Abstract

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.

Public Health Relevance

MotorsymptomsofParkinson?sdisease(PD),aneurodegenerativedisorderaffectingnearly1million Americansareattributedtodysfunctionofmotorcircuitsinthebasalganglia.Experimentsinthisproposal investigatetheorganizationandfunctionofcell-specificoutputpathwaysoftheGPewhosebidirectional modulationinduceslong-lastingmotorrescueindopaminedepletedmice.Thisworkdemonstrateshow knowledgeabouttheorganizationofbasalgangliacircuitrycanleadtobetter,morepersistenttreatmentsfor motordysfunctionindisease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS104835-02
Application #
9614343
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
David, Karen Kate
Project Start
2017-12-15
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Carnegie-Mellon University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213