SpinalInterneurons PlasticityafterSpinalCordInjury
Editedby
LyandyshaViktorovnaZholudeva GladstoneInstitutes,UniversityofCalifornia,SanFrancisco,CA, UnitedStates
MichaelAronLane
DrexelUniversity,CollegeofMedicine,DepartmentofNeurobiology& Anatomy,andtheMarionMurraySpinalCordResearchCenter Philadelphia,PA,UnitedStates
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DedicationtoMarionMurray (1937e2018):aleaderinspinal cordinjuryresearchanda pioneerinadvancingCNS plasticity
WededicatethisbodyofworktoDr.Marion Murray,PhD,ProfessorEmeritusinthe DepartmentofNeurobiologyandAnatomy atDrexelUniversity,Philadelphia,who passedawayonSeptember9,2018.
TogetherwithDr.MichaelGoldberger,a closefriendandcollaborator,Dr.Marion MurrayestablishedtheSpinalCord ResearchCenter(SCRC),nowtheMarion MurraySCRC,atDrexelUniversity.Sheled theresearchactivitiesoftheCenterforover 30years,servedasPrincipalInvestigatorof anexceptionalNIHProgramProjectto createoneofthemostprominent,worldrenowned,researchcenters.Sheinspired andmentoredcountlessstudents,fellows andfaculty,publishedmorethan150scientificarticlesandreviews,andestablished atraditionofexcellencethatcontinuesto thriveinthecurrentDepartmentof Neurobiologywhichwearepartof.
Anexemplaryscientificleader,Marion fearlesslyandpassionatelytackled
challengingproblemsofspinalcordinjury toimprovehumanhealthbecomingpart ofthelegacyofwomeninscienceover severalgenerations.Shehada“BigPicture”visioncoupledwithskepticismover establisheddogmainscience,andtaught usconstructivecriticism beitinpublishingpapersorgrantapplications drivingtheCentertothehighestof standardsinresearchandmentoring.
Shepioneeredresearchinspinalcordplasticityatatimewhenneuroscientistswere skepticalaboutaxonalsproutingandthe neuroplasticpotentialoftheinjuredspinal cord.Thisbookhighlightshowmuchthe fieldnowreadilyacceptstheideasthat Marionhelpedtolaythefoundationfor.We areextremelygratefulforhavinghadthe chancetointeractwithheratDrexel,which contributedtohowthisbookwasdeveloped.
Wehopethatthisbookwillnotonlyserve asamemorytoMarion’slegacybutwould havebeenavolumeshekeptonheroffice bookshelf,frequentlyread,andshared withherstudentsassheoftendidwithher otherbooks.
Wemissyou,Marion.
LyandyshaV.ZholudevaandMichaelA.Lane Editors
1. Theneuronalcelltypesofthespinalcord StephanieC.KochandArielJ.Levine
2. Identifiedinterneuronscontributingtolocomotionin mammals
ErikZ.Li,LeonardoD.Garcia-Ramirez,NgocT.B.Haand KimberlyJ.Dougherty
3. Decodingtouch:peripheralandspinalprocessing
MarkA.Gradwell,ManonBohicandVictoriaE.Abraira
4. Spinalinterneuronsandpain:identityandfunctional organizationofdorsalhornneuronsinacute andpersistentpain
Myung-chulNoh,SuhJinLee,CynthiaM.Arokiarajand RebeccaP.Seal
5. Cholinergicspinalinterneurons
PatriciaE.PhelpsandAlexaMarieTierno
6. Spinalinterneurons,motorsynergies,andmodularity
SimonF.Giszter,TrevorS.SmithandAndreyP.Borisyuk
Listofcontributors
VictoriaE.Abraira,DepartmentofCellBiologyandNeuroscience,Rutgers,The StateUniversityofNewJersey,Piscataway,NJ,UnitedStates;W.M.KeckCenter forCollaborativeNeuroscience,Rutgers,TheStateUniversityofNewJersey, Piscataway,NJ,UnitedStates
MiriamAceves,DepartmentofBiology,TexasA&MUniversity,CollegeStation,TX, UnitedStates;TexasA&MInstituteforNeuroscience,TexasA&MUniversity, CollegeStation,TX,UnitedStates
ClaudiaAngeli,KentuckySpinalCordInjuryResearchCenter,UniversityofLouisville,Louisville,KY,UnitedStates;DepartmentofBioengineering,Universityof Louisville,Louisville,KY,UnitedStates;FrazierRehabilitationInstitute,UniversityofLouisvilleHealth,Louisville,KY,UnitedStates
