Cerebellar Learning PDF
Preview Cerebellar Learning
Advisory Editors Stephen G. Waxman BridgetMarieFlahertyProfessorofNeurology Neurobiology,andPharmacology; Director,CenterforNeuroscience& Regeneration/NeurorehabilitationResearch YaleUniversitySchoolofMedicine NewHaven,Connecticut USA Donald G. Stein AsaG.CandlerProfessor DepartmentofEmergencyMedicine EmoryUniversity Atlanta,Georgia USA Dick F. Swaab ProfessorofNeurobiology MedicalFaculty,UniversityofAmsterdam; LeaderResearchteamNeuropsychiatricDisorders NetherlandsInstituteforNeuroscience Amsterdam TheNetherlands Howard L. Fields ProfessorofNeurology EndowedChairinPharmacologyofAddiction Director,WheelerCenterfortheNeurobiologyofAddiction UniversityofCalifornia SanFrancisco,California USA Elsevier Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands TheBoulevard,LangfordLane,Kidlington,Oxford,OX51GB,UK Firstedition2014 Copyright#2014ElsevierB.V.Allrightsreserved Nopartofthispublicationmaybereproduced,storedinaretrievalsystemortransmitted inanyformorbyanymeanselectronic,mechanical,photocopying,recordingor otherwisewithoutthepriorwrittenpermissionofthepublisher PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights DepartmentinOxford,UK:phone(þ44)(0)1865843830;fax(þ44)(0)1865853333; email:permissions@elsevier.com.Alternativelyyoucansubmityourrequestonlineby visitingtheElsevierwebsiteathttp://elsevier.com/locate/permissions,andselecting ObtainingpermissiontouseElseviermaterial Notice Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersonsor propertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseoroperation ofanymethods,products,instructionsorideascontainedinthematerialherein.Becauseof rapidadvancesinthemedicalsciences,inparticular,independentverificationofdiagnoses anddrugdosagesshouldbemade LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguinginPublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN:978-0-444-63356-9 ISSN:0079-6123 ForinformationonallElsevierpublications visitourwebsiteatstore.elsevier.com PrintedandboundinGreatBritain 14 15 16 11 10 9 8 7 6 5 4 3 2 1 Contributors Egidio D’Angelo Department ofBrainand Behavioral Sciences, University ofPavia,and Brain Connectivity Center,C. MondinoNational NeurologicalInstitute, Pavia, Italy Suryadeep Dash Robarts Research Institute, Western University, London,Ontario,Canada ChrisI. De Zeeuw Department ofNeuroscience,ErasmusMC Rotterdam,Rotterdam, and Netherlands Institutefor Neuroscience,Royal Netherlands Academy ofArts & Sciences, Amsterdam, The Netherlands Paul Dean Department ofPsychology, Sheffield University, Sheffield, United Kingdom Elisa Galliano Department ofNeuroscience,ErasmusMC Rotterdam,Rotterdam, The Netherlands GermundHesslow Department ofExperimentalMedical Science,Lund University, Lund,Sweden MasaoIto RIKEN Brain Science Institute,Saitama,Japan RichardB. Ivry DepartmentofPsychology,andHelenWillsNeuroscienceInstitute,Universityof California, Berkeley, CA, USA Michael Longley Department ofNeuroscience,Physiology and Pharmacology, University College London,London,UK Soichi Nagao RIKEN Brain Science Institute,Saitama,Japan John Porrill Department ofPsychology, Sheffield University, Sheffield, United Kingdom Narender Ramnani Department ofPsychology, RoyalHolloway, University of London, Egham, UK Anders Rasmussen Department ofExperimentalMedical Science,Lund University, Lund,Sweden JeroenB. Smaers Department ofAnthropology, Stony Brook University, Stony Brook, NY,USA JordanA. Taylor Department ofPsychology, Princeton University, Princeton, NJ, USA v vi Contributors Peter Thier Department ofCognitiveNeurology, Hertie Institutefor Clinical Brain Research, University ofTuebingen, Tuebingen, Germany Kazuhiko Yamaguchi RIKENBrain Science Institute,Saitama, Japan Tadashi Yamazaki Graduate SchoolofInformatics and