Editor-in-Chief John H. Byrne Department of Neurobiology & Anatomy, The University of Texas Medical School at Houston, Houston, Texas, USA Volume Editors Volume 1 LEARNING THEORY AND BEHAVIOUR Volume Editor Randolf Menzel Institut fu¨r Biologie – Neurobiologie, Freie Universita¨t Berlin, Berlin, Germany Volume 2 COGNITIVE PSYCHOLOGY OF MEMORY Volume Editor Henry L. Roediger III Department of Psychology, Washington University in St. Louis, St. Louis, Missouri, USA Volume 3 MEMORY SYSTEMS Volume Editor Howard Eichenbaum Department of Psychology, Boston University, Boston, Massachusetts, USA Volume 4 MOLECULAR MECHANISMS OF MEMORY Volume Editor J. David Sweatt Department of Neurobiology and McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA FOREWORD A comprehensivereferenceworkonlearningandmemorycouldnotbebettertimedthanthis.Duringthe second half of the twentieth century, the study of learning and memory moved from a descriptive science largely based on the pioneering behavioral analyses of Pavlov, Thorndike, Watson, Skinner, Kamin, Rescorla, and Wagner to a new mechanistic science of mind that combines these brilliant behavioral studies withananalysisoftheunderlyingneuralmechanisms,firstinaregionalmannerbyMilner,Tulving,Mishkin, Squire,Schachter,andMorris,thenonthecellularlevel,andfinallyonthemolecularlevel. Thechallengesthatnowfacethefieldareoutlinedbythefivegreatpioneersinthestudyofmemory–the editor-in-chief Jack Byrne and the editors of these four extraordinary volumes: Learning Theory and Behavior, editedbyRandolfMenzel;CognitivePsychologyofMemory,editedbyHenryRoediger;MemorySystems,editedby HowardEichenbaum;andMolecularMechanismsofMemory,editedbyDavidSweatt.Thechallengefacedbythe contributorstothesevolumeswastocombinethemolecularmechanismswiththeotherthreelevelsinorderto provideacoherent,systematicallyandintellectuallysatisfyingunderstandingoflearningandmemory.Thisis central to the new science of mind. Since memory is the glue that holds our mental life together, the topics coveredbythesefourvolumesarecentraltoandparadigmaticforallaspectsoftheneurobiologyofmentallife, which has as its goal the understanding of all mental processes in neurobiological terms. Indeed, it is the plasticityofthebrainthatisthekeytounderstandingthecontinuityofallmentalfunction.Thegoalforeachof these four volumes was to bridge the subdisciplines concerned with the various forms of memory into a coherentscience.Thechaptersofeachofthesevolumessucceedadmirablyindoingjustthat.Asaresult,this richandrewardingreferenceworkwillserveasasuperbframeworkforthedecadesahead,areferencethatwill provide both the student and the working scientist with the intellectual background necessary to understand andfunctioneffectivelyinthestudyoflearningandmemory. EricR.Kandel,M.D. UniversityProfessor,FredKavliProfessorandDirector,KavliInstituteforBrainSciences SeniorInvestigator,HowardHughesMedicalInstitute,CenterforNeurobiologyandBehavior ColumbiaUniversity,NewYork,NY,USA xvii PREFACE L earningandMemory:AComprehensiveReferenceisthemostauthoritativesetofvolumeseverproducedon learning and memory and represents the state of the science in the early 21st century. The study of learning(theprocessofacquiringnewinformation)andmemory(retentionofthatinformationforfutureuse) hasintriguedphilosophersandwritersforcenturiesbecauseourmemoriesandplansforthefutureconsolidate whoweare,anddisruptionoftheseprocessesdramaticallyinterfereswithourdailylives.Thefascinationwith learning and memory is not limited to the humanities, but has been the subject of intense scientific research. Psychologists are concerned with elucidating the features of learning and memory processes and systems, neurobiologists seek to determine the neuronal mechanisms of learning