CynthiaM.Arokiaraj,DepartmentofNeurobiology,PittsburghCenterforPain Research,CenterfortheNeuralBasisofCognition,UniversityofPittsburghSchool ofMedicine,Pittsburgh,PA,UnitedStates
DerinBirch,NorthwesternUniversity,FeinbergSchoolofMedicine,Chicago,IL, UnitedStates
ManonBohic,DepartmentofCellBiologyandNeuroscience,Rutgers,TheState UniversityofNewJersey,Piscataway,NJ,UnitedStates;W.M.KeckCenterfor CollaborativeNeuroscience,Rutgers,TheStateUniversityofNewJersey,Piscataway,NJ,UnitedStates
AndreyP.Borisyuk,NeurobiologyandAnatomy,MarionMurraySpinalCord ResearchCenter,DrexelUniversityCollegeofMedicine,Philadelphia,PA,United States;JointNeuroengineeringInitiative,CollegeofMedicineandSchoolof BiomedicalEngineering,ScienceandHealthSystems,DrexelUniversity,Philadelphia,PA,UnitedStates
JessicaC.Butts,DepartmentofMolecularandHumanGenetics,BaylorCollegeof Medicine,Houston,TX,UnitedStates
BoChen,DepartmentofNeuroscience,CellBiology,&Anatomy,TheUniversityof TexasMedicalBranch,Galveston,TX,UnitedStates
StevenA.Crone,CincinnatiChildren’sHospitalMedicalCenter,DivisionsofPediatricNeurosurgeryandDevelopmentalBiology,Cincinnati,OH,UnitedStates; UniversityofCincinnatiCollegeofMedicine,DepartmentofNeurosurgery,Cincinnati,OH,UnitedStates
JaclynH.DeFinis,MarionMurraySpinalCordResearchCenter,Departmentof Neurobiology&Anatomy,DrexelUniversityCollegeofMedicine,Philadelphia, PA,UnitedStates
KimberlyJ.Dougherty,MarionMurraySpinalCordResearchCenter,Departmentof NeurobiologyandAnatomy,DrexelUniversityCollegeofMedicine,Philadelphia, PA,UnitedStates
JenniferN.Dulin,DepartmentofBiology,TexasA&MUniversity,CollegeStation, TX,UnitedStates;TexasA&MInstituteforNeuroscience,TexasA&MUniversity, CollegeStation,TX,UnitedStates
V.ReggieEdgerton,RanchoResearchInstitute,LosAmigosNationalRehabilitation Center,Downy,CA,UnitedStates;USCNeurorestorationCenter,Universityof SouthernCalifornia,LosAngeles,CA,UnitedStates;InstitutGuttmann.Hospital deNeurorehabilitacio ´ ,InstitutUniversitariadscritalaUniversitatAuto ` nomade Barcelona,Barcelona,Badalona,Spain
LeonardoD.Garcia-Ramirez,MarionMurraySpinalCordResearchCenter, DepartmentofNeurobiologyandAnatomy,DrexelUniversityCollegeofMedicine, Philadelphia,PA,UnitedStates
YuryGerasimenko,KentuckySpinalCordInjuryResearchCenter,Universityof Louisville,Louisville,KY,UnitedStates;DepartmentofPhysiology,Universityof Louisville,Louisville,KY,UnitedStates;PavlovInstituteofPhysiologyofRussian AcademyofScience,St.Petersburg,Russia
SimonF.Giszter,NeurobiologyandAnatomy,MarionMurraySpinalCordResearch Center,DrexelUniversityCollegeofMedicine,Philadelphia,PA,UnitedStates; JointNeuroengineeringInitiative,CollegeofMedicineandSchoolofBiomedical Engineering,ScienceandHealthSystems,DrexelUniversity,Philadelphia,PA, UnitedStates
MarkA.Gradwell,DepartmentofCellBiologyandNeuroscience,Rutgers,TheState UniversityofNewJersey,Piscataway,NJ,UnitedStates;W.M.KeckCenterfor CollaborativeNeuroscience,Rutgers,TheStateUniversityofNewJersey,Piscataway,NJ,UnitedStates
NgocT.B.Ha,MarionMurraySpinalCordResearchCenter,DepartmentofNeurobiologyandAnatomy,DrexelUniversityCollegeofMedicine,Philadelphia,PA, UnitedStates
SusanHarkema,KentuckySpinalCordInjuryResearchCenter,Universityof Louisville,Louisville,KY,UnitedStates;FrazierRehabilitationInstitute,UniversityofLouisvilleHealth,Louisville,KY,UnitedStates;DepartmentofNeurosurgery,UniversityofLouisville,Louisville,KY,UnitedStates
ZhigangHe,F.M.KirbyNeurobiologyCenter,BostonChildren’sHospital,Boston, MA,UnitedStates;DepartmentsofNeurology,HarvardMedicalSchool,Boston, MA,UnitedStates
ShaopingHou,MarionMurraySpinalCordResearchCenter,DepartmentofNeurobiology&Anatomy,DrexelUniversityCollegeofMedicine,Philadelphia,PA, UnitedStates