Engineering, The University of Electro-Communications, Tokyo, Japan Christopher H.Yeo Department ofNeuroscience, Physiology and Pharmacology, University College London,London,UK Preface Theideathatcerebellarcircuitryplaysanimportantroleinlearning,thesubjectof thisvolume,isonethathasrobustlywithstoodthetestoftimeatleastsincethesem- inalpapersofBrindleyandMarrinthe1960s.Inrecentyears,therehavebeenim- portant transformations in our understanding of cerebellar biochemistry, anatomy, and physiology that have changed the way that we think about cerebellar mecha- nismsthatsupportlearningandtheformsofbehaviorthatthecerebellumcancontrol. Researchers have revised their accounts ofcerebellar learning toaccount for these changes,andthisvolumebringssomeofthesetogether.Aswithmosttopicsinbe- havioralneuroscience,theseaccountsneedtospanmultiplelevelsofanalysis,from molecules throughtobehavior.Theorganizationofthe volume reflects thisrange. MasaoItocontributestheopeningchaptertothevolumewithanaccountofthe cellularmechanismsthatsupportlong-termdepressionasaclassical modelofcer- ebellarplasticity.EgidioD’Angelothendiscussesthepotentialformultipleformsof plasticitytoexistinthecerebellum.Inthethirdchapter,ElisaGallianoandChrisDe Zeeuw continue the narrative that challenges three long-held traditional ideas and proposewaysin which thesecouldberevised. Therefollowthreechaptersthatstudycerebellarlearningusingrelativelysimple, cerebellar-dependent formsoflearninginwell-understoodmodels.Thebenefits of these models include relatively specific questions that can be addressed and high levels of experimental control that can be achieved. In the first of these, Michael LongleyandChristopherYeodiscussthevalueofusingtheclassicallyconditioned eyeblink and nictitating membrane responses to study cerebellar mechanisms of learning, and summarize findings from lesion and inactivation experiments. The chapter makes comparisons between learning mechanisms that support eye blink and NMR conditioning with those that support the vestibulo-ocular reflex (VOR). In the next chapter, Anders Rasmussen and Germund Hesslow discuss how work using classical eyeblink conditioning has contributed to an understanding of how learning-related feedback is itself regulated by learning-related cerebellar outputs. In the last of the three chapters that focus on simple behaviors, Suryadeep Dash andPeter Thierdiscusstherolesplayedbyspecific areas oftheprimatecerebellar cortexintheadaptationofthreekindsofeyemovementbehaviors(theadaptationof the VOR,saccades, and smooth pursuit). InChapter7,PaulDeanandJohnPorrillcontributeacomputationalaccountof decorrelationlearninginthecerebellum,whereparallelfibersynapsesareweakened iftheycorrelatepositivelywithclimbingfiberinputbutstrengthenediftheyareneg- ativelycorrelated.Theauthorsdiscusstheapplicationofthisapproachtomotorcon- trol, sensory prediction, andhighercognitivefunction. Theevolutionofthecorticocerebellarsystemisanimportantsubjectinitsown right, butinthisliterature littleattentionhasbeen paid toitinthecontext ofcere- bellar learning. Jeroen Smaers therefore contributes a chapter that takes a vii viii Preface comparativeapproachinwhichhediscussestheevolutionaryexpansionofthecer- ebellum inthe context ofenhancedmotor andcognitive skills. Thelasttwochaptersfocusoncerebellarinteractionswithfrontallobeareasand therolesthatthisplaysinmorecomplexformsoflearning.Theyacknowledgethe factthatsuchlearningmustinvolveinteractionsbetweenexplicitandimplicitpro- cessesinvolvingboth thecerebellumandthe neocortex.Inthefirst,Jordan Taylor andRichardIvryconsidertheroleofthecerebelluminadaptation,strategy,andre- inforcement learning. They suggest that cerebellar mechanisms are engaged in the skilledmovementexecution.However,theauthorsareskepticalabouttheinvolve- mentofcerebellarcircuitryinskilledactionselectionandsuggestthatprefrontaland