and memory, and neurologists and psychiatristsfocusonresearchandtreatmentoffailuresordisruptionsinlearningandmemory. The study of learning and memory represents a scientific field that has matured at all levels – from the discovery of the protein chemistry and molecular biology of the cellular events underlying learning and memory, through the delineations of the properties and functions of neuronal networks, to formulating and testing the psychological and behavioral neuroscientific theories of learning and memory. In addition, many basic research findings have applied implications on such diverse fronts as education, legal issues hinging on eyewitnesstestimony,learningdisordersinchildren,memorydisordersfollowingbraindamage,anddeclinesin memoryinolderadults. ThevolumesinthisComprehensiveReferencearetheresultofameetinginLondoninJulyof2005wherethe editorsplannedthemassiveworkofconsolidatingallfacetsofthestudyoflearningandmemory.Wecollected nearly all the topics (albeit from many different disciplines and directions) that we considered constituted scientificapproachestolearningandmemoryandproceededtoparcelthetopicsintofourvolumes,resultingin LearningTheoryandBehavioreditedbyRandolfMenzel;CognitivePsychologyofMemoryeditedbyHenryRoediger III;MemorySystemseditedbyHowardEichenbaum;andMolecularMechanismsofMemoryeditedbyDavidSweatt. Thiswasaformidabletask,notonlybecauseoftherichnessanddiversityofthesubjectmatter,butalsobecause we needed to logically place topics in the appropriate volume. Although some of the decisions may seem arbitrary, and indeed there is overlap both within and between volumes, each editor ended up with a set of coherenttopicsthattheycouldorganizeandintroduceinalogicalmanner. Withapproximately40chapterspervolume,itisnosurprisethattheeditorscoveranunusuallywiderange of intellectual territory or that there is a difference in interpretation by some authors. The organization is a significanteditorialchallengeandinvestmentinandofitself.However,itistheeditor’sselectionofauthors,and the ensuing scholarship on learning and memory from different perspectives, that make this series unique. Authors were identified and invited based on their expertise on a particular topic, and their contributions representamarvelouscompendiumofresearchinlearningandmemory.Thechaptersinthisseriesnotonly representscientificstrengthandbreadth,butalsorangefromlearningatthesynapticleveltoasystemslevel approach,andincludestudiesofremarkablelearningcapabilitiesinavarietyofinvertebratesandvertebrates, includinghumanbeings. Thefirstvolumeintheseries,LearningTheoryandBehavioreditedbyRandolfMenzel,consistsof38chapters andsetsthetonefortheinterdisciplinaryandcomparativeapproachtothestudyoflearningandmemory.He introducesthevolumebyemphasizingboththevalueandthelimitationofthecomparativeapproachinnatural and laboratory settings, stressing that we need information from the behaving animal as well as the neuronal xix xx Preface structuresinordertounderstandtheprocessesinvolvedininformationstorageandretrieval.Severalchapters review progress fromusinganimalmodels,includingworms,molluscs,insects,rodents,birds,andnonhuman andhumanprimates.Inaddition,conceptssuchasplanning,decision-making,self-awarenessandepisodic-like memory,usuallyreservedforhumanbeings,arediscussedatseveraltaxonomiclevels.Thefinalchapterstake an engineering perspective and describe synthetic approaches, including modeling neuronal function and developingaconcisetheoryofthebrain. The second volume, Cognitive Psychology of Learning edited by H. Roediger, is comprised of 48 chapterson variousaspectsofcognitiveabilityandtheunderlyingneuroscience.Thebasicsofattention,workingmemory, forgetting, false memories, remembering vs. knowing, the process of recognition, and