Listofcontributors xv
StephanieC.Koch,DepartmentofNeuroscience,PhysiologyandPharmacology, DivisionofBiosciences,UniversityCollegeofLondon,London,UnitedKingdom
MichaelA.Lane,DrexelUniversity,DepartmentofNeurobiologyandMarionMurray SpinalCordResearchCenter,Philadelphia,PA,UnitedStates
SuhJinLee,DepartmentofNeurobiology,PittsburghCenterforPainResearch,Center fortheNeuralBasisofCognition,UniversityofPittsburghSchoolofMedicine, Pittsburgh,PA,UnitedStates
ArielJ.Levine,SpinalCircuitsandPlasticityUnit,NationalInstituteofNeurological DisordersandStroke,NIH,Bethesda,MD,UnitedStates
ErikZ.Li,MarionMurraySpinalCordResearchCenter,DepartmentofNeurobiology andAnatomy,DrexelUniversityCollegeofMedicine,Philadelphia,PA,United States
DavidS.K.Magnuson,DepartmentofNeurologicalSurgery,KentuckySpinalCord InjuryResearchCenter,UniversityofLouisville,Louisville,KY,UnitedStates
AmrA.Mahrous,NorthwesternUniversity,FeinbergSchoolofMedicine,Chicago, IL,UnitedStates
FeliciaM.Michael,SpinalCordandBrainInjuryResearchCenter,Universityof Kentucky,Lexington,KY,UnitedStates;DepartmentofPhysiology,Universityof Kentucky,Lexington,KY,UnitedStates
Myung-chulNoh,DepartmentofNeurobiology,PittsburghCenterforPainResearch, CenterfortheNeuralBasisofCognition,UniversityofPittsburghSchoolof Medicine,Pittsburgh,PA,UnitedStates
BauPham,DepartmentofBioengineering,UniversityofCalifornia,LosAngeles,CA, UnitedStates
PatriciaE.Phelps,UCLA,DepartmentofIntegrativeBiologyandPhysiology,Los Angeles,CA,UnitedStates
AlexanderG.Rabchevsky,SpinalCordandBrainInjuryResearchCenter,University ofKentucky,Lexington,KY,UnitedStates;DepartmentofPhysiology,University ofKentucky,Lexington,KY,UnitedStates
MargoL.Randelman,DrexelUniversity,DepartmentofNeurobiologyandMarion MurraySpinalCordResearchCenter,Philadelphia,PA,UnitedStates
ShellySakiyama-Elbert,DepartmentofBiomedicalEngineering,UniversityofTexas atAustin,Austin,TX,UnitedStates
AlfredoSandoval,Jr.,DepartmentofNeuroscience,CellBiology,&Anatomy,The UniversityofTexasMedicalBranch,Galveston,TX,UnitedStates
RebeccaP.Seal,DepartmentofNeurobiology,PittsburghCenterforPainResearch, CenterfortheNeuralBasisofCognition,UniversityofPittsburghSchoolof Medicine,Pittsburgh,PA,UnitedStates
OwenShelton,NorthwesternUniversity,FeinbergSchoolofMedicine,Chicago,IL, UnitedStates
Listofcontributors
TrevorS.Smith,NeurobiologyandAnatomy,MarionMurraySpinalCordResearch Center,DrexelUniversityCollegeofMedicine,Philadelphia,PA,UnitedStates; JointNeuroengineeringInitiative,CollegeofMedicineandSchoolofBiomedical Engineering,ScienceandHealthSystems,DrexelUniversity,Philadelphia,PA, UnitedStates
AlexaMarieTierno,UCLA,DepartmentofIntegrativeBiologyandPhysiology,Los Angeles,CA,UnitedStates
AshleyTucker,DepartmentofBiology,TexasA&MUniversity,CollegeStation,TX, UnitedStates;TexasA&MInstituteforNeuroscience,TexasA&MUniversity, CollegeStation,TX,UnitedStates
VickiTysseling,NorthwesternUniversity,FeinbergSchoolofMedicine,Chicago,IL, UnitedStates
NicholasWhite,DepartmentofBiomedicalEngineering,UniversityofTexasat Austin,Austin,TX,UnitedStates
LyandyshaV.Zholudeva,GladstoneInstitutes,UniversityofCaliforniaSanFrancisco, SanFrancisco,CA,UnitedStates
Preface
Spinalinterneuronshavelongbeenrecognizedasessentialcomponentsinall spinalnetworks.Theyarealsonowquicklybecomingidentifiedaskeyelements ofplasticitywithinjuryordisease,capableofalteringtheirconnectionsandtheir activitytofacilitate orattimeshinder functionalrecovery.Thisbookprovidesathoroughoverviewofwhatispresentlyknownaboutspinalinterneurons intheintactandinjuredspinalcord,presentedbyleadingscientistsandclinical professionals.
