Corelit

Incontrasttocomponentsofthemotorsystemwhichcontainuppermotorneuronsthatinitiate
movementbycontrollingtheactivityoflocalcircuitandlowermotorneurons,therearetwo
additionalregionsinvolvedinmotorcontrolthatinfluencemovementbyregulatingtheactivityof
uppermotorneuronsThebasalganglia(fromhereonout)BG)andthecerebellum.TheBGisa
functionallydiversesetofnuclei,ofwhichasubsetisrelevanttomotorfunction;thecaudate,
putamenandglobuspallidus.Togetherwiththesubstantianigra(inbaseofmidbrain)andthe
subthalamicnucleus(intheventralthalamus)theycreateasubcorticalloopthatlinksmostareasof
thecerebralcortexwithuppermotorneuronsintheprimarymotorandthepremotorcortexandin
thebrainstem.Neuronsinthisloopmodulatetheiractivityinanticipationofandduringmovements
andtheireffectsonuppermotorneuronsarerequiredforthenormalcourseofvoluntarymovements.
Whenoneofthesecomponentsiscompromised,themotorsystemscannotswitchsmoothlybetween
commandsthatinitiateandterminatemovements.Theresultingdisorderedmovementscanbe
understoodasaconsequenceofabnormaluppermotorneuronactivityinabsenceoftheregulatory
controlnormallyprovidedbytheBG.

ProjectionstotheBG
ThemotornucleioftheBGaredividedintofunctionallydistinctgroups.TheinputzoneoftheBGis
comprisedbythecaudateandtheputamen,whichtogetherformthecorpusstriatum(=CS).
IncomingaxonsoffromthecortexgotothedendritesofcellsintheCScalledmediumspiny
neurons(=MSNs).AxonsarisingfromtheMSNsconvergeontheneuronsinthepallidum,
consistingoftheglobuspallidus(=GP)andthesubstantianigrapasreticulate(SNr).Allprojections
fromthecortextotheCSarereferredtocollectivelyasthecorticostriatalpathway.Differentcortical
areasprojecttodifferentregionsofthestriatum,thisimpliesthatthecorticostriatalpathwayconsists
ofmultipleparallelpathwaysservingdifferentfunctions.Moreover,thecorticalareasthatare
functionallyinterconnectedatthelevelofthecortex,giverisetoprojectionsthatoverlapextensively
inthestriatum.Therostrocaudalbandswithinthestriatumappeartobefunctionalunitsconcerned
withmovementofparticularbodyparts.Themoreextensivecorticalareasareinterconnectedby
corticocorticalpathways,thegreatertheoverlapintheirprojectionstothestriatum.TheMSNs
receiveadivergenceofinputfromcorticostriatalaxons,allowingthemtointegratetheinfluenceof
thousandsofcorticalcells.CorticalinputssynapseattheendsofMSNdendrites,localcircuitneuron
andthalamicsynapsesaremadeondendriticshaftsandclosetothecellsoma,wheretheycan
modulatetheeffectivenessofcorticalsynapticactivationarrivingfrommoredistaldendrites.The
mainaminergicinputsaredopaminergic,andoriginateinthesubstantianigraparscompacta(SNc)
becauseoftheirdenselypackedcells.WhenMSNsbecomeactive,theirfiringisassociatedwiththe
occurrenceofamovement,recordingsshowthattheseneuronstypicallyincreasetheirrateof
dischargebeforeanimpendingmovement.

