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Molecularly distinct striatonigral neuron subtypes differentially regulate locomotion

Author

Listed:
  • Jie Dong

    (National Institutes of Health)

  • Lupeng Wang

    (National Institutes of Health)

  • Breanna T. Sullivan

    (National Institutes of Health)

  • Lixin Sun

    (National Institutes of Health)

  • Victor M. Martinez Smith

    (National Institutes of Health)

  • Lisa Chang

    (National Institutes of Health)

  • Jinhui Ding

    (National Institutes of Health)

  • Weidong Le

    (Dalian Medical University
    Medical School of University of Electronics & Technology of China)

  • Charles R. Gerfen

    (National Institutes of Health)

  • Huaibin Cai

    (National Institutes of Health)

Abstract

Striatonigral neurons, traditionally known for promoting locomotion, comprise diverse subtypes with distinct transcriptomic profiles. However, their specific contributions to locomotor regulation remain incompletely understood. Using the genetic markers Kremen1 and Calb1, we demonstrate in mouse models that Kremen1+ and Calb1+ striatonigral neurons exerted opposing effects on locomotion. Kremen1+ neurons displayed delayed activation at locomotion onset but exhibited increasing activity during locomotion offset. In contrast, Calb1+ neurons showed early activation at locomotion onset and decreasing activity during locomotion offset. Optogenetic activation of Kremen1+ neurons suppressed ongoing locomotion, whereas activation of Calb1+ neurons promoted locomotion. Activation of Kremen1+ neurons induced a greater reduction in dopamine release than Calb1+ neurons, followed by a post-stimulation rebound. Conversely, activation of Calb1+ neurons triggered an initial increase in dopamine release. Furthermore, genetic knockdown of GABA-B receptor Gabbr1 in Aldh1a1+ nigrostriatal dopaminergic neurons (DANs) reduced DAN inhibition and completely abolished the locomotion-suppressing effect of Kremen1+ neurons. Together, these findings reveal a cell type-specific mechanism within striatonigral neuron subtypes: Calb1+ neurons promote locomotion, while Kremen1+ neurons terminate ongoing movement by inhibiting Aldh1a1+ DAN activity via GABBR1 receptors.

Suggested Citation

  • Jie Dong & Lupeng Wang & Breanna T. Sullivan & Lixin Sun & Victor M. Martinez Smith & Lisa Chang & Jinhui Ding & Weidong Le & Charles R. Gerfen & Huaibin Cai, 2025. "Molecularly distinct striatonigral neuron subtypes differentially regulate locomotion," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58007-x
    DOI: 10.1038/s41467-025-58007-x
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    References listed on IDEAS

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    1. Jeffrey E. Markowitz & Winthrop F. Gillis & Maya Jay & Jeffrey Wood & Ryley W. Harris & Robert Cieszkowski & Rebecca Scott & David Brann & Dorothy Koveal & Tomasz Kula & Caleb Weinreb & Mohammed Abdal, 2023. "Spontaneous behaviour is structured by reinforcement without explicit reward," Nature, Nature, vol. 614(7946), pages 108-117, February.
    2. Zhenhua Liu & Nannan Yang & Jie Dong