimulationisgiveneveryminuteorsofor15–30minutestoensurethatthebaselineresponseisstable.Then,thesameaxonsaregivenatetanus,abriefburstofhigh-frequencystimulation(typically50–100stimuliatarateof100/sec).SubsequentteststimulationevokesanEPSPthatismuchgreaterthanitwasduringtheinitialbaselineperiod.InductionofLTPinCA1RequirementofLTPinductionSynapsesmustbeactiveatthesametimethatthepostsynapticCA1neuronisstronglydepolarized.(Hebb’sLaw)SynapsesmustbestimulatedatfrequencieshighenoughtocausetemporalsummationoftheEPSPsEnoughsynapsesmustbeactivesimultaneouslytocausesignificantspatialsummationofEPSPs.

TheCA1regionhasbothNMDAandAMPAreceptors.GlutamatefirstactivatesAMPAreceptors.NMDAreceptorsdonotresponduntilenoughAMPAreceptorsarestimulatedandtheneuronispartiallydepolarized.NMDAreceptorsatresthaveamagnesiumion(Mg2+)blockontheircalcium(Ca2+)channels.MolecularmechanismofLTPAfterpartialdepolarization,theblockisremovedandtheNMDAreceptorallowsCa2+toenterinresponsetoglutamate.ThelargeCa2+influxactivatescertainproteinkinases.CaMKIIaffectsAMPAreceptorsinseveralways:1.CausesmoreAMPAreceptorstobeproducedandinsertedinthepostsynapticmembrane.2.MovesexistingnearbyAMPAreceptorsintotheactivesynapse.3.IncreasesconductanceofNa+andK+ions.TheactivatedproteinkinasesalsoactivateCREB.CREBchangesthetranscriptionrateofgenes.TheregulatedgenesthenproduceproteinsthataffectsynapticfunctionandcontributetoLTP.Strongstimulationofapostsynapticcellreleasesaretrogrademessengerthattravelsacrossthesynapseandaltersfunctioninthepresynapticneuron.Moreglutamateisreleasedandthesynapseisstrengthened.LTPmaybeonepartoflearningandmemoryformationTimecourseofLTPissimilartothatofmemoryformation.PharmacologicaltreatmentsthatblockLTPimpairlearning.TrainingananimalinamemorytaskcaninduceLTP.VertebrateModelsofLearningLearningandmemorycanresultfrommodificationsofsynaptictransmissionSynapticmodificationscanbetriggeredbyconversionofneuralactivityintointracellularsecondmessengersMemoriescanresultfromalterationsinexistingsynapticproteinsNeuralandmolecularbasisoflearningandmemory

-knowledgefromlabanimalsAplysia：Vertebrates:LTPandLTDMolecularmechanismofLTMTheMolecularBasisof

Long-TermMemoryPhosphorylationasalongtermmechanism:

PersistentlyActiveProteinKinasesPhosphorylationmaintained:Kinasesstay“on”CaMKIIandLTPMolecularswitchhypothesisTheregulation