episodic memory are covered.Inaddition,topicsthatareoftennotincludedin‘‘memory’’volumesdeservedlyreceiveattentionhere, e.g.,learningofconceptsandcategories,learningofperceptualandmotorskills,languagelearning,andimplicit learning.Thisvolumealsocoversmemoryprocessesthroughoutthehumanlifespanandincludeschapterson individualdifferencesinmemoryability,bothsubnormal(learningdisabilities)andsupranormal(performance of mnemonists and experts in particular domains). Finally, chapters on applied aspects of memory research, dealing with such topics as eyewitness identification in the legal system and applications of research to educationalissues,areincluded. Volume3,editedbyH.Eichenbaum,consistsof29chapterswhichrepresenta‘‘progressreport’’onwhatwe knowaboutmemorysystemsandtheirrelationshiptodifferentpartsofthebrain.MemorySystemsreturnstoa comparative approach of learning and memory. This volume introduces the concepts of multiple memory systems,andmanychaptersdiscussinextensivedetailthedifferent featuresofdeclarativememoryandtheir underlyingbrainstructures.Procedurallearninginhumansandotheranimalsisaddressed,andashortsection detailstheinvolvementofhormonesandemotionsonmemoryretentionorloss.Finally,changesin memory systemsassociatedwithaging,diseaseprocesses,anddruguseareaddressed. The final 42 chapters in Volume 4, Molecular and Cellular Mechanisms of Memory edited by J.D. Sweatt, represent a review of the state of the science of what we know at the systems, cell, and molecular levels on learningandmemoryformation,aswellasprovidingalookattheemergingandfutureareasofinvestigation. Onceagain,thisvolumecoversanimpressiveamountofinformationderivedfromstudiesatmanytaxonomic levels,frommolecularassociativelearningmechanisms,throughanarrayofstudiesonsynapticplasticity,tothe cellleveloffearconditioning. The centrality of learning and memory to our daily lives has led to intense analysis by psychologists and neurobiologistsforthepastcentury,anditwillundoubtedlyremainattheforefrontofresearchthroughoutthis newcenturyaswell.Itisourintentionthatthissetofvolumeswillcontributesignificantlytotheconsolidation of this field, and it is meant as a resource for scientists and students interested in all facets of learning and memory.Nootherreferenceworkcoverssowideaterritoryandinsomuchdepth. LearningandMemory:AComprehensiveReferencewouldnothavebeenpossiblewithoutthetremendousworkof theEditorialBoard,whoidentifiedthetopicsandtheirauthors,andreviewedeachcontribution.Specialthanks alsogotoJohannesMenzel,SeniorAcquisitionsEditoratElsevier,forsupportingtheprojectandAndrewLowe and Laura Jackson, Production Project Managers, and Joanna De Souza, Developmental Editor, for ensuring thattheproductionschedulewasmaintained. JohnH.Byrne Permission Acknowledgement ThefollowingmaterialisreproducedwithkindpermissionofNaturePublishingGroup Figure1ofNeurofibromatosisTypeILearningDisabilities Figures2&5ofSecondMessengers:CalciumandcAMPSignaling Figure1bofActionPotentialsinDendritesandSpike-Timing-DependentPlasticity Figure4ofNeurogenesis Figure12a-cofNeuralandMolecularMechanismsofFearMemory Figures3&4ofTransmissionofAcquiredInformationinNonhumanPrimates Figure4a-bofBehavioralAnalysisofLearningandMemoryin:C.elegans Figures2a,6a-c,7,8a-b,10a-b&12a-bofNavigationandEpisodic-likememoryinMammals Figures1,4&6ofAnimalmodelsofamnesia Figure4a-eofCorticalPlasticityinAssociativeLearningandMemory Figures7a-b&9a-bofNeurophysiologyofBirdsonglearning Figure6a-bofVisualPriming Figures2a&4ofTheRoleofSleepinMemoryConsolidation ThefollowingmaterialisreproducedwithkindpermissionofAmericanAssociationforthe AdvancementofScience Figures13&14ofCognitivedimensionofoperantlearning ThefollowingmaterialisreproducedwithkindpermissionofTaylor&FrancisLtd Figure10ofLearningtoTimeIntervals xxi 4.01 Introduction and Overview J.D.Sweatt,UniversityofAlabamaatBirmingham,Birmingham,AL,USA ª2008ElsevierLtd.Allrightsreserved. 