ProjectionsfromtheBGtootherbrainregions.
TheMSNsofthecaudateandputamengiverisetoinhibitoryGABAergicprojections,terminating
inthepallidalnucleiintheBG(theGPandtheSNr).Bothcontainthesametypesofneuronsand
performcomparablefunctions,theSNrmaybeunderstoodaspartoftheGP.Thereisalargedegree
ofconvergenceintheprojectionsfromtheMSNstotheneuronsoftheGPandSNr.ManyMSNs
innervateeachcellintheGP.However,despitethisconvergence,individualaxonsfromtheCS
sparselycontactmanypallidalneuronsbeforeterminatingdenselyonthedendritesofaparticular
neuron.EnsemblesofMSNsexertabroadbutfunctionallyweakinfluenceovermanypallidal
neurons,whileatthesametimestronglyinfluencingasubsetofneuronsintheGPorSNr.TheBG
havetwooutputpathwayswhichoriginateintheinternalsegmentoftheGPandtheSNr.Efferent
neuronsinboththesepathwaysallowtheBGtoinfluencetheactivityofuppermotorneurons
locatedinthemotorcortexandbrainstem.TheefferentGPiaxonsprojecttothemotorcortex,
supplementarymotorareaandprefrontalcortexviarelaytroughthethalamicnuclei.Theefferent
SNraxonsprojecttoandterminateprimarilyinthesuperiorcolliculus(tectum)(commandheadand
eyemovement)withoutrelayviathalamus.EfferentcellsofGPandSNrarebothGABAergic,sothe
mainoutputoftheBGisinhibitory.IncontrasttotheMSNsneurons,boththeseoutputzoneshave
highlevelsofspontaneousactivitythatpreventsunwantedmovementbytonicallyinhibitingcellsin
thethalamusandsuperiorcolliculus.DuetotheMSNsofthestriatumalsobeingGABAergisand
inhibitory,theneteffectofexcitatoryinputsthatreachthestriatumfromthecortexistoinhibitthe
tonicallyactiveinhibitorycellsoftheGPandSNr.Thismeansthatinabsenceofvolitional
movement,theGPneuronstonicallyinhibittherelaycellsinthethalamus.Forthethalamicneurons
tobedisinhibited(andabletorelaysignalstouppermotorneurons),theinhibitingpallidalcellsmust
beinhibitedfromactivitybytheMSNs.
TheseprojectionsfromtheBGtotheuppermotorneuronscanbeseenasaphysiologicalgate
whichopenswhenactivationfromtheMSNsishighenough.ThismeansthattheBGfacilitate
theinitiationofmotorprogramsandsuppressionofcompetingornonsynergisticmotorprograms
thatwouldotherwiseinterferewiththeexpressionofsensorydrivenorgoaldirectedbehavior.

Circuitry
TherearetwopathwaysalongwhichprocessingthroughtheBGtakesplace.Thedirectpathway;
involvesfast,direct,inhibitoryconnectionsfromthestriatumtotheGPiandSNrasdescribedabove
andservestoreleasethethalamicneuronsthatdrivetheuppermotorneuronsfromtheirtonic
inhibition,thusfacilitatingtheinitiationofvolitionalmovement.Theindirectpathwayreinforces
suppressionofinappropriatemovementswithaslower,roundaboutroutetotheGPiandSNrto
increasetheleveloftonicinhibition.Intheindirectpathway,distinctMSNsprojecttotheexternal
segmentoftheGP,whichsendsprojectionstoboththeGPiandtothesubthalamicnucleus(STN)of
theventralthalamus.TheSTNalsoreceivesexcitatoryprojectionfromthecortexwhichwork
synergisticallywiththeprojectionfromtheGPe.Inturn,theSTNprojectsbacktotheGPiandthe
SNr.Thispathwaymodulatesthedisinhibitoryactionsofthedirectpathway.TheSTNneurons
glutamatergicandareexcitatory.Incontrastwiththedirectpathway,whichwhenactivatedreleases
thalamocorticalandcollicularcircuitsfromtonicinhibition,theneteffectoftheindirectpathway
increasestheinhibitoryinfluencesoftheBG.
TheinfluenceofthedirectpathwayistightlyfocusedonparticularfunctionalunitsintheGPiand
theinfluenceoftheindirectpathwayismorediffuse,coveringabroadrangeoffunctionalunits.

DopaminemodulatedtheBGcircuits.
ThefinalpathwayofnoteistheprojectionoftheSNctothestriatumknownasthedopamine
pathway.ItexertsaprofoundinfluenceovertheintegrationofcorticalinputintheCS.TheMSNs
oftheCSprojectdirectlytotheSNc,whichinturnsendswidespreaddopaminergicprojectionsback
totheMSNs.ThesamenigralneuroncanprovideexcitatoryandinhibitoryinputstotheMSNs,
thisdualityisachievedbydifferentialexpressionoftwotypesofdopaminereceptors,D1andD2.
ThedirectpathwayhadD1receptors,whichareexcitatoryandproduceEPSPs,andtheindirect
pathwayhadD2receptors,whichareinhibitoryandproduceIPSPs.Thenetresultisthatdopamine
releasepromotesselectedactionsrepresentedinthedirectpathway(byincreasingresponsivenessof
thedirectpathway(D1effect)anddiscouragingnonselectedactionsviatheindirectpathwayby
decreasingtheresponsivenessoftheindirectpathway(D2effect).

