TactileModulationofWhiskingviatheBrainstemLoop:StatechartModelingandEx - PDF document

TactileModulationofWhiskingviatheBrainstemLoop:StatechartModelingandExperimentalValidationDanaSherman,TessOram,DudiDeutsch,GorenGordon,EhudAhissar,DavidHarelDepartmentofNeurobiology,WeizmannInstituteofScience,Rehovot,Israel,DepartmentofComputerScienceandAppliedMathematics,WeizmannInstituteofScience,Rehovot,IsraelAbstractRatsrepeatedlysweeptheirfacialwhiskersbackandforthinordertoexploretheirenvironment.Suchexplorativewhiskingappearstobedrivenbycentralpatterngenerators(CPGs)thatoperateindependentlyofdirectsensoryfeedback.Nevertheless,whiskingcanbemodulatedbysensoryfeedback,andithasbeenhypothesizedthatsomeofthismodulationalreadyoccurswithinthebrainstem.However,theinteractionbetweensensoryfeedbackandCPGactivityispoorlyunderstood.Usingthevisuallanguageofstatecharts,adynamic,bottom-upcomputerizedmodelofthebrainstemloopofthewhiskingsystemwasbuiltinordertoinvestigatetheinteractionbetweensensoryfeedbackandCPGactivityduringwhiskingbehavior.Asabenchmark,weusedapreviouslyquantifiedclosed-loopphenomenonofthewhiskingsystem,touched-inducedpump(TIP),whichisthoughttobemediatedbythebrainstemloop.First,weshowedthatTIPsdependonsensoryfeedback,bycomparingTIPoccurrenceinintactratswiththatinratswhosesensorynervewasexperimentallycut.WetheninspectedseveralpossiblefeedbackmechanismsofTIPsusingourmodel.Themodelruledoutallhypothesizedmechanismsbutone,whichadequatelysimulatedthecorrespondingmotionobservedintherat.ResultsofthesimulationssuggestthatTIPsaregeneratedviasensoryfeedbackthatactivatesextrinsicretractormusclesinthemystacialpad.Themodelfurtherpredictedthatinadditiontothetouchingwhisker,allwhiskersfoundonthesamesideofthesnoutshouldexhibitaTIP.Wepresentexperimentalresultsthatconfirmthepredictedmovementsinbehavingrats,establishingthevalidityofthehypothesizedinteractionbetweensensoryfeedbackandCPGactivitywesuggesthereforthegenerationofTIPsinthewhiskingsystem. PLOSONE|www.plosone.org1November2013|Volume8|Issue11|e79831 Int_MNs,ExtP_MNs,andExtR_MNs,respectively[30].5.Anobstacle,which,ifpresentinthewhiskers’sweepingrange,inducedwhisker-obstaclecontacts.6.Amanager,whichactedasanexternalenvironmentobjectthatpassedinformationbetweenobjectsandsupportedtechnicalissues.Thiscomponentdidnotsimulateanybiologicalcomponentdirectly.Modelassumptions.Fiverowsofwhiskerslocatedatonesideofthesnoutweremodeled.Tworowswereimplementedasfour-whiskerrows,representingrowsA–Bintherat,andtheotherthreeasseven-whiskerrows,representingrowsC–E(Figure1A).Inbothtypesofrows,eachwhiskerwasattachedtoseveralmuscles[31](Figure1B):(1)Twointrinsicmuscles:onerostralandonecaudal.Inallrows(A–E),themostrostralwhiskerwasattachedtoonlyoneintrinsicmuscle,caudally,asobservedintherat[31].(2)Onesuperficialextrinsicprotractingmuscle.InrowsA–B,themostrostralwhiskerwasattachedtoanadditionaldeepextrinsicprotractingmuscle–apseudo-intrinsicmuscle[31].