Preclinicalstudiesofspinalcordneurobiologyhaverecognizedtheir importanceinmotor,sensory,andautonomicactivitysincetheearlyworkof SantiagoRamonyCajalandSirCharlesSherrington.Oneofthefirstdedicated textstothetopicofinterneurons “theInterneuron,”editedbyMaryA.B. Brazier followedasymposiumonthetopicatUCLAin1967.Thistext highlightedthegrowinginterestinspinalinterneurons,asscientistsrecognized theirimportance.In1968,G.AdrianHorridgewroteinhisbooktitled Interneurons;“Whatanymanoranimalperceivesordoes,andallhumanconceptions,arerestrictedbythelimitationsofinterneurons.”Thepresentbooknow revealstheremarkableadvancesthathavebeenmadeinthisfieldoverthepast 50years,whichwehopemakesaworthyadditiontotextsonthesubjectof “SpinalInterneurons.”
Ashighlightedinthefirstsectionofthisbook,advancesingenetic,molecular,electrophysiological,andanatomicalassays,withconsiderationsfor comparativeneurobiologyandcross-speciesdifferences,continuetoreshapeour understandingofhowspinalinterneuronsareintegratedwithinandbetween spinalnetworks.Ongoingresearchandcharacterizationofspinalinterneuronsin developmentalneurobiology,computationalneuroscienceandmodeling,systemsneuroscience,neurophysiology,andneuroanatomyisexpandingthe breadthofourknowledgeatrapidrates.Withtheseadvancesalsocomesthe appreciationthatthenumberofidentifiablespinalinterneuronsfarsurpasses whatwehadrecognizedonlyadecadeago.
Astheyareessentialtofunctionintheintactspinalcord,theyarealsointegral tofunctionafterspinalcordinjuryanddisease,asdiscussedinthesecondpartof thisbook.Importantly,compromiseofthespinalnetworkswitheithertraumatic injuryordegenerativediseaserarelyresultsinatotallossofcellsorconnectivity, andsparedneuralsubstratescancontributetoextensiveplasticity.Evenwiththe mostsevereoftraumaticspinalcordinjuries(e.g.,completespinaltransection),
xviii Preface
sparedspinalnetworksbelowthelevelofinjury(thatloseinputsfromthebrain) retainthecapacitytobeactivatedandfunctional.Theinjuredspinalcordisnow widelyrecognizedascomprisinga“newanatomy,”richininterneuronalnetworks.Althoughongoingpreclinicalandclinicalresearchstillaimstobetter definethisnewanatomy,thereisalreadywidespreadrecognitionthatspinal interneuronsarecrucialcomponentsforpostinjuryfunction,andassuch, representimportanttherapeutictargets.Theiralteredneurophysiologicalfunctionandsynapticconnectivityafterinjuryhasledtowidespreadeffortto manipulatethemwiththerapeuticintervention,andasdescribedinthisbook, therehasbeensomeconsiderablesuccess.Infact,spinalinterneuronsarenow oftenseenas“thegatewaytoneuroplasticity” bothbeneficialand maladaptive followinginjuryanddisease.
