Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069777-08
Application #
9625173
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Sieber, Beth-Anne
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

David, François; Çarçak, Nihan; Furdan, Szabina et al. (2018) Suppression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function in Thalamocortical Neurons Prevents Genetically Determined and Pharmacologically Induced Absence Seizures. J Neurosci 38:6615-6627
Hunt Jr, Albert J; Dasgupta, Rajan; Rajamanickam, Shivakumar et al. (2018) Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus. Brain Struct Funct 223:2685-2698
Poulin, Jean-Francois; Caronia, Giuliana; Hofer, Caitlyn et al. (2018) Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches. Nat Neurosci 21:1260-1271
Abrahao, Karina P; Chancey, Jessica H; Chan, C Savio et al. (2017) Ethanol-Sensitive Pacemaker Neurons in the Mouse External Globus Pallidus. Neuropsychopharmacology 42:1070-1081
Glajch, Kelly E; Kelver, Daniel A; Hegeman, Daniel J et al. (2016) Npas1+ Pallidal Neurons Target Striatal Projection Neurons. J Neurosci 36:5472-88
Cui, Qiaoling; Pitt, Jason E; Pamukcu, Arin et al. (2016) Blunted mGluR Activation Disinhibits Striatopallidal Transmission in Parkinsonian Mice. Cell Rep 17:2431-2444
Hegeman, Daniel J; Hong, Ellie S; Hernández, Vivian M et al. (2016) The external globus pallidus: progress and perspectives. Eur J Neurosci 43:1239-65
Neuner, Sarah M; Wilmott, Lynda A; Hope, Kevin A et al. (2015) TRPC3 channels critically regulate hippocampal excitability and contextual fear memory. Behav Brain Res 281:69-77
Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling et al. (2015) Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus. J Neurosci 35:11830-47
Chávez, Andrés E; Hernández, Vivian M; Rodenas-Ruano, Alma et al. (2014) Compartment-specific modulation of GABAergic synaptic transmission by TRPV1 channels in the dentate gyrus. J Neurosci 34:16621-9

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