(3)Twoextrinsicretractingmuscles:asuperficialmuscleandadeepmuscle.TheextrinsicmusclesinthemodelandtheirequivalentsintheratcanbefoundinTable1.Acombined,tri-phasicactivationoftheabovemusclessimulatedfree-airwhiskingmotion(Figure2)[30]:First,extrinsicprotractingmuscleswereactivated,pullingthepadforwardandinitiatingwhiskerprotraction(Phase1).Second,theintrinsicandpseudo-intrinsicmuscleswereactivated,furthermovingthevibrissaeforward(Phase2).Third,relaxationofprotractingmuscles(bothextrinsicandintrinsic)occurred,whileextrinsicretractingmuscleswereactivated,pullingthepadandthewhiskersbackward(Phase3).Phases1and2gaverisetoaforwardwhisker Figure1.Thespatialarrangementofthewhiskersandmusclesinthemodel.)Fiverowsofipsilateralwhiskers.()Eachwhisker(black)isattachedtotwointrinsicmuscles(blue),twoextrinsicretractingmuscles(red),andoneextrinsicprotractingmuscle(green).InrowsA–B,therosintrinsicmuscleofthemostrostralwhiskerisreplacedbyapseudo-intrinsicmuscle(lightgreen),whereasinrowsC–Ethismuscleisremoved.Intrinsicmusclesandwhiskersareindexedinanincreasingorder,startingat1,fromcaudaltorostral.doi:10.1371/journal.pone.0079831.g001ModelingTactileModulationofWhiskinginRatsPLOSONE|www.plosone.org3November2013|Volume8|Issue11|e79831 motion(protraction),whichwasfollowedbyabackwardmotion(retraction),evokedbyphase3.ThetimedactivationofthedifferentmuscleswascontrolledbythecoordinatedfiringpatternsofthedifferentCPGs,excitingthedifferenttypesofMNsattheappropriatetimes.EachCPGstimulatedalltheMNsofacertaintype,whichtogetherinnervatedallthemodeledwhiskers(Figure2B).Thus,theactivationofaCPGaffectedthemotionofalltheipsilateralwhiskersinasamemanner.Inthismodel,eachCPGwaspartofanopenloopandthusitsbehaviorwasnotregulated.Free-airwhiskingmotioninducedbythebehavioroftheCPGsisfurtherdescribedinthe‘‘ModelbehaviorinStatecharts’’section.CPG-inducedMNsactivity,andthuswhiskermotion,couldbemodulatedbyanotherpre-synapticsource,SN2s,whichtookpartinafeedbackloop.Separatedsensorimotorfeedbackloopswereimplementedforthedifferentwhiskers,toalloweachwhiskertoaffectitsownmotion(Figure2B).FeedbackloopsimplementationisdescribedinmoredetailinFigure3andinFileS1.Althougheachwhiskerwasinnervatedbyaseparatepoolofneurons,sensoryfeedbackderivedfromonewhiskercouldaffectthemotionofotherwhiskers,viamusclesthatconnectedthewhiskers.Theextrinsicmuscles(eitherprotractingorretracting)wereassembledintogroupsthataffectedthemotionofseveralrowsofwhiskers,asdescribedinTable1[32].Forexample,whenMNsinrowCactivatedthesuperficialextrinsicprotractingmuscleofrowC(partofthePMIcomplexinTable1),allthreesuperficialextrinsicprotractingmusclesinrowsC–Econtracted,movingallwhiskersinrowsC–E.Inaddition,sensoryfeedbackthatactivatedtheintrinsicmusclesattachedtotheinnervatedwhisker,affectedthemovementofthatwhiskertogetherwithitstwoneighboringwhiskers,boththecaudalandtherostralwhisker(iftheyexisted).Thewhiskerswithinarowwereassumedtomovewithinasingleplane,withoutrotatingabouttheirownaxis.Forsimplicity,thewhiskersinthemodelwereconsideredrigid.Modelbehaviorinstatecharts.Toillustrateamodelsimulation,wedescribeherethedynamicprocessofgeneratingfree-airwhiskingmotion.Inthemodel,whiskingmotionresultedfromthedynamicallycombinedbehavioroffourtypesofelements:aCPG,aMN,amuscle,andawhisker.Westartbydescribingthebehaviorofeachofthesefourelementsseparately,andthendescribehowtheircombinedbehaviorsgaverisetowhiskingmotion.SimilardescriptionsofothermodelelementscanbefoundinFileS1(seeModelbehaviorinstatecharts)andinFigureS2.TheCPGstatechart,whosetransitiondiagramisshowninFigure4A,describesthebehaviorofaCPG.TheCPGhastwostates,andatanymomentitcanbeinexactlyonestate:(1)‘‘Activate’’–astimulationperiod,duringwhichtheCPGstimulatesallMNsofthecorrespondingtypesimultaneously,andataconstantrate,and(2)‘‘Relax’’–a‘‘silent’’period,duringwhichnostimuliaresenttotheMNs.TheCPGcanmovebetweenstatesfollowingtheoccurrenceofatriggeringeventspecifiednexttothetransitionarrow.Inthemodel,theCPGstaysseveraltensofmillisecondsineachstate,andcontinuouslyswitchesbetweenthetwostatesupontheoccurrenceofatimeout(tm)trigger.TheMNstatecharthasfourstates(Figure4B):(1)‘‘Rest’’–inwhichtheMNisinactive,(2)‘‘Generateactionpotential’’(generateAP)–inwhichtheMNpreparestoevokeanactionpotential(AP)andtotransmitthesignaltoitspost-synapticmuscle/s,(3)‘‘Absoluterefractoryperiod’’(ARP)–inwhichtheMNisinactive,butincomparisontothe‘‘Rest’’state,itcannotrespondtoanystimulusitreceives.Thus,whenbeinginthisstatethecellcanneverevokeanAP,(4)‘‘Relativerefractoryperiod’’(RRP)–whichisverysimilartothe‘‘Rest’’state,duringwhichtheMNisinactive,butfromwhichitcanbecomeactivated.Thedifferencebetweenthisstateandthe‘‘Rest’’stateisthatheretheishigher;i.e.,thestimulusshouldbestronger.Themusclestatecharthastwostates(Figure4C):(1)‘‘Rest’’–inwhichthemuscleisrelaxed,and(2)‘‘Contract’’–inwhichitThewhiskerstatechartalsohastwostates(Figure4D):(1)‘‘Rest’’–inwhichthewhiskerdoesnotmove,and(2)‘‘Move’’–inwhichthewhiskermoves.Sincestatechartsarefullyexecutable,onecancapturethedynamicsofthemodeledbehaviorsbyexecutingthemodel.Whenthesimulationisinitiated,manycomponentsarecreatedforeachelement,witheachcomponentreceivingitsowncopyofitsparent’sinitializedstatechartandinitializedsetofparameters,whichtogetherdescribethecomponent’sindependentbehavior.ThenumberofcomponentsinthemodelandafulllistofmodelparametersarespecifiedinFigureS1andinFileS1.Thesimultaneousexecutionofthestatechartsofallthemodel’scomponentsresultedinacombineddynamicbehaviorofthesystem,asfollow:Uponmodelexecution,threecopiesoftheCPGstatechartweregenerated,oneofeach(aCPGparameter):extrinsicprotractor(ExtP_CPG),intrinsic(Int_CPG),andextrinsicretractor(ExtR_CPG).EachCPGstartedinthe‘‘Activate’’stateanditsparameterwasassignedtozero.Afterafewmilliseconds(),theCPGexitedthe‘‘Activate’’stateandreachedaconditionconnector,fromwhichitcouldmovetoeitherthe‘‘Activate’’stateorthe‘‘Relax’’state,dependingonthefulfillmentofaspecificcondition:Ifthevalueoflowerthantheconstant,anotherparameteroftheCPG,theCPGtransmittedastimulationeventtoallofitsMNs(ofthe)andre-enteredthe‘‘Activate’’state(andincrementedits),otherwiseitmovedtothe‘‘Relax’’state.Theconditionheldforseveraliterations,keepingtheCPGinthe‘‘Activate’’stateforseveraltensofmilliseconds.Whentheconditionwasnolongervalid,theCPGmovedtothe‘‘Relax’’state.Afteratmofseveraltensofmilliseconds()theCPGreturnedtothe‘‘Activate’’state(andresetitsWhileinthe‘‘Activate’’state,eachMNinnervatedbytheCPGreceivedsuccessivestimulationevents.Uponthefirststimulation,theMNexitedtheinitial‘‘Rest’’stateandenteredthe