Parkinson?sdisease(PD)isthesecondmostcommonneurodegenerativediseaseassociatedwithaging.The diseaseischaracterizedbymotorsymptomsattributedtothelossofmesencephalicdopaminergicneuronsand theirinnervationtothebasalgangliamacrocircuit.InpatientsandanimalmodelsofPD,thismacrocircuit exhibitsaberrantactivitypatternsincludingsynchronous,rhythmicburstingofneuronsintheexternalglobus pallidus(GPe).However,thefactorsthatshapethesesynchronousandtemporallystructuredeventsinPD remainunknown.ItisouroverarchinghypothesisthatGABAergicinputsshapetheactivitylevel,pattern,and synchronyofbothparvalbuminandNpas1neuronswithintheGPe.Usingcellandcircuitspecifictools,we willinvestigatetheconnectivityofstriatalinputsandlocalcollateralinputstoparvalbuminandNpas1neurons within the GPe and how this connectivity becomes altered in the chronic 6OHDA lesion model of PD. Furthermore,wewilldeterminehowparvalbuminandNpas1neuronsandtheirstriatalinputsareinvolvedin motor function and dysfunction. The proposed experiments capitalize on a combination of cuttingedge approachesthatwillovercomeobstaclesthathadimpededprogressuntilnow.Theseapproachesincludeviral genedelivery,Creloxrecombination,optogenetics,chemogenetics,electrophysiology,andfiberphotometry. Additionally, anatomical, analytical, and computational approaches will be used to help interpret research findings. The successful achievement of these aims will significantly advance our understanding of the mechanismsunderlyingPDand,indoingso,promotethedevelopmentofnewtherapiesforPDpatients.

Public Health Relevance

Theproposedstudiesareaimedatdetermininghowinhibitorysynapticinputsareorganizedintheexternal globuspallidusandtheiralterationsinananimalmodelofParkinson?sdisease.Theknowledgegainedwill provideaframeworkfornewandimprovedtherapeuticstrategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069777-09
Application #
9868332
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Sieber, Beth-Anne
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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