Hypokineticandhyperkineticmovementdisorders
NormallythedopaminergiceffectsservetodecreasetheinhibitoryoutflowoftheBGandthus
increasingtheexcitabilityoftheuppermotorneurons.WhenthedopaminergiccellsoftheSNcare
destroyed,likeinParkinsonsdisease,theinhibitoryoutflowoftheBGisabnormallyhigh,and
timelythalamicactivationofuppermotorneuronsislesslikely.Hypokineticmovementdisorders
likethesereflectafailureofthedisinhibitionnormallymediatedbytheBG.Anymovementis
thereforedifficulttoinitiateand,onceinitiated,oftendifficulttoterminate.
InhyperkineticmovementdisorderslikeHuntingtonsdisease,theMSNsthatprojecttotheGPe
degenerate.InabsenceoftheirnormalinhibitoryinputfromtheMSNs,theGPebecomeabnormally
active,thisactivityreducestheexcitatoryoutputoftheSTNtotheGPi,andtheinhibitoryoutflowof
theBGisthusreduced.WithoutthisrestraintfromtheBG,theuppermotorneuronsvanbeactivated
withoutappropriatesignals,resultinginundesiredballisticandchoreiformmovements.Imbalances
inthefinecontrolmechanismsrepresentedbytheconvergenceofthedirectandindirectpathwayin
thepallidumareapparentindiseasesthataffectprimarilytheSTN.
Furtherreading

Martin:(41lines)

TheereaderstartswithdescribingtheseparatecomponentsoftheBGprocessofincoming
informationandmediatingtheoutput.Incontrasttothecoreliterature(corelitfromnowon),thereis
notonlytheinputnucleiandtheoutputnuclei,butalsoanothercomponentoftheBG,theintrinsic
nuclei.Itsays,theinputnucleiarecomprisednotonlybythecaudatenucleusandtheputamenbut
alsothenucleusaccumbens(NA).Thecaudatenucleusparticipatesineyemovementandcognition,
theputamenparticipatesincontroloflimbandtrunkmovementsandtheNAparticipatesin
emotions.Inadditiontothecorelit,thereisalsoadetaileddescriptionoftheanatomicalpositionsof
thesenucleiintheBG.Itsays,theoutputsideoftheBGnotonlyconsistsoftheGPiandtheSNr,
butalsotheventralpallidum.Theaxonsoftheoutputnucleiprojecttothalamicnuclei,whichproject
todifferentregionsinthefrontallobe.Thesenucleiincludetheventrolateralnucleus,theventral
anteriornucleusandthemedialdorsalnucleus.Inaddition,theoutputnucleialsoprojecttothe
pedunculopontinenucleusandthesuperiorcolliculus.Thisnewaspectbeingintroduced,theintrinsic
nucleiconsistoftheGPe,theSTN,theSNcandtheventraltegmentalarea.Connectionsofthe
intrinsicnucleiarelargelyrestrictedtotheBGndarecloselyrelatedtotheinputandoutputnuclei.
TheGPeendtheSTNarepartoftheBGcircuitthatreceivesinputfromotherBGnucleiandinturn
projectback.Thepathfromthestriatumtothesetwointrinsicnucleicomprisestheindirectpathway.
TheSNcandtheventraltegmentalareacontaindopaminergicneuronsthatprojecttothestriatum.
WhatwasnotexplainedinthecorelitisthatvariouscomponentsoftheBGareseparatedaxonsof
theinternalcapsule.CellsoftheSNrandtheGPiarescatteredbetweeneachotherwithintheinternal
capsule.Asdescribedinthecorelit,themorphology,neurotransmittercontentandconnectionsof
neuronsintheSNrandGPiaresimilar.Inadditiontoproducingmovementcontroldeficits,BG
diseasecanalsoimpairintellectualcapacity,suggestinganimportantroleincognition.Thisisbriefly
mentionedinthepartaboutHuntingtonsdisease,becausethereisalsodementiainHuntingtons.
Thiscanbeexplainedbythefollowing.Inthecorelit,alittlewasexplainedaboutseveral
anatomicalloopsthatmediateadifferentsetoffunctions.Hereitisexplainedthateachloopmust
originatefrommultiplecorticalregionsthathavesimilarfunctions,eachlooppassesthrough
differentBGandthalamicnuclei(orseparateportionsofthesamenucleus)andthecorticaltargetsof
theloopsareseparateportionsofthefrontallobe.Theygoalittlebitmoreindetailontherolesof
theloops.Theskeletomotorloopplaysimportantrolesinthecontroloffacial,limbandtrunk
musculature.Itsinputsoriginatefromtheprimarysomaticsensoryandfrontalmotorareasand
projectbacktothefrontalmotorareas.Theoculomotorloopplaysaroleinthecontrolofsaccadic
eyemovements.Itskeyinputsderivefromthefrontaleyefieldandtheposteriorparietalassociation
cortex.Theprefrontalcortexloopplaysaroleincognitionandexecutivebehavioralfunctions,
receivinginputsfromdiverseassociationareasandprojectingtothedorsolateralprefrontalcortex.
Thelimbicloopparticipatesinmotivationalregulationofbehaviorandinemotions.Thelimbic
associationcortexandthehippocampalformationprovidethemajorinput.Theloopengagesinthe
mostdistinctsetofBGcircuits,theventralstriatumandtheventralpallidum.Thenthetextcontinues
abouttheneurotransmittersandneuromodulatersoftheBG,suchasGABAandglutamate,whichis
explainedinmoredetailinthecorelit.Whatisnotsaidinthecorelitisanotherneurotransmitter,
achetylcholine.Itispresentinthestriatalinterneuronswhereitisanimportantneurotransmitterin
thefunctionoflocalneuronalcircuits(whichwerementionedinthecorelit).