Table1.Theextrinsicmusclesinthemodel.RowsA–BRowsC–ESuperficialprotractingPMSPMIDeepprotractingPI*-SuperficialretractingNLDeepretractingPIPMPEachrowofwhiskersisattachedtoonesuperficialextrinsicprotractingmuscle,whichrepresentsParsmediasuperior(PMS)orParsmediainferior(PMI)oftheM.nasolabialisprofundus,forrowsA–BorC–E,respectively.EachofthemostrostralwhiskersinrowsA–Bisalsoattachedtoadeeperextrinsicprotractingmuscle,whichrespresentsthepseudo-intrinsic(PI)portionsoftheParsinternaoftheM.nasolabialisprofundus.ThePIcanbeactivatedtogetherwiththePMS,orseparately(byintrinsicMNs).Inaddition,eachrowisattachedtotwoextrinsicretractingmusclegroups:superficialretractingmusclesanddeepretractingmuscles.ThesuperficialretractingmusclesrepresentM.nasolabialis(NL)andM.nasolabialissuperficialis(NLS)forrowsA–E.ThedeepretractingmusclesrepresentParsinternaprofunda(PIP)oftheM.nasolabialisprofundusforrowsA–B,andParsmaxillarisprofunda(MP)andParsmaxillarissuperficialis(MS)oftheM.nasolabialisprofundusforrowsC–E.*AttachedonlytowhiskersA4andB4.doi:10.1371/journal.pone.0079831.t001 ModelingTactileModulationofWhiskinginRatsPLOSONE|www.plosone.org4November2013|Volume8|Issue11|e79831 theidentityofthe‘‘pumping’’whiskersin80%(27of34)ofallcountedtouchevents.(2)Quantitativeinspection:AllmanuallycountedTIPswerealsoanalyzedusingtheMatlab-basedWhiskerTrackerimageprocessingsoftware[37].Thisallowedabetterinspectionofindividualwhiskers’movementfordeterminingtheoccur-renceofTIPs.Results(1)SensoryfeedbackisrequiredforTIPsgenerationinnaturallybehavingratsSensoryfeedbackwasindicatedtobenecessaryforTIPgenerationinhead-fixedrats[11].HereweverifyinfreelymovingratsthatTIPsindeeddependonsensoryfeedback,byexaminingTIPoccurrenceinbehavingratswhoseinfraorbitalbranchofthetrigeminalmaxillarynerve(IoN)wascutbilaterally.WepostulatedthatinIoN-transectedrats,wheretransmissionofsensoryinformationfromthevibrissaetothebrainwaseliminated,TIPswouldbeabsentifsensoryfeedbackisindeedrequired.RatsinwhichallwhiskersweretrimmedbesidesrowC(bilaterally)werefilmedusingahigh-speedvideocamera.Twelvemovieswithdurationsof0.67–4minuteswereacquiredbefore(seven)andafter(five)bilateralIoNtransection.IncontrasttoaTIPoccurrenceof27%(34TIPsoutof126touchevents)inresponsetowhisker-obstaclecontactsinintactrats,only3%(2/61)oftoucheventsyieldedTIPsinIoN-cutrats(p=0.028,one-tailedbinomialtest).Thus,bilateralIoNtransectionbringsTIPoccurrenceratetoitsspontaneouslevel(7%[11],p=0.19,binomialtest).BesidesthesignificantreductioninTIPprobability,IoNtransectiondidnotaffectsignificantlycharacteristicsofwhiskinginairasmeasuredviacycleduration,protractionduration,whiskingset-pointorwhiskingamplitude(Dependentt-testforpairedsamples,n=28;p=0.161,p=0.869,p=0.125,p=0.053,respectively).TheseresultsconfirmthatsensoryfeedbackisrequiredforTIPgenerationinnaturallybehavingratswhilenotsignificantlyaffectingparametersofwhiskinginair.