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Neurobiology

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Neurobiologypeer

    Neurobiology

    CurrentZoology56(6):819-833,2010

    Neurobiologyofmammalianolfactorylearningthatoccurs

    duringsensitiveperiods

    HidetoKABA

    DepartmentofPhysiology,KochiMedicalSchool,Nankoku,Kochi7838505,Japan

    AbstractThisreviewexaminestheorganizationalprinciplesunderlyingolfactorylearninginthreespecializedcontextsthat

    OCCBrduringsensitiveperiodsofenhancedneuralplasticityandemphasizessomeoftheirco/nlTlonfeatures.Allthreeformsof

    olfactorylearningareassociatedwithneuralchangesintheolfactorybulb(OB)atthefirststageofsensoryprocessing.These

    changesrequiretheassociationoftheolfactoryandsomatosensorysignalsintheOB.Theyalldependonsomatosensorystimula-

    tion??inducedreleaseofnoradrenalinethatinducesstructuralandfunctionalchangesatmitralgranulecellreciprocalsynapsesin

    theOB,resultinginincreasesininhibitorytransmission.Intheaccessoryolfactorybulb,thisrepresentstheenhanced

    self-inhibitionofmitralcells,whichselectivelydisruptsthetransmissionofthematingmale'spregnancy-blockingsignalatthis

    leve1.Incontrast,anextensivenetworkofsecondarydendritesofmitralcellsinthemainolfactorybulbprobablyresultsina

    sharpeningoftheodor-inducedpattemofactivity,duetoincreasesinlateralinhibition,leadingtooffspringrecognitioninsheep

    andneonatallearninginratsandrabbits.Thesefindingsshowthatinhibitoryintemeuronsplayacriticalroleinolfactorylearning.

    Furtherworkonhowtheseneuronsshapeolfactorycircuitfunctioncouldprovideimportantcl

uestoundeBtandmemoryfunc-

    fionsofintemeuronsinothersystems.Moreover,recentresearchhassuggestedthatthreefor

    msofolfactorylearningalecon-

    trolledbysynergistic,redundant,anddistributedneuralmechanisms.Thishasgeneralimplic

    ationsregardingthemechanismsthat

    maycontributetotherobustnessofmemoriesCurrentZoology56(6):819-833,2OLO]. KeywordsMaterecognitionmemory,Maternalrecognition,Olfactorybulb,Olfactorylearn

    ing,Sensitiveperiod

    1Inoduction

    Experienceexecsaprofoundinfluenceonthebrain and,therefore,onbehavior.entheefrectofexpert. enceonthebrainisparticularlystrongduringalimited period,itisreferredtoasasensitiveperiod.Thelearn. ingthatoccursduringthissensitiveperiodexecsa long..1astinginfluenceonthedevelopmentoftheindi.. vidual'ssocialandemotionalbehavior.Thebestchar- acterizedformsofmanllTlaltanlearningthatoccurdur. ingsensitiveperiods.andthoseforwhichthemostis knownatthesynapticandeellularlevels.arethelearn

    ingofmalepheromonalsignalsbyfemalemiceduring mating(Brennan,2004,2009;Brermaneta1.,1990; BrennanandKeverne,1997,2004;BrenllanandZufall, 2006;KabaandNakanishi,1995),thelearningofnew. bomlambodorsafterparturitioninsheep(Kendricket a1.,1997a;LdvyandKeller,2009;Ldvyeta1.,2004; SanchezdradeandKendrick,2009;Sfi.nchezdrade eta1.,2005),andolfactoryconditioninginneonatal animalssuchasratsandrabbits(Hudson,1993;Leon, 1992;MoriceauandSullivan.2005;SullivanandWil

    ReceivedMay13,2010;acceptedSept.10,2010

+Correspondingauthor.Email:kabah@kochiu.ac.jp

    2010CurrentZoology

    son,2003;WilsonandSullivan,1994;Wilsoneta1., 2004).Inthisreview,Icomparetheneuralbasisofol? factorylearninginthreedifferentcontextsanddefine whatiscommonordifferentamongthem,andthenat

    tempttoidentifythefundamentalneurobiologicalprin- ciplesofolfactorylearning.

