Amajorchallengeinthetreatmentofneurologicaldiseasesistheelaborateanddiffusenatureofneural circuits,wherephysicallyproximalneuronsareengagedinfunctionallydifferentpathways.Theabilitytotarget neuronsbasedonfunction,ratherthanlocation,iscriticaltoimprovingtreatmentsfordisease.InParkinson?s disease,improvedtreatmentshavebeendrivenbythediscoveryofcelltypediversityinthestriatum,providing accesstofunctionallyopposingcircuits:thedirectandindirectpathways.However,withtheexceptionof neuronaldiversityinthestriatum,allotherdownstreamnucleiinthebasalgangliaaredepictedas homogeneousrelaynuclei,anoversimplificationwhoselimitsareincreasinglyapparentastechniquestostudy circuitfunctionbecomemoresophisticated.Recently,mylabhaspioneeredtheuseoftransgenicmouselines tosubdivideneuronsintheexternalglobuspallidus(GPe)intosubpopulationsthatdifferinanatomyand electrophysiologicalproperties.Leveragingtoolstooptogeneticallymanipulatethesegeneticsubpopulations, wearenowinpositiontodiscovertheircontributionstobehavior.Inpreliminarystudies,wefoundthat optogeneticinterventionstargetedtoparticularsubpopulationsintheGPe(butnotglobalstimulationofthe entirenucleus)couldrestoremotorfunctionindopaminedepletedmiceandtheeffectspersistedforhours afterstimulation.Thisfindingchallengeslong-standingmodelsofcircuitorganizationinthebasalgangliaand hasrelevanceforPD,wherecurrentinterventionsprovideonlytransientreliefofmotorsymptomsthatrapidly returnoncestimulationstops.Experimentsinthisproposalwillidentifywhichneuronalsubpopulationsinthe GPearerequiredtoinducelong-lastingmotorrescue(Aim1)andwillelucidatethepathwaysthroughwhich theymediatetheireffects(Aim2).
Aim1, willuseoptogeneticsandinvivorecordingstoassesstheimpactof modulatinggenetically-definedneuronalsubpopulationsonlocalcircuitdynamicsintheGPeandtheireffects onbehavior.Specifically,wewilltestthehypothesisthatrecoveredmovementsfollowingoptogenetic stimulationaregoal-directedandrestoretheabilityofmicetoseekoutfood,socialinteractions,andavoid anxiety-provokingenvironments.
In Aim2, wewilluseinvivorecordings,coupledwithviral-assistedcircuit mapping,toelucidatethepathwaysthroughwhichneuronalsubpopulationsintheGPeexerttheirprokinetic effectsonmovement.Ourpreliminarydatasuggestthattherapeuticinterventionsshareacommonmechanism ofreversingpathologicalfiringpatternsinthesubstantianigrareticulata(SNr),theprimarybasalgangliaoutput nucleusinrodents.Ourproposedexperimentswilldeterminewhetherthiseffectismediatedbydirect projectionsofGPeneuronstotheSNr,orwhetheritismediatedthroughadisynapticpathwayinvolvingthe subthalamicnucleus(STN).Combined,resultsfromthesestudieswillelucidatethepathwaysandcircuit mechanismsresponsibleforlong-lastingmotorrescueindopaminedepletedmiceandwillreviselong-standing modelsofindirectpathwaydysfunctionindisease.
MotorsymptomsofParkinson?sdisease(PD),aneurodegenerativedisorderaffectingnearly1million Americansareattributedtodysfunctionofmotorcircuitsinthebasalganglia.Experimentsinthisproposal investigatetheorganizationandfunctionofcell-specificoutputpathwaysoftheGPewhosebidirectional modulationinduceslong-lastingmotorrescueindopaminedepletedmice.Thisworkdemonstrateshow knowledgeabouttheorganizationofbasalgangliacircuitrycanleadtobetter,morepersistenttreatmentsfor motordysfunctionindisease.