(2)EstablishingmodelcredibilityBeforeinspectingpossiblecontrolmechanismsthatcouldmodulatewhiskingmotioninresponsetotouch,wefirstestablishedamodelthatmimickedthemotiontoberegulated,i.e.,free-airwhisking.Intherat,whiskingisassumedtoresultfromtri-phasicactivationofmystacialpadmusculature[30].Weimplementedallvibrissalmusclesthatparticipateingeneratingfree-airwhisking[32]:extrinsicprotracting,intrinsic,andextrinsicretractingmuscles(seeModelspecificationsunderMaterialsandMethods).Thesequentialcontractionofthesethreetypesofmuscles,timedbasedonFisheretal.[25],resultedinaperiodicmotionofallmystacialpadwhiskersbackandforthinasweepingmotion(Figure2).Simulatedmovementsobtainedbythemodelwerequalitativelyandquantitativelycomparedwithcorrespond-ingmotionsobservedinbehavingratsinordertofine-tunethemimicryofexploratorywhiskingmotion.Accuratemimicryoffree-airwhiskingmotion.free-airwhisking,ratsrepeatedlymovetheirwhiskersalongtherostral–caudalaxisinordertoscantheirimmediateenvironment[1,4,38].Thelargevibrissaeoneachsideoftherat’ssnoutarearrangedinagridoffiverowsandseveral(4–7)arcs(Figure1A).Althougheachwhiskerhassomecapabilityforindependentmovement,thewhiskersoneachsideofthesnoutgenerallymovetogether[10,11].Thus,inprinciple,themodelingofanindividualwhiskerwouldbesufficienttodescribethemotiontrajectoriesofallipsilateralwhiskers.Yet,wemodeledtheentirearrayofipsilateralwhiskers,inordertolateroninvestigatetheeffectofcontactmadebyonewhiskeronthemotiontrajectoriesofotherwhiskerslocatedindifferentrowsandarcs.Westartbydescribingthemotioninasinglerow.Themovementofarowischaracterizedbyhomogeneousmovementofalltherow’swhiskers[39],sweepingperiodicallybackandforth[11](Figure6A).Thisperiodicmovementcanbedividedintowhiskcycles,suchthateachcyclelasts100–200msecandiscomposedofaforward(protraction,78.418.1msec,SD)followedbyabackward(retraction,70.321msec,SD)movementofthewhiskers[11].Behavingratsexhibitawholerangeofwhiskingfrequencies(mostlybetween5–15Hz[4,12]),amplitudes(typically10–40[11]),andtrajectories(coveringtherangebetweenpuresinusoidstosquarewaves,[e.g.,fig.2Bin[10],figs.2,9in[12],figs.2C,3Ain[40],fig.2inn)Ourmodelgeneratedwhiskingtrajectoriesthatcanbemappedtothelow-frequency,low-amplitude,andsquare-waverangeofthein-vivorepertoire.Themovementofthefiverowsofwhiskersfoundononesideofthesnoutwassimulated.Tworowswereimplementedasfour-whiskerrows,equivalenttorowsA–Bintherat,andtheotherthreeasseven-whiskerrows,equivalenttorowsC–E(seeModelassumptionsunderMaterialsandMethods).Forsimplicity,asynchronizedmovementwithinthewhiskerarraywasassumed[10].Wepresentherewhiskermotionoftworepresen-tativerows,since,intheabsenceofcontacts,similarmotionwasobtainedinrowswithasimilarnumberofwhiskers.Figure6B,Cdisplaystheangleofwhiskersfoundintworowsasafunctionoftime.Thegraphshowsacoordinatedmovementofthewhiskerswhilemovingbackandforth.Inthemodel,awhiskcyclelastedabout150msec,andwascomposedofprotractionandretractionphasesthatlastedabout80and70msec,respectively,thusmimickingbiologicalwhiskingatthelowendofthefrequencyspectrum[11].Interestingly,thesquaredshapeofsinglewhiskcyclesgeneratedintheselowfrequencieschangedtoasinusoidalshapewhenthewhiskingfrequencywasincreased(notshown).Whiskingamplitudewassettobe,atthelowerendoftheamplituderangeobservedinawakerats,inordertoallowaccuratecalculationofwhiskingmotion(seeMuscleforces&whiskermotioninFileS1).Fromarestingangleof70,allwhiskersreachedaverysimilarmaximalprotractingangle(79–81)exceptfortherostral-mostwhiskersintheseven-whiskerrows,whichonly.Thisreductioninprotractionamplituderesultedfromthemodel’sassumption(basedonanatomicaldata)thatinaseven-whiskerrow,therostral-mostwhiskerisnotattachedtoanyprotractingmusclethatisactiveduringthesecondphaseofwhiskingmotion(seeModelassumptionsunderMaterialsandMethods).Thismodelpredictioncouldnotbetestedinourratsduetoinsufficientwhiskerlengthforreliabletracking.Consistencywithexperimentaldata.Theresultsde-scribedabovewereobtainedusinganeuralconfigurationinwhichwhiskingwasgeneratedsolelybytheactivityofaCPG.SimilarresultswereobtainedwhenwhiskingwascontrolledbybothaCPGandsensoryfeedback(datanotshown).Inthislatterconfiguration,CPGactivitycouldnotactivatetheMNsalone.Rather,theMNsrequiredsimultaneousinputfromboththeCPGandtheSN2s(seeModelconfigurationsunderMaterialsandMethods;Notethatindependentlyofthesemechanisms,threehypothesizedTIP-inducingmechanismsareexamined).Incon-trasttothesetwoconfigurations,athirdconfiguration,inwhichwhiskingwashypothesizedtobegeneratedbytheactivationofMNsbySN2salone,couldnotproducethedesiredwhiskingpattern(datanotshown).TheseresultsareconsistentwithModelingTactileModulationofWhiskinginRatsPLOSONE|www.plosone.org9November2013|Volume8|Issue11|e79831 References1.KleinfeldD,BergRW,O’connorSM(1999)Anatomicalloopsandtheirelectricaldynamicsinrelationtowhiskingbyrat.SomatosensMotRes16:69–2.KnutsenPM,AhissarE(2009)Orthogonalcodingofobjectlocation.TrendsNeurosci32:101–109.3.YoungentobSL,MozellMM,SheehePR,HornungDE(1987)AQuantitativeAnalysisofSniffingStrategiesinRatsPerformingOdorDetectionTasks.Physiology&Behavior41:59–69.4.WelkerWI(1964)Analysisofsniffingofthealbinorat.Behaviour22:223–244.5.HalpernBP(1983)Tastingandsmellingasactive,exploratorysensoryprocesses.AmJOtolaryngol4:246–249.6.KnutsenPM,BiessA,AhissarE(2008)Vibrissalkinematicsin3D:tightcouplingofazimuth,elevation,andtorsionacrossdifferentwhiskingmodes.Neuron59:7.PietrMD,KnutsenPM,ShoreDI,AhissarE,VogelZ(2010)Cannabinoidsrevealseparatecontrolsforwhiskingamplitudeandtiminginrats.JNeurophysiol104:2532–2542.8.AhissarE,KnutsenPM(2008)Objectlocalizationwithwhiskers.BiolCybern98:449–458.9.LandMF(2006)Eyemovementsandthecontrolofactionsineverydaylife.ProgRetinEyeRes25:296–324.10.BermejoR,VyasA,ZeiglerHP(2002)Topographyofrodentwhisking–I.Two-dimensionalmonitoringofwhiskermovements.SomatosensMotRes19:341–11.DeutschD,PietrM,KnutsenPM,AhissarE,SchneidmanE(2012)FastFeedbackinActiveSensing:Touch-InducedChangestoWhisker-ObjectInteraction.PLOSONE7:e44272.12.GaoP,BermejoR,ZeiglerHP(2001)WhiskerDeafferentationandRodentWhiskingPatterns:BehavioralEvidenceforaCentralPatternGenerator.TheJournalofNeuroscience21:5374–5380.13.BergRW,KleinfeldD(2003)Rhythmicwhiskingbyrat:retractionaswellasprotractionofthevibrissaeisunderactivemuscularcontrol.JNeurophysiol89:14.LovickTA(1972)Thebehaviouralrepertoireofprecolliculardecerebraterats.JPhysiol226:4P–6P.15.SembaK,KomisarukBR(1984)Neuralsubstratesoftwodifferentrhythmicalvibrissalmovementsintherat.Neuroscience12:761–774.16.MooreJD,DescheˆnesM,HuberD,SmearMC,DemersM,etal.(Inpress)Acommonbrainstemoscillatorcoordinateswhiskingwithbreathinginrodents:Evidenceforamasterclockinorofacialbehaviors.17.HattoxA,LiY,KellerA(2003)Serotoninregulatesrhythmicwhisking.Neuron39:343–352.18.MitchinsonB,MartinCJ,GrantRA,PrescottTJ(2007)Feedbackcontrolinactivesensing:ratexploratorywhiskingismodulatedbyenvironmentalcontact.ProcBiolSci274:1035–1041.19.HarelD(1987)Statecharts:Avisualformalismforcomplexsystems.ScienceofComputerProgramming8:231–274.20.HarelD(2003)AGrandChallengeforComputing:TowardsFullReactiveModelingofaMulti-CellularAnimal.BulletinoftheEATCS,EuropeanAssociationforTheoreticalComputerScience81:226–235.21.EfroniS,HarelD,CohenIR(2007)EmergentDynamicsofThymocyteDevelopmentandLineageDetermination.PLoSComputationalBiology3:127–22.SettyY,CohenIR,DorY,HarelD(2008)Four-dimensionalrealisticmodelingofpancreaticorganogenesis.ProcNatlAcadSciUSA105:20374–20379.23.SwerdlinN,CohenIR,HarelD(2008)TheLymphNodeBCellImmuneResponse:DynamicAnalysisIn-Silico.ProceedingsoftheIEEE(specialissueonComputationalSystemBiology)96:1421–1443.24.HarelD,GeryE(1997)ExecutableObjectModelingwithStatecharts.IEEEComputer30:31–42.25.FisherJ,HarelD,HenzingerTA(2011)Biologyasreactivity.CommunicationsoftheACM54:72.26.SzwedM,BagdasarianK,AhissarE(2003)EncodingofVibrissalActiveTouch.Neuron40:621–630.27.YuC,DerdikmanD,HaidarliuS,AhissarE(2006)ParallelThalamicPathwaysforWhiskingandTouchSignalsintheRat.PLoSBiology4:819–824.28.KleinBG,RhoadesRW(1985)RepresentationofWhiskerFollicleIntrinsicMusculatureintheFacialMotorNucleusoftheRat.TheJournalofComparativeNeurology232:55–69.29.HerfstLJ,BrechtM(2008)Whiskermovementsevokedbystimulationofsinglemotorneuronsinthefacialnucleusoftherat.JNeurophysiol99:2821–2832.30.HillDN,BermejoR,ZeiglerHP,KleinfeldD(2008)Biomechanicsofthevibrissamotorplantinrat:rhythmicwhiskingconsistsoftriphasicneuromus-cularactivity.JNeurosci28:3438–3455.31.HaidarliuS,GolombD,KleinfeldD,AhissarE(2012)Dorsorostralsnoutmusclesintheratsubservecoordinatedmovementforwhiskingandsniffing.AnatRec(Hoboken)295:1181–1191.32.HaidarliuS,SimonyE,GolombD,AhissarE(2010)Musclearchitectureinthemystacialpadoftherat.AnatRec(Hoboken)293:1192–1206.33.AhissarE,AhissarM(1994)Plasticityinauditorycorticalcircuitry.CurrOpinNeurobiol4:580–587.34.AhissarE,AbelesM,AhissarM,HaidarliuS,VaadiaE(1998)Hebbian-likefunctionalplasticityintheauditorycortexofthebehavingmonkey.Neuropharmacol37:633–655.35.Ego-StengelV,ShulzDE,HaidarliuS,SosnikR,AhissarE(2001)Acetylcholine-dependentinductionandexpressionoffunctionalplasticityinthebarrelcortexoftheadultrat.JNeurophysiol86:422–437.36.AertsenA,VaadiaE,AbelesM,AhissarE,BergmanH,etal.