    2Pr0iectionPathwaysoftheMain

    O1factoryEpitheliumandtheVo

    meronasalOrgan

    Thenasalcavityofmostmammalscontainstwoma

    jorsetsofchemosensoryneuronslocatedinthemain olfactoryepitheliumandinthevomeronasalorgan (ScaliaandWinans,1975;ShipleyandEnnis,1996)(Fig 1).Whereastheolfactorysensoryneurons(OSNs)send theiraxons,whicharebundledtoformtheolfactory nerve,tothemainolfactorybulb(MOB),thevomero- nasalsensoryneurons(VSNs)sendaxons,whichto

    gethermakeupthevomeronasalnerve,totheaccessory olfactorybulb(AOB),astructurethatisspatiallyand histologicallydistinctfromtheMOBandlocatedatits 820CurrentZoology,,01.56N0.6

    )R/

    ATP

    Posterior\()l{

    McA

    Fig.1Projectionpathwaysofthemainolfactoryepitheliumandthevomeronasalorgan

    ACIII.adenylylcyclasctypeIlkCaM,calmodulin;CNGC,cyclicnucleotidegatedchannel;

DAG'diacylglycerol:GGprotein;IP3,inosi

    tol-I,4,5

    trisphosphate;LH,luteinizinghormone;MD,mediodorsalthalamus;MeA,medialamygdal

    a;MOPA,medialpreopticarea;OE,olfactory

    epithelium;OFC,orbitofrontalcortex;OR,odorantreceptor;PDE,phosphodiesterase;PIP2

    ,phosphatidylinositol-4,5bisphosphate;Pir,piriform

    cortex;PLC,phospholipaseC;PRL,prolactin;ST,striaterminalis;TIDA,tuberoinfundibula

    rdopaminergic;VNO,vomeronasalorgan.

    caudal-dorsalend.TheMOBprojectstovariousfore

    brainandcorticaltargetsincludingtheanteriorolfactory nucleus,olfactorytubercle,taeniatecta,piriformcortex, anteriorcorticalandposterolateralcorticalamygdala, andtheentorhinalcortex(ShipleyandEnnis,1996).In contrasttothediverseprojectionsoftheMOB,thepro

    jectionsoftheAOBarelimited.Theprincipalneurons oftheAOBsendtheiraxonsprimarilytothebednu

    cleusofthestriaterminalis,thebednucleusoftheac

    cessoryolfactorytractandthemedialandposteromedial corticalnucleioftheamygdala,whichinrum,sends projectionstoseveralhypothalamicnuclei(Spehreta1., 2006).

    Whilethemainolfactorysystemandvomeronasal systemexhibitsegregatedpathwaysatthelevelofthe firstolfactoryrelay,thetwosystemsconvergedown

    streamatseverallevels,includingthemedialamygdala (SwansonandPetrovich,1998).Inaddition,theAOB receivesbackwardconnectionsfromseveralforebrain sitesincludingthebednucleusoftheaccessoryolfac- torytract,therostralportionofthemedialamygdala, andtheposteromedialcorticalnucleusoftheamygdala

(Barber,1982).Ithasbeensuggestedthatmainolfac

    tory??medialamygdala??AOBsignalingmaymotivate approachbehaviortooppositesexpheromonalsignals

    thatensuresuccessfulreproduction(MartelandBaum, 2009).Therefore,themainolfactorysystemandVO

    meronasalsystemshouldbeviewedascomplementary ratherthanseparatepathwaysforchemosensorycom? munication.

    3OlfactoryandVomeronasal

    ChemosensoryDetection

    Molecularbiologicaltechniqueshaveyieldedvalu

    ableinformationaboutthechemosensoryreceptorsof themainolfactoryepitheliumandvomeronasalorgan (DulacandTorello,2003;ZhangandFirestein,2002). Thereareasmanyas1000odorantreceptorsinthe mammaliangenome.EachOSNexpressesonlyonetype ofodorantreceptor,butmanyseparateOSNsexpress thesametypeofodorantreceptor.AxonsofOSNsof thesametypeconvergetOformglomeruliintheMOB. ?2(

    KABAH:Neurobiologyofmammalianolfactorylearning82l Considerableprogresshasbeenmadeinourunder. standingoftransductionmechanismsinOSNs(Piffefiet a1.,2006;SchildandRestrepo,1998).Odorantmole

    culesbindtoodorantreceptorsintheciliarymembrane, activatingaGproteinthatinturnstimulatesanade. nylatecyclase.cAMPdirectlygatesanolfac. toryspecificcyclicnucleotidegatedchannel,causing

    anodorant?inducedinwardcurrentcarriedbvNa+and Ca2ions.TheincreasedCaconcentrationinthecilia

causestheopeningofCa2+activatedC1'channelsand

    subsequentC1'effiux,whichfurtherdepolarizesthecel1. IntracellularCa2alsobindstocalmodulin,lowering ligandsensitivityofthecAMPgatedchannels.