Youdim:39lines
ThearticleelaboratesonParkinsonsdisease.Itstartswithadetaileddescriptionofwhatthedisease
entails,symptomsattheonsetofthediseaseandlateron.Itprogressivelydestroysapartofthebrain
thatiscriticaltocoordinatedmovement.InthebeginninganindividualwithParkinsonsdisease
likelydisplayrhythmictremorsinahandorfoot,particularlywhenatrest.Withtime,theindividual
maybecomeslowerandstifferandmayalsoexperiencedifficultyinitiatingmovements,mightlose
theirbalanceandcoordinationandmayfreezeunpredictablyastheiralreadytightenedmuscleshalt
altogether.Inaddition,nonmotorsymptomscanappearalso,suchasexcessivesweatingorother
disturbancesintheinvoluntarynervoussystemandpsychologicalproblemsasdepressionor
dementia,whichcanariseinthelatestages.Mostoftheproblems,motorandnonmotorstartout
subtleandworsenovertime.Likedescribedinthecorelit,itsaysthatthemotordisturbancesstem
primarilyfromdestructionofcertainnervecells.Morespecificallytheneuronsinthesubstantia
nigra,theeffectsofthisdestructionareexplainedinmoredetailinthecorelit.Thenonmotor
symptomsapparentlyresultmainlyfromtheeliminationofotherkindsofneuronselsewhereinthe
brain.Inadditiontothecorelit,itexplainsthatsome4%ofouroriginaldopamineproducing
neuronsdisappearsineachdecadeduringadultlifeduetoage.InParkinsonsdisease,theusualcell
deathisamplified.Symptomsarisewhen70%ofneuronshavebeendestroyed.
Whatwasnotmentionedinthecorelitisthatnormally,dopaminereleasedintothestriatumis
neededto(atleastinpart)counteracttheeffectsofacetylcholine.Intheabsenceofsuchmoderation,
theacetylcholineoverexitedtheneuronsthatprojecttouppermotorneurons.Alotissaidabout
treatmentsforParkinsonsdisease,likeacetylcholineinhibitors,whichdidnthelpenoughandhad
sideeffects.Thenlevodopa(Ldopa)whichisbrieflymentionedinthecorelit.itsdesignedto
compensateforthedeclineofdopamineinthebraininpatients.Itsadrugthatcanbeconvertedinto
dopamineinthebrain.Itcancontrolsymptoms,butitisnotacure.Overtime,mostpatientslose
sensitivitytothecompound.Alsoundesirablesideeffectswerepresent.Afterthis,theydevelopeda
drugthatwasabitmoreimprovedthanLdopabuttheyweremoreexpensiveandhadsideeffectsof
theirown.Thencamesegeline,whichcanblockthebreakdownofdopaminealthoughitfallsshortof
ideal.Explorationofthisdrugledtodevelopmentofnewenzymeinhibitorsaspotentialtreatment
forParkinsonsandAlzheimersdisease.Newaspectsintroducedaretheroleofoxygenfree
radicals.Thesearemoleculesthatamplifythedestructionofdopamineproducingcells.Andthe
declineinactivityofenzymecomplex1inmitochondria.Whencomplex1isfaulty,energy
productiondropsandfreeradicallevelsrise.
Asmentionedinthecorelit,MPTPcandestroydopamineproducingcells.HereitissaidthatMPTP
wouldbeharmlessifnotalteredbythebody.Butinabsenceofaprotectiveagent,alteredMPTPwill
enternigralneuronsandinhibitcomplex1inthemitochondria.Anothertheorymentionedhereis
thatmicrogliaplayaroleinParkinsons.Normally,thebrainblocksmicrogliafrombecomingtoo
active,becauseintheirmostactivestatetheycanproducefreeradicals.InParkinsonspatients,the
SNoftencontainsunusuallyactivemicroglia.Allinall,thearticlepresentsseveralpossible
explanationsforthedevelopmentofParkinsonsdiseaseandsometreatmentoptionsinmoredetail
thanthecorelit.