(1991)Neuralinteractionsinthefrontalcortexofabehavingmonkey:signsofdependenceonstimuluscontextandbehavioralstate.JHirnforsch32:735–743.37.PerkonI,KosirA,ItskovPM,TasicJ,DiamondME(2011)Unsupervisedquantificationofwhiskingandheadmovementinfreelymovingrodents.JNeurophysiol105:1950–1962.38.KnutsenPM,PietrM,AhissarE(2006)Hapticobjectlocalizationinthevibrissalsystem:behaviorandperformance.JNeurosci26:8451–8464.39.HillDN,CurtisJC,MooreJD,KleinfeldD(2011)Primarymotorcortexreportsefferentcontrolofvibrissamotiononmultipletimescales.Neuron72:344–356.40.MooreJD,DeschenesM,FurutaT,HuberD,SmearMC,etal.(2013)Hierarchyoforofacialrhythmsrevealedthroughwhiskingandbreathing.Nature497:205–210.41.DiamondME,HeimendahlM,ArabzadehE(2008)Whisker-MediatedTextureDiscrimination.PLoSBiology6:1627–1630.42.LiYQ,TakadaM,KanekoT,MizunoN(1997)DistributionofGABAergicandGlycinergicPremotorNeuronsProjectingtotheFacialandHypoglossalNucleiintheRat.TheJournalofComparativeNeurology378:283–294.43.SzwedM,BagdasarianK,BlumenfeldB,BarakO,DerdikmanD,etal.(2006)Responsesoftrigeminalganglionneuronstotheradialdistanceofcontactduringactivevibrissaltouch.JNeurophysiol95:791–802.44.NguyenQT,KleinfeldD(2005)Positivefeedbackinabrainstemtactilesensorimotorloop.Neuron45:447–457.45.FisherJ,HenzingerTA(2007)Executablecellbiology.NatBiotechnol25:46.SolomonEP,SchmidtRR,AdragnaPJ(1990)HumanAnatomy&physiology:SaundersCollegePublishing.47.AhissarE,ArieliA(2012)Seeingviaminiatureeyemovements:Adynamichypothesisforvision.FrontiersinComputationalNeuroscience6:89.48.KepecsA,UchidaN,MainenZF(2006)Thesniffasaunitofolfactoryprocessing.ChemSenses31:167–179.49.BaharA,DudaiY,AhissarE(2004)Neuralsignatureoftastefamiliarityinthegustatorycortexofthefreelybehavingrat.JNeurophysiol92:3298–3308.50.WiseSP,JonesEG(1977)Cellsoforiginandterminaldistributionofdescendingprojectionsoftheratsomaticsensorycortex.JCompNeurol175:129–157.51.KillackeyHP,KoralekKA,ChiaiaNL,RhodesRW(1989)Laminarandarealdifferencesintheoriginofthesubcorticalprojectionneuronsoftheratsomatosensorycortex.JCompNeurol282:428–445.52.WoolstonDC,LaLondeJR,GibsonJM(1983)Corticofugalinfluencesintheratonresponsesofneuronsinthetrigeminalnucleusinterpolaristomechanicalstimulation.NeuroscienceLetters36:43–48.53.LeeSH,CarvellGE,SimonsDJ(2008)Motormodulationofafferentsomatosensorycircuits.NatureNeuroscience11:1430–1438.54.KleinfeldD,AhissarE,DiamondME(2006)Activesensation:insightsfromtherodentvibrissasensorimotorsystem.CurrOpinNeurobiol16:435–444.55.XiaoB,OramT,ZlochiverV,BagdasarianK,AhissarE.Fastmotorpathwayfromposteromedialthalamicnucleustofacialnucleus;2012;NewOrleans.56.HemeltME,KellerA(2008)Superiorcolliculuscontrolofvibrissamovements.JNeurophysiol100:1245–1254.ModelingTactileModulationofWhiskinginRatsPLOSONE|www.plosone.org16November2013|Volume8|Issue11|e79831