    Ca.calmodulinalsostimulatestheactivityofaphos. phodiesterase.OSNsrespondtoarelativelybroadrange ofrelatedmolecularstructures;thusagivenodorantwill stimulatemorethanonetypeofOSN.andeachOSN willbeactivatedbymorethanoneodorant.Theolfac

    torysystemcanthereforerepresentawiderangeof odorantsbydifferentpatternsofactivityacrossthere

    ceptorrepertoire.

    TwomainclassesofreceptortermedV1RandV2R havebeenclonedfromrodentVSNs(DulacandAxe1. 1995;HerradaandDulac,1997;MatsunamiandBuck, 1997).ThemouseV1RandV2Rgenefamiliesinclude respectiveintactgenesof187and70(ShiandZhang, 2007),andbothbelongtotheGproteincoupledrecep-

    torgenesuperfamily.V1RexpressingVSNswithcell

    bodiesintheapicalzoneofthesensoryepitheliumcon

    taintheG..proteinsubunitGtxi2andprojecttotheante.. riorAOB.whereasV2RexpressingVSNsinthebasal

    zonecontaintheG-proteinsubunitGaoandprojectto theposteriorAOB(Berghardeta1.,1996;Jiaeta1.,1997; Shinoharaeta1.,1992)(Fig.1).Invitrorecordingsfrom guineapigsCaviaporcellusAOBhavedemonstrateda preciseboundaryineachsubdivisionoftheAOB(Sugai eta1.,1997).VomeronasalrectorsshareliRlehomo.

    1ogywitholfactoryreceptorsfromtheolfactoryepithe- liumandthereislittlehomologybetweenthetwo

    classes,suggestingthattheyhavedistantevolutionary origins.RecentstudieshaveshownthatV1R?expressing VSNsrespondtosmallorganicpheromonessuchas 6-hydroxy6methyl-3-heptanone,,)-3,4dehydro

    exobrevicomin,(2-sec-but),l_4,5dihydrothiazole

    (DelPuntaeta1.,2002;Leinders-Zufal1eta1.,2000), whileV2R-expressingVSNsrespondtopeptidessuch aspeptideligandsofmajorhistocompatibilitycomplex (MHC)molecules,amalespecific,7kDapeptidecalled

    ESP1andmajorurinaryproteins(MUPs)(Chameroet a1..2007;Kimotoeta1.,2005;Leinder-Zufa11eta1., 2004;TouharaandVosshall.2009).VSNshaveadif- ferenttransductionmechanismfromOSNs(Mungeret a1.,2009;Zufalleta1.,2005)(Fig.1).V1Rsignaling reliesontheactivationofphospholipaseCandresultsin generationofphosphatidylinositol3-phosphateand

    diacylglycerol,whichinturnactivatethetran

    sient..receptor-potential(TRP)C2cationchannelloca1.. izedinthemicrovilliofVSNs(Lucaseta1.,2003).Re. centstudieshaveshownthatdeletionOfTI'C2gene impairssignaltransductionofESP1butnotCpep?

    tideligandsinV2R-expressingVSNs(Kelliheretal

    2006;TouharaandVosshall2009).etherthissig.

    nalingappliesalsotoV2R-expressingVSNsremainsto beclarified.althoughitisclearthatstimulationofthese VSNselevatesintracellularCa(Mungereta1..2009; Zufalleta1.,2005).

    4OlfactoryBulbCircuitryand

    ContrastingDifferencesBetween

    theMOBandAOB

    Thefirststagesofprocessinginthemainolfactory systemandvomeronasalsystemaretheMOBandthe AOB,respectively.Withintheglomeruli,theolfactory nerveterminalsformaxodendriticsynapsesontothe dendritictuftsofthemitral,tuftedandperiglomerular celldendrites,followedbyobligatorydendrodendritic anddendroaxonicinteractionsbetweenmitral/tufledeell dendritictuftsandperiglomerularcelltufts(Pinching andPowell,1970a'b).Anatomica1studiesarerevealing awealthofcomplexsynapticinterconnections(Kosaka andKosaka,2005).Aftertheinitialinputtothemitral, tuftedandperiglomerularcells,furtherprocessingmay takeplacewithintheglomerulusthroughtheden

    drodendriticmicrocircuits.Theperiglomerularcells containy-aminobutyricacid(GABA),dopamine,en- kephalin,thyrotropinreleasinghormone(Kosakaand