4.01.1 Introduction 1 4.01.2 Organization 2 4.01.2.1 Part2A:Systems-LevelApproaches 2 4.01.2.1.1 Nonassociativelearning 2 4.01.2.1.2 Associativelearningandmemoriesofcontingency 4 4.01.2.1.3 Associativelearningininvertebratemodels 4 4.01.2.1.4 Associativelearninginvertebratemodels 4 4.01.2.1.5 Memorydisruption 5 4.01.2.2 Part2B:Cellular-LevelApproaches 5 4.01.2.3 Part3A:Molecular-LevelApproaches 6 4.01.2.3.1 TheNMDAreceptoranditsimmediatetargets 6 4.01.2.3.2 Genomicandpostgenomicsignaling 6 4.01.2.3.3 Synapticstructureandsignaling 7 4.01.2.3.4 Plasticityofcellularstructureandretrogradesignaling 7 4.01.2.4 Part3B:EmergingAreas 8 4.01.1 Introduction experimentaldesignofthesestudiesfromtheoutset. Aseconddevelopmentwastheadventofthetechni- This fourth volume of the Comprehensive Handbook of cal capacity to genetically engineer mice through Learning and Memory delves deeply into the cellular means of homologous gene recombination. This andmolecularmechanismsmediatinglastingchanges allowed those interested in the molecular basis of in behavior, changes that occur in response to envi- vertebrate memory to bridge from molecule to be- ronmental signals. This volume is indeed the most havior within a single animal and ushered in a new comprehensive description in existence concerning era in neurobiology. The final development is more thegenetics, biochemistry,andcell biologyofmem- sociological than technical. Many of the leading ory formation. Cumulatively, the reviews in this investigators in the area of molecular and cellular volume describe an impressive range of processes mechanismsofmemoryactuallystartedoutasbehav- underlying memory, from atom-level resolution in ioral psychologists. Therefore, tying molecular and some paradigms to cell circuit-level mechanisms in cellular mechanisms directly back to the behaving others,andessentiallyallpointsinbetween.Moreover, animal always was an intellectual emphasis for the phylogenetic range of the contents is equally them.Thisestablishedaculturewithinthesubdisci- impressive, with descriptions of memory processes in pline that placed a priority on interdisciplinary animal systems on a continuum from one of the sim- studiesbridgingfrommoleculestobehavior. plest, Caenorhabditis elegans, to the most complex, Inthecurrentera,wealsoarecompelledtoalways humans. consider the relevance of our basic neurobiological Itisstrikingthatwhilethechaptersinthisvolume studies to the human condition. Advances over the deal with specific cellular and molecular mech- last 20 years in our understanding of the basic mo- anisms, there are in most chapters strong and direct lecularandcellularbiologyofmemoryhavelaidthe tie-instobehaviorinthelivinganimal.Thisappeal- foundationforacapacitytodevelopnewtreatments ing aspect of these studies arises in large part from for human diseases of learning and memory. This is three historical developments, in my opinion. First, not an abstract principle but rather a declarative many of the invertebrate systems were specifically statement concerning important recent advances in chosenbecausetheanimallentitselftobridgingfrom the field. Descriptions of these recent advances are behaviortocellstomolecules.Thustyingthemole- containedinmanychapters,andsectionsofchapters, cules and cells to the behavior was built into the in this volume. These descriptions are not split out 1 2 IntroductionandOverview into a separate translational or disease section of the section will be given): Section 1 deals with non- volume, but rather are distributed throughout in associative learning mechanisms. Section 2 discusses