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Diametric neural ensemble dynamics in parkinsonian and dyskinetic states

Author

Listed:
  • Jones G. Parker

    (Stanford University
    Pfizer Inc.)

  • Jesse D. Marshall

    (Stanford University
    Stanford University
    Harvard University)

  • Biafra Ahanonu

    (Stanford University
    Stanford University)

  • Yu-Wei Wu

    (Stanford University School of Medicine)

  • Tony Hyun Kim

    (Stanford University)

  • Benjamin F. Grewe

    (Stanford University
    University of Zürich and ETH Zürich)

  • Yanping Zhang

    (Stanford University
    Stanford University)

  • Jin Zhong Li

    (Stanford University
    Cegeim Bio-Engineering (Changchun) Co. Ltd.)

  • Jun B. Ding

    (Stanford University School of Medicine)

  • Michael D. Ehlers

    (Pfizer Inc.
    Biogen)

  • Mark J. Schnitzer

    (Stanford University
    Stanford University)

Abstract

Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson’s disease with the dopamine precursor l-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during l-DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, l-DOPA or agonism of the D2 dopamine receptor reversed these abnormalities more effectively than agonism of the D1 dopamine receptor. The opposite pathophysiology arose in l-DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity.

Suggested Citation

  • Jones G. Parker & Jesse D. Marshall & Biafra Ahanonu & Yu-Wei Wu & Tony Hyun Kim & Benjamin F. Grewe & Yanping Zhang & Jin Zhong Li & Jun B. Ding & Michael D. Ehlers & Mark J. Schnitzer, 2018. "Diametric neural ensemble dynamics in parkinsonian and dyskinetic states," Nature, Nature, vol. 557(7704), pages 177-182, May.
    • Handle: RePEc:nat:nature:v:557:y:2018:i:7704:d:10.1038_s41586-018-0090-6
    DOI: 10.1038/s41586-018-0090-6
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    Cited by:

    1. Bérénice Coutant & Jimena Laura Frontera & Elodie Perrin & Adèle Combes & Thibault Tarpin & Fabien Menardy & Caroline Mailhes-Hamon & Sylvie Perez & Bertrand Degos & Laurent Venance & Clément Léna & D, 2022. "Cerebellar stimulation prevents Levodopa-induced dyskinesia in mice and normalizes activity in a motor network," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Christophe Varin & Amandine Cornil & Delphine Houtteman & Patricia Bonnavion & Alban Kerchove d’Exaerde, 2023. "The respective activation and silencing of striatal direct and indirect pathway neurons support behavior encoding," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Allen P. F. Chen & Lu Chen & Kaiyo W. Shi & Eileen Cheng & Shaoyu Ge & Qiaojie Xiong, 2023. "Nigrostriatal dopamine modulates the striatal-amygdala pathway in auditory fear conditioning," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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