    Kosaka,2005).Physiologicalstudiesarerevealingthe activeproperties,includingcalciumtransients,ofden

    dritictufts(Zhoueta1.,2006).Thisisbelievedtocon

    tributetosigna1..to..noiseenhancementandenablethe mitral/tufledcellstorespondtoweakthresholdodor concentrations(ChenandShepherd,2005).Interneurons intheglomerularlayerappeartoinvolvelateralinhibi

    tOryeffectsthatmaymediatecontrastenhancementand initialextractionofmolecularfeaturesstrength(Aungst eta1..2003).Externaltuftedcellsappeartoestablish complexnetworksthatsetthebackgroundIeveIofex

    citabmtyindependentofodorstimulus(Clelandeta1., 2007).

    822VbI.56NO.6

    Atthesecondleveloforganization,themaintypeof microcircuitiSthedendrodendriticreciprocalsynapses betweenmitral/tufiedcellsandgranulecellintemeurons. Themitralcells,whenactivatedbyolfactoryorvo- meronasalnerveinputs,depolarizethegranulecell spinesbymeansofglutamatereleasedattheden. drodendriticsynapses(Fig.2).Thisdepolarizationin turnreleasesGABAfromthegranulecellspinesand hyperpolarizesthemitral/tuftedcells.Thesynapticmi- crocircuitismediatedprimarilybyN-methyl?-D?-aspartate (NMDA)receptorsonthegranulecellspinesreceiving theglutamatergicinputfromthemitral/tuftedcellden- drites(Isaacsoneta1.,l998;Schoppaeta1.,1998;Tani

    guchiandKaba,2001).

    Recently,characteristicsofdifferentcellsincludedon theAOBoftherat(Ruttus)havebeenstudiedindepth SJtrall~demale's

    chcmosignals

    MatimzmaleS

    claemosignals-_.

    VNE

    (Larriva-Sahd,2008).Essentially,thestructureofthe AOBiSsimilartotheMOB.Howeverl,therearesevera importantanatomicaldifierencesbetweentheAOBand M0Bthatmayreflectdifferencesintheprocessingof chemosignals.TheglomerularlayeriSlessdistinctin theAOBthanintheMOB.Inaddition.periglomerular cellsintheAOBarefarfewerthanintheMOB.The mostsignificantdifierencesbetweentheAOBandMOB arethoseofmitralcellmorphology.whichinfluencethe

samplingofglomerularsignalsandthefunctionofin

    hibitorymechanisms(BrennanandKeveme.1997).A singlemitralcellintheA0Bprojectsseveralprimary dendritestodifierentglomeruli.whereasasinglemitral cellintheMOBprojectsaprimarydendritetoasingle glomerulus(Mori.1987).MitralcellsoftheM0Bhave anextensivenetworkofsecondarydendritesthatproject A()B

    t)utput

    f"tom

    theA()Ij

    Blocked

    pregnanc.~

    Fig.2Neuralmechanismsunderlyingmaterecognitionmemoryandselectivegatingofpregn

    ancyblockingsignalsinfe?

    malemice

    Signalingpathwaysthatinhibittransmitterreleasearemarkedbyminussigns.ohR,0

    2?adrenergicreceptor;E,intracellulareffector;GGprotein; GABAAR,GABAAreceptor;Glu,glutamate;GluR,ionotropicglutamatereceptor;VNE,v

    omeronasalepithelium;VNN,vomeronasalrlelve;VSCC, voltagesensitivecalciumchanne1.

    KABAH:Neurobiologyofmammalianolfactorylearning radially,intheexternalplexiformlayer,inaplanetan. gentialtothemitraIeelllayer.Thisneuronalarchitec. turemayresultinasharpeningoftheodor-inducedpat

    ternofactivity,duetoincreasesinlateralinhibition.In contrast,mitralcellsoftheAOBhavepoorlydeveloped secondarydendrites;dendrodendriticreciprocalsyn- aDsesintheA0Bareformedmainlyonprimaryden. dritesratherthallsecondarydendrites.Althoughden.

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