placesappropriatetotheirspecificintellectualmilieu. associative learning and memory, as investigated in Ifindthisamoresatisfyingconceptfororganizationof invertebratemodelorganisms.Section3makesanim- the volume, and an accurate representation of the portant transition and describes studies of associative ongoing cross talk between human and basic science and spatial memory in vertebrates. Section 4 reviews studiesoflearningandmemory. topics related to memory disruption, and section 5 Afinalcommentisthatinmanywaysthisvolume describes types and forms of plasticity at the cellular isasnapshotofthestateofscientificunderstandingof andsynapticlevelthatunderliememoryformationand the neurobiology of learning and memory at the storage. beginning of the twenty-first century. Thus, besides The last section of Part 2, describing cellular being a valuable resource for contemporary scien- mechanisms and synaptic plasticity, also serves as a tists, I believe this volume will provide a useful foundationforandtransitiontoPart3ofthevolume. historical reference point as well. I am only embol- Part3coversmolecular-levelapproachesandemerg- dened to make this statement because of the very ing areas of discovery. This second half of the book many outstanding scholars and scientists who have has five sections as well: Section 1 deals with the contributedtheirindividualchapterstothisworkand N-methyl-D-aspartate (NMDA) receptor and its because of the exceptionally important discoveries immediate biochemical targets. Section 2 describes bythemanyscientiststhattheycitetherein. genomicandpostgenomicsignaling.Section3covers theimportantareasofsynapticstructureandsignal- ing, and section 4 covers plasticity of cell structure 4.01.2 Organization andretrogradesynapticsignaling.Section5,thefinal section, is admittedly based on a subjective assess- The organization of the volume is fairly straightfor- ment on my part. This section highlights what I ward consideringthecomplexityofthetopic at hand considertobeseveralemergingareasofinvestigation (seeFigure1).Part 1, the introduction and overview that will have a large impact on our thinking about component,isthischapterandChapter4.02.Iamvery cellular and molecular mechanisms of memory for- gratefultoEricKandel,CraigH.Bailey,AngelBarco, mationinthenearfuture. andRobertD.Hawkinsfortheircontributioninwriting Having delivered this brief overview, in the Chapter 4.02. I commissioned Eric and his colleagues remainderofthischapterIwilldescribemorespecif- towriteapersonaloverviewofcontemporarydiscov- icallythecontentsofParts2and3ofthevolume(see eriesandapproachesinthelearningandmemoryfield. Figure1). Iexpectedthattheywoulddeliveraveryreadableand interestingreview concerningthe overall topicof the 4.01.2.1 Part2A:Systems-Level molecular and cellular biology of memory formation, Approaches describing a diverse set of model systems and approaches.Theycertainlyhitthemarkinthisregard. 4.01.2.1.1 Nonassociative learning Unbeknownst to them, I also anticipated that they Inthisfirstmajorsectionofthebook,wewillstartby might write an excellent bridge chapter that would coveringthesimplestformsoflearning,thatis,non- serve to help guide a knowledgeable reader into the associativeformsoflearningandmemory.Studiesof much more detailed following chapters in the book. these simple forms of learning and memory have WhenIreceivedandreadtheirchapterIwasdelighted yielded greatinsights into theenormous complexity thattheyhadachievedthisaswell.Istronglyencour- ofinformationacquisitionandstorageinthenervous ageanyonelookingforaconceptualstartingpointfor system,when approachedatthecellular andmolec- consideringthedetailedmolecularandcellularbasisof ularlevels.InChapter4.03,oneofthepioneersofthis