basalgangliamechanismsarelikelytoplayaprominentroleinthis.Icontributethe finalchapterofthevolumeandfocusonsimilarissues.Incontrasttotheauthorsof thepreviouschapter,Isuggestthatthecerebellummightplayanimportantroleinthe acquisitionofbothmotorandcognitiveskillsandintheformationofhabitsthrough instrumentallearning.Ialsosuggestthatjustascerebellaroutputssuppressthepro- cessingoferrorfeedback inclassicaleyeblinkconditioning, itmightalsosuppress higherformsoffeedbacksuchasrewarderrorinmorecomplexformsoflearning. Thestudyofcerebellarlearninghasaverybroadspanandthisresearchareais growingfast.Itisnotpossibletodojusticetoalloftheideasinthefieldinasingle volume,butthehopeisthatthechaptersinthisvolumereflectcurrentperspectives that range from molecular and cellular mechanisms of learning-related plasticity, through computational accounts and simple forms of learning in animals, to systems-level accounts ofcomplex learningin humans. Narender Ramnani CHAPTER 1 Long-Term Depression as a Model of Cerebellar Plasticity Masao Ito*,1,Kazuhiko Yamaguchi*,Soichi Nagao*,Tadashi Yamazaki{ *RIKENBrainScienceInstitute,Saitama,Japan {GraduateSchoolofInformaticsandEngineering,TheUniversityofElectro-Communications, Tokyo,Japan 1Correspondingauthor:Tel.:þ81-48467-6984;Fax:þ81-48467-6975, e-mailaddress:[email protected] Abstract Long-term depression (LTD) here concerned is persistent attenuation of transmission effi- ciencyfromabundleofparallelfiberstoaPurkinjecell.Uniquely,LTDisinducedbycon- junctiveactivationoftheparallelfibersandtheclimbingfiberthatinnervatesthatPurkinje cell. Cellular and molecular processes underlying LTD occur postsynaptically. In the 1960s,LTDwasconceivedasatheoreticalpossibilityandinthe1980s,substantiatedexper- imentally.Throughfurtherinvestigationsusingvariouspharmacologicalorgeneticmanipu- lationsofLTD,aconceptwasformedthatLTDplaysamajorroleinlearningcapabilityofthe cerebellum(referredtoas“Marr-Albus-Itohypothesis”).Inthischapter,followingahistorical overview,recentintensiveinvestigationsofLTDarereviewed.Complexsignaltransduction andreceptorrecyclingprocessesunderlyingLTDareanalyzed,androlesofLTDinreflexes andvoluntarymovementsaredefined.ThesignificanceofLTDisconsideredfromviewpoints ofneuralnetworkmodeling.Finally,thecontroversyarisingfromtherecentfindinginafew studies that whereas LTD is blocked pharmacologically or genetically, motor learning in awakebehavinganimalsremainsseeminglyunchangedisexamined.Weconjecturehowthis mismatcharises,eitherfromamethodologicalproblemorfromanetworknature,andhowit mightberesolved. Keywords Albus,climbingfiber,long-termdepression,LTD,long-termpotentiation,LTP,Marr,motor learning,parallelfiber,perceptron 1 ProgressinBrainResearch,Volume210,ISSN0079-6123,http://dx.doi.org/10.1016/B978-0-444-63356-9.00001-7 ©2014ElsevierB.V.Allrightsreserved. 2 CHAPTER 1 Cerebellar LTD and Learning 1 A HISTORICAL OVERVIEW OF LTD STUDIES 1.1 Leading Theories Donald Hebb (1904–1985) early proposed synaptic plasticity as a cellular mecha- nism of memory and learning (Hebb, 1949). In the 1960s, neuronal connections in the cerebellum composed of Purkinje cells, molecular layer interneurons, Golgi cells, granule cells, mossy fibers, climbing fibers, and nuclear neurons were dis- sected in terms of excitation/inhibition and divergence/convergence (see Eccles et al., 1967). The beauty of the circuitry diagram suggested that the cerebellum is a“neuronalmachine”thatisengagedintheprocessingofsomeimportantinforma- tion,buttherewasnoideaaboutwhetherthemachineiscapableoflearningorwhere amemoryelementislocated(seeIto,2006).DavidMarr(1945–1980),JamesAlbus, andafewothersassumedcertaintypesofsynapticplasticityassuchamemoryel- ementpurelyonatheoreticalground (Albus,1971;Marr,1969);thiswasamonu- mental