Thecontributionsinthisbook,fromsomeoftheworld’sleadersinspinal interneurons,highlightourcurrentunderstandingofthishighlymolecularly, anatomically,andfunctionallydiversepopulationofcells.Yetit’sclearthatthis isjustthetipoftheiceberg.Wehopethattheinformationherehelpstoguide increasedresearcheffort,harnessinganever-expandingtoolkitforcharacterizingspinalinterneuronsandtheirneuroplasticpotential.Withagreaterunderstandingofhumanhealthandspinalneurobiology,thereishopethatnovel therapeutictargetswillbeidentified,andthatnewandimprovedstrategieswill bedevelopedfortreatingspinalcordinjuryordisease.
LyandyshaViktorovnaZholudeva,PhD MichaelAronLane,PhD
Theneuronalcelltypesofthe spinalcord
StephanieC.Koch1 andArielJ.Levine2
1DepartmentofNeuroscience,PhysiologyandPharmacology,DivisionofBiosciences,University CollegeofLondon,London,UnitedKingdom; 2SpinalCircuitsandPlasticityUnit,National InstituteofNeurologicalDisordersandStroke,NIH,Bethesda,MD,UnitedStates
Introduction
Overthepastcentury,perhapsthemosttransformativeperspectiveinneurosciencehasbeentoviewthefunctionofthenervoussystemasthecoordinated actionofdiversepopulationsofneuronsandtheircommunicationwitheach other(reviewedinRef.1).Therefore,inoureffortstounderstandcognition, emotion,somatosensation,andmovement,greatemphasishasbeenplacedon theneedtodefinetheconstituentcelltypesofthebrainandspinalcordwhich couldcoordinatethesecomplexbehaviors.2,3 Cell“types”areregularly occurringvarietiesthatshareacoherentsetofcellfeaturessuchaslocation, morphology,markergenes,and/orfunction.
Theneuronalcelltypesofthespinalcordserveasthecriticallinksbetween thebrainandthebody.Aswenavigatethroughtheworld,weareconstantly usingoursenses,suchastouch,pain,andlimbposition,toguidehowwemove andinteractwithourenvironment.Throughthesesenseswecanprotect ourselvesfromharmandfinelycorrectourmovementstoadjusttochanging conditions.Weareabletoquicklymodifyourmovementsaccordingto environmentalneedsasaresultofspecializednetworksofcellsinthespinal cord,whichreceiveinformationfromtheexternalworld,andrelaythisto motorcircuits,aswellastohighercommandcenters.
Thespinalcordservesasthefirstintegrativepointofprimaryafferent sensoryinformationwithmotornetworksandspinalcircuitsarethereforekey inthetransformationofsensoryinformationanddescendingsignalsfromthe brainintobehavior.Withinthespinaldorsalhorn,sensoryinputisrelayed locallybeforetransmissiontohighercenters.Hereitcanbemodulatedand influencedbybothexcitatoryandinhibitoryneurotransmittersreleasedfrom localinterneurons;regulationoftheseinterneuronsandthebalancebetween inhibitionandexcitationcanthereforestronglyaffecttheperceptionand SpinalInterneurons. https://doi.org/10.1016/B978-0-12-819260-3.00005-6 Copyright
discriminationofsensoryinformation.Withintheventralhorn,spinalcord neuronsrelaydescendingcues,coordinatetheactivityoffunctionallyrelated groupsofmuscles,andaresufficienttoexecutesimplebehaviorsthrough “centralpatterngenerators”andmotorsynergies.
Whereasspinalcircuitfunctioniscarefullymanagedinthehealthyadult system,studiesinbothanimalsandhumansrevealthattheexquisitebalance withinspinalcircuitscanbedisruptedinpathology,leadingtopainandthe lossofvoluntarymovement.Forexample,removalofspinalinhibitionusing pharmacologicalblockadeofinhibitorytransmitterreceptorsystemsresultsin excessiveneuralactivityandmodelsofpathologicalpainstatesinrats.4 7 In starkcontrasttothis,increasinginhibitionbymeansofclinicallyutilized medicinescandampendownallafferentinformationfrombothperipheral tissuesanddescendingfrombrainstemstructures,resultinginanesthesia, analgesia,andparalysis.8 Directinjurytothespinalcordorlossofbraininputs tothecordfollowingstrokecausesparalysisand,paradoxically,spasticitydue toexaggeratedspinalreflexes.9 Underscoringthediversefunctionsofspinal cordcells,spinalcordinjurycanalsocausefailureofnormalbreathing, autonomicregulation,andbowel,bladder,andsexualfunction.9
Advancesinthescientificunderstandingofbiologicalsystemshave allowedustotakeadvantageoftheversatilityofthehumanorganisminorder tobettertreatadultpathologies.Suchtreatments,however,havethusfar provedineffectiveandwithalargerangeofsideeffects,largelyduetothelack ofknowledgeoftheunderlyingspecializedcircuitsinthespinalcordwhich allowustosenseandadapttoourenvironment.Itremainsthereforetonot onlyidentifytheindividualcomponentunitsoffunctionalbehavior,butto understandtheseunitsatsuchaleveltotargetandmanipulatethemwithina functionalcontext.Dissectingthecellsandcircuitsunderlyingthefundamentalinterplaybetweensensationandmovementwillprovideacrucial frameworktobuilduponstudyinghowtheseprocessesmayinturngowrong inthecaseofdiseaseorinjury.