memory,asdescribedinthisoverallvolume,tobegin typeofwork,JackByrne,providesareviewofstudies byreadingChapter4.02. of sensitization and habituation using invertebrate Part2ofthevolume,comprisingChapters4.03–4.19, modelsystems. coversmodelsystems-levelandcellular-levelappro- This overview chapter is then followed by a aches to investigating learning and memory. This description of sensitization and habituation in the part can be broadly subdivided into five sections C. elegans model system by Cathy Rankin, who pio- (more specific descriptions of the contents of each neered the adaptation of this organism for use in Molecular and Cellular Mechanisms of Memory – Volume 4 Ch 1 Introduction and Overview Ch 2 Molecular Studies of Learning and Memory in Aplysia and the Hippocampus: A Comparative Analysis of Implicit and Explicit Memory Storage Systems Molecular and Cellular and “Emerging” Cellular Ch 16 Long-Term Potentiation: A Candidate Cellular Mechanism Emerging for Information Storage in the CNS Systems Molecular Ch 39 Action Potentials in Dendrites and Spike-Timing-Dependent Plasticity Ch 17 LTD – Synaptic Depression and Memory Storage Ch 40 Plasticity of Intrinsic Excitability as a Mechanism for Memory Storage Ch 18 GABAergic Interneurons in Synaptic Plasticity and Information Storage Ch 41 Neurogenesis Ch 19 Neurofibromatosis Type I Learning Disabilities Ch 42 Epigenetics – Chromatin Structure and Rett Syndrome Non-Associative Genomic and postgenomic Ch 3 Sensitization and Habituation Invertebrate Ch 4 Molecular Mechanisms of Habituation Ch 26 Proteolysis and Synaptic Plasticity in C. elegans Ch 27 Transcription Regulation of Memory: CREB, CaMKIV, Fos/Jun, Ch 5 Pain Sensitization Associative CBP, and SRF Ch 28 The NF-kappaB Family in Learning and Memory Ch 29 Dendritic Transport of mRNA, the IEG Arc, and Synaptic Modifications Invertebrate Involved in Memory Consolidation Ch 6 Molecular Mechanism of Associative Learning–Bee Ch 7 Molecular and System Analysis of Olfactory Memory in Drosophila Ch 8 Molecular Mechanisms of Associative Learning in Hermissenda Ch 9 Molecular Mechanism of Associative Learning in Lymnaea Synaptic structure Ch 10 Molecular Mechanism of Associative Learning in Aplysia Ch 30 Glutamate Receptor Trafficking in LTP Ch 31 AMPA Receptor Regulation and the Reversal of Synaptic Plasticity - LTP, LTD, Memory disruption Depotentiation, and Dedepression Ch 14 Memory Reconsolidation Ch 32 The Role of the Postsynaptic Density and the Spine Cytoskeleton in Synaptic Plasticity Ch 15 Molecular Aspects of Memory Dysfunction Ch 33 Translational Control Mechanisms in Synaptic Plasticity and Memory in Alzheimer’s Disease NMDAR and targets Cellular structure and retrograde signaling Ch 20 The N-methyl-D-aspartate Receptor Ch 21 Second Messengers Calcium and cAMP Signaling Ch 34 Activity-Dependent Structural Plasticity of Dendritic Spines Ch 22 PKMz, LTP Maintenance, and Long-Term Memory Storage Ch 35 Integrins and Cadherins – Extracellular Matrix in Memory formation Vertebrate Ch 23 CaMKII: Mechanisms of a Prototypical Memory Model Ch 36 Presynaptic Mechanisms in Plasticity and Memory Ch 11 Neural and Molecular Mechanisms of Fear Memory Ch 24 Angelman Syndrome Ch 37 Regulation of Synaptic Function by Endocannabinoids Ch 12 The Molecular Mechanisms of Reward Ch 25 Mitogen-Activated Protein Kinases in Synaptic Plasticity and Memory Ch 38 Transsynaptic signaling by NO during learning related synaptic plasticity Ch 13 Conditioned Taste Aversion and Taste Learning: Molecular Mechanisms Figure1 ContentsandorganizationofVolume4oftheComprehensiveHandbookofLearningandMemory.Thisvolumecoversmolecularandcellularmechanismsofmemory formation.Thisfiguredescribestheoverallorganizationandmajortopicareasofthevolume.