assumption inthe historyof cerebellarresearch (Strata, 2009). Marr (1969) followed Brindley’s (1964) suggestion that, when both parallel fi- bers and climbing fibers are activated synchronously, parallel fiber–Purkinje cell synapses are activated both presynaptically and postsynaptically, that is, the type of condition that induces a Hebbian form of plasticity (Hebb, 1949), that is, long- termpotentiation(LTP).InMarr’s(1969)neuralnetworkmodel,thepathwaysfrom mossyfiberstogranulecells(theoriginofparallelfibers)toPurkinjecellsconstitute athree-layeredassociativelearningnetwork.Eachclimbingfiberconveysacerebral instruction for an elemental movement, and the receiving Purkinje cell is also ex- posedviathemossyfiberinputtoinformationaboutthecontextinwhichtheclimb- ingfiberfired.Duringrehearsalofanaction,eachPurkinjecelllearnstorecognize suchcontexts,andlater,aftertheactionhasbeenlearned,theoccurrenceofthecon- textaloneisenoughtofirethePurkinjecell,whichtheninitiatesthenextelemental movement. Ontheotherhand,Albus(1971)assumedthattheopposite,thatis,synchronous activationofparallelfibersandclimbingfibersleadstolong-termdepression(LTD). Albus’(1971)neuralnetworkmodelisacloseanalogytoRosenblatt’s(1962)simple perceptron,thefirstman-madelearningmachine.Inthismodel,climbingfibersact asanoutsideteacherwhochangestheintensityofthoseparallelfiber–Purkinjecell synapsesactivatedat thatmoment.When theperformance ofthecerebellumiser- roneous,relevantclimbingfiberssenderrorsignalsandtherebydepressconcurrently activatedparallelfiber–Purkinjecellsynapsesthatareresponsiblefortheerroneous performance of the cerebellum. BoththeMarrandAlbusmodelswereprimarilydesignedfordiscriminationof spatialpatternsandhavenocapabilityofdiscriminatingtemporalpatterns.Adecade later,Fujita(1982)proposedanadaptivefiltermodelofthecerebellumthatwasca- pable of discriminating temporal patterns. The essential assumption in Fujita’s modelisthattheneuronalcircuitsinvolvingmossyfibers,granulecells,andGolgi cellsconstituteaphaseconverter,whichgeneratesasetofmultiphaseversionsofa mossyfiberinputinparallelfibers.Theadaptivefiltermodelofthecerebellumhas 1 A Historical Overview of LTD Studies 3 been developed further (Dean and Porrill, 2011) and is discussed further in a later chapter.Byamalgamatingthesemodels,currentneuralnetworkmodelsofthecer- ebellum can deal with spatiotemporal information (e.g., Buonomano and Mauk, 1994; Yamazaki and Tanaka, 2009). 1.2 Experimental Approach to LTD and Motor Learning EarlyeffortstoobserveLTPorLTDinPurkinjecellsexperimentallywerehampered byvarioustechnicaldifficulties,buteventuallyevidenceforLTDwasobtainedbyin vivo electrophysiological experiments (Ekerot and Kano, 1985; Ito, 1989; Ito and Kano,1982; Ito etal., 1982).Then, thesuccessfulreproductionofLTD ininvitro cerebellar slices (Crepel and Jaillard, 1991; Karachot et al., 1994; Sakurai, 1987; Schreurs et al., 1996) and tissue-cultured Purkinje cells (Hirano, 1990; Linden, 1991; Shigemoto et al., 1994) greatly facilitated characterization of cerebellar LTDandanalysesofmolecularprocessesunderlyingLTD.Sincethe1990s,signal transductionprocessesthatoccurinsynapticspinestoinduceLTDhavebeenana- lyzed indetail(see Section2). While LTD was drawing attention, Sakurai(1987) early recognized that, if not accompanied by conjunctive activation of climbing fibers, repetitive stimulation ofparallelfibersaloneleadstopersistentpotentiationoftheparallelfiber–Purkinje celltransmission.LaterstudiesrevealedanimportantroleofthistypeofLTPasthe counterpart ofLTD (see Sections 2and 4). Inparallelwiththeseprogressesatcellular/molecularlevels,systemlevelstudies havealsoprogressed.Severaltypesofmotorlearninghavebeenidentifiedforana- lyzingthelearningmechanismofthecerebellum(Section3).Examplesincludead- aptation of horizontal vestibulo-ocular