Surmeier:30lines
AnewaspectofthistextisthatwhentheBGhelpsustodecidewhattodowhenpresentedwitha
choice,thestriatumretrievesinformationthatisstoredonpastexperiencesandpassesona
recommendationthroughthethalamusbacktothecerebralcortex,whichmakesadecision.WhichIs
abitdifferentthancallingthestriatumafilterlikeinthecorelit,althoughitcanbeseenasa
simplification.
Themodelinthecorelitisexplainedintwoparallelpathways,onetopromoteactionandoneto
suppressit.However,someobservationsaredifficulttoreconcilewiththismodel.Heretheyexplain
thatthedirectandindirectpathwaySPNsareintermingledanddifficulttotellapart.Tohelpwith
thisobstacletheyperformedanexperimentofconditioninginmicewhilemonitoringtheactivityof
thepathways.Themodelexplainedinthecorelit(theclassicalmodel)predictsthattheindirect
pathwaybecomesactivewhendemousestartstomove,andtheindirectpathwaywouldbecome
activewhenitstopped.However,theyfoundthatbothgroupsofSPNsbecameactivebefore
initiationofmovement,asifbothweremakingrecommendationsonwhattodo.Whenthemouse
stopped,bothwouldbecomeinactive.ThismeanstheSPNsdonotmakebinaryrecommendations,it
ismorelikelythatthestriatumissimultaneouslymakingrecommendationsonwhattodoandwhat
nottodo.
Acompletelynewsubjectinthistextisthatthisnewmodelalsofitswithcurrentknowledgeof
synapticplasticityinthestriatum.Ifwedosomethingthathasapositiveoutcome,apulseof
dopamineisreleasedinthestriatum,strengtheningthesynapticconnectionsbetweencortical
neuronsanddirectpathwaySPNs,makingthemmorelikelytorespondtothesecorticalneuronsin
thefuture.Whennextfacedwithadecisioninwhichthissameactionispossible,thosecortical
neuronsbecomeactive.Becauseofthestrengthenedconnections,directpathwaySPNswilltendto
becomeactivetooandwouldsubsequentlysendamessagebacktothecortexindicatingthatthisisa
goodcourseofaction.Theopposingscenariowouldbeifacourseofactionhadabadoutcome.
Dopaminereleasedinthestriatumwouldpromotethestrengtheningofconnectionsbetweencortical
neuronsandtheindirectpathwaySPNs,sowhenthecorticalneuronsbecomeactive,indirect
pathwaySPNsfollowsuit,sendingbackawarningmessage.Thistheorycontradictsthemodelfrom
thecorelitinwhichstriatalrecommendationsarenotgeneralizedstoporgocommands.The
questionsremainhowever,ifensemblesofdirectandindirectpathwaysSPNsexist.AndhowtheBG
neuronssittingbetweenthestriatumandthethalamuscouldpassonmorethanonerecommendation.