Multiplemethodshavebeenusedtoidentifyandcategorizedifferent populationsofneuronswithinthespinalcord.Whilenoneoftheseinisolation havebeenentirelyproductive,incombinationtheyhaverevealedimportant insightsintothecellularbasisofcodingofsensorystimuliandtheexecution ofbehavior.
Historyofresearchonspinalcordneurons
Spinalcordneuronsandtheirclassificationhaveenjoyedaspecialplaceinthe historyofneuroscience.SantiagoRamonyCajalformulatedtheneuron doctrine thatdistinctcellsarethemainanatomicalsubstrateinthenervous system basedpartiallyonhisstudiesofthespinalcord.10 Aroundthesame time,CharlesSherringtoncoinedthetermsynapsetodescribethespecialized connectionsbetweenneuronsanddiscoveredtheroleofinhibition,bothbased
onhisinvestigationsofspinalreflexarcs.11 Later,hisprote ´ ge ´ JohnEccles performedthefirstinvivointracellularrecordingsofthemammaliancentral nervoussystemincatspinalmotorneurons.12
Thesetwintraditionsofformandfunctionshapedresearchonspinalcord neuronalcelltypesforthefollowingdecades.Romanes,Rexed,Scheibel,and othersprovidedmeticulousanalysesofcelltypelocationandmorphology, whileEccles,Lundberg,Jankowska,andothersprobedtheelectrophysiologicalpropertiesofcellsandtracedconnectivitywithinspinalcordcircuits.13 21 Byrecordingfrom,andsubsequentlyfilling(e.g.,withatracer),singleidentifiedspinalcordneurons,theseresearchersalsobegantolinktogether anatomicalandelectrophysiologicalfeaturesofspinalcordneurons.These studieshavesinceledtothedevelopmentanduseofawidearrayofapproachesforcharacterizingspinalcordneurons,asdescribedbelow.
Classificationsystemsforspinalcordinterneuron celltypes
Todate,ourknowledgeofspinalcordneuronshasbeengainedthrougharange ofdifferenttechniques,yieldingarichliteratureandmultifacetedknowledge ofspinalcordcelltypes.However,thistechnicaldiversityhasalsofractured ourperspectives,witheachmethodrevealingcelltypespecificfeaturesand thusprovidingmultipleschemesforclassifyingspinalcordinterneurons (Fig.1.1).
Anatomy
Anatomyhasbeenapowerfulschemeforclassifyingspinalcordcelltypes becausethelocationofspinalcordneurontypesisintimatelylinkedtotheir function.Alongtherostro-caudalaxis,eachregionofthespinalcordisdedicatedtoparticularoutputssuchasrespirationatmid-cervicallevels,handuseat lowercervicallevels,andautonomiccontrolatthoracicandsacrallevels.Within eachspinalcordsegment,thereisarepeatingarchitectureofhistologicalcell types,organizedbyRexedintolaminaeIthroughX,eachwithitsowncharacteristiccellularmorphologies.14 Neuronsinthesamelaminaoftensharethe samedescendingandsensorysynapticinputs,localconnectivity,andextracellularmilieu(includingneuropeptidevolumetransmissionandsignalsfromglia). However,anatomicalorganizationisanincompletesystemforclassification,as eachlaminacontainsneuronsthatvarywidelyinothercellularfeaturessuchas neurotransmitterstatusandfiringproperties.
Morphology
Morphologyhascommonlybeenusedasacategorizationtool,tosomesuccess.Dendriticbranchingpatterncaninfluenceintegrationcapabilitiesofa
SECTION|I
FIGURE1.1 Summaryschematicofthemainclassificationscurrentlyusedtocatalogspinal interneuronalsubpopulationsandexampleswithineachcategorization.Embryoniclineagetracing, dendriticmorphology,anatomyorconnectivity,electrophysiologicalproperties,neurochemistry,or multiomicsprofilinghaveallbeenusedtosubparsespinalinterneuronsintoindividualclasses, highlightingthediversityofinterneuronalpopulations althoughnomethodhasproventobe entirelyeffectiveinisolation.Seemaintextfordetails. 1a-IN:1ainterneuron; CR:calretinin positiveinterneuron; DYN:dynorphinpositiveinterneuron; En1: Engrailed1; EXIN:excitatory interneuron; Foxp2:ForkheadboxproteinP2; GRP:gastrinreleasingpeptidepositiveinterneuron; IN:interneuron; Prdm12:PRdomainzincfingerprotein12; PV:parvalbuminpositiveinterneuron; SOM:somatostatinpositiveinterneuron. Imagecreatedwith BioRender.com.
singleinterneuron,whetherthisisconfinedtoasinglelaminaoracrossseveral segmentsaswellasinstructneuronalfiringproperties.22,23 Morphological classificationhasbeenespeciallyinstructiveindorsalhornpopulations,where interneuronswithinlaminaIIofthesuperficialdorsalhornhavebeenbroadly subdividedintoisletcell,medial-lateral,radialcell,centralcell,andvertical
cellmorphologies.22 WithinlaminaI,neuronshavebeendescribedtohave fusiform,pyramidal,ormultipolarmorphologies.24,25 Substantialeffortshave beenmadetomatchtheseclassificationstofunctionalneurochemicalgroups andlaminarlocations,butwithlimitedsuccess.
Connectivity
Asprimaryafferentsensoryinputentersthespinaldorsalhorn,itissubjected tolocalsegmentalmodulationallowingatightcontrolonpainful,ornoxious, informationaswellasinnocuoussensoryinformation.Thissensoryinformationenteringthespinalcordisorganizedbysensorymodality.Primary afferentterminalsexhibitlaminarorganizationdependingontheirfunctional classwithnociceptiveafferentsterminatinginlaminaeI II,lowthreshold cutaneousafferentsterminatinginlaminaeIII V,andproprioceptiveafferents terminatingindeeperlaminaeV VIandwithintheventralhorn.26 30 An individualneuron’sRexedlaminarpositioncanthereforeprovideanindication ofitsrolewithinspinalcircuitry.Aninhibitoryinterneuroninthesuperficial dorsalhornwilllikelyreceivepredominantlynociceptiveafferentinputandbe involvedinthecontrolofnoxioussensation,whereasaninterneuroninthe intermediatedorsalorventralhornwilllikelybeinvolvedinproprioceptive afferentcontrolortheexecutionofmovement.Withintheventralhorn,two classicexamplesofconnectivity-definedneuronalpopulationsareRenshaw cells,whichreceivecollateralinputfrommotorneuronsandinturnprovide “recurrentinhibition”backtomotorneurons,andIainhibitoryinterneurons, whichreceiveprimaryinputsfromIasensoryafferentsandprovideoutputto motorneurons.19,31
Importantlyhowever,laminardistributionisnotnecessarilyanaccurate gaugeofcellactivity.Thisisinpartduetothefactthatsensoryinformation fromperipheralafferentsistransmittedbothbydirectmonosynapticinputs (fromprimaryafferentsthemselves),andindirectpolysynapticinputsfrom excitatoryinterneurons.32 36 Forthisreason,electrophysiologistshaveused thedetailedmappingofmonosynapticandpolysynapticinputontoindividual neuronsasaclassifier,fromtheperipheryandfromneighboring interneurons.21,37,38
Electrophysiology
Whereastheanatomicallocalizationoftheneuronwilldetermineitsprimary afferentresponseprofile,intrinsicdifferencesinsynapticchemistryand membranepropertiescanaffectneuronalfiringpatterns,andsohaveastrong impactonincomingsensoryprocessing.Electrophysiologicalpropertiesof neuronalpopulationsareafunctionofbothmorphology22,39 andintrinsic channelexpression.40 43 Firingpropertiestosustainedmembranedepolarizationrangefromtonicfiring(withlittleadaptationtothestimulus),toburst