reflex (HVOR), horizontal optokinetic eye movement response (HOKR), saccade, eyeblink conditioning, hand reaching, and cursortracking.Neuronalcircuitsforeachofthesefunctionsinvolveacombination ofasmallcerebellarcorticalarea(microzone)andacorrespondingsmallgroup of vestibularorcerebellarnuclearneurons.Thiscorticonuclearmicrocomplexreceives mossy fiber inputs and converts them to nuclear outputs. Each microcomplex receives climbing fiber inputs from a small group of inferior olivary neurons for learning (see Section 3), and peptidergic or aminergic inputs for neuromodulation (e.g., Nisimaru et al., 2013). A microcomplex constitutes a unit of cerebellar learning machinery. Note that, within a microcomplex, whereas LTD occurs in the microzone, another memory element, LTP, occurs at the mossy fiber–nuclear neuron synapses. With both cortical LTD and nuclear LTP involved, learning proceedsintwo steps (see Section 3). 1.3 Memory Mechanisms in the Cerebellum Ithasbeenmorethan40yearssinceMarr(1969)andAlbus(1971)publishedtheir theoreticalpapers.Acentralanddebatedissuethatfollowsupthesepapersconcerns the role of climbing fibers in motor learning. We recall earlier discussions about 4 CHAPTER 1 Cerebellar LTD and Learning whetherclimbingfibersignalsrepresenterrorsinthemotorperformance(Ito,2001, 2002a). On the basis of accumulating evidence indicating that climbing fiber discharges represent errors in motor learning, we take the view that climbing fiber-driven LTD is a major memory mechanism in the cerebellar cortex (Ito, 2000, 2001, 2013). This and relevant notions may collectively be called the Marr–Albus–Itohypothesis(seeSchonewilleetal.,2011).Ontheotherhand,how- ever,thecerebellumisregardedasacontrolmachinewithoutlearning(Roknietal. 2008),orLTDhasnoroleinlearning(Welshetal.,2005).ThesignificanceofLTD asanessentialelementofalearningneuronalnetworkwillbediscussedinSection4. 1.4 Recent Issues Very recently, a question has been raised about the Marr–Albus–Ito hypothesis on the basis of the finding that, although many pharmacologicalor genetic manipula- tionsthatblockLTDalsoblockmotorlearning(Ito,2000,2001,2013),afewcases have shown a mismatch. In them, LTD was blocked, but motor learning remained virtuallyunaffected(Schonewilleetal.,2011;Welshetal.,2005).Variousreasons, eithertechnicalorfundamental,arepresentlyexploredtoexplainthismismatch,and we willdiscussthem inSection5. 2 MOLECULAR MECHANISMS OF LTD The past two decades have been particularly fruitful in the analysis of molecular mechanisms of LTD, as reviewed previously (Daniel et al., 1998; Ito, 2001, 2002b). The availability of specific inhibitors and gene manipulation techniques (especially,Purkinjecell-specificones)providesapowerfultooltoexplorethemol- eculesinvolvedinLTD(e.g.,Aibaetal.,1994;DeZeeuwetal.,1998).Underlying LTD, complex signal transduction processes are triggered by parallel fiber and climbingfiberinputs,andproceedindendriticspinesofPurkinjecellsinthreesuc- cessive major phases (I, II, and III). Eventually, a-amino-3-hydroxy-5-methyl-4- isoxazolone propionic acid (AMPA)-type glutamate receptors (AMPA receptors) on the synaptic membrane are destabilized and removed from the synaptic mem- branebyinternalization.ThisresultsinadecreaseinthenumberofAMPAreceptors onthesynapticmembrane,whichisrepresentedbyadecreaseofparallelfiber-stim- ulation-evokedexcitatorypostsynapticcurrentorpotential(PF-EPSCorPF-EPSP), that is, LTD. 2.1 Signal Transduction Underlying LTD Figure1showsaflowchartofchemicalsignalsfortheinductionofLTDintegrating theresultsreportedfrommanylaboratories.InphaseI,climbingfibersignalsinduce thestrongentryofCa2þionsthroughvoltage-sensitiveCa2þchannels.Parallelfiber signals also contribute to the Ca2þ responses because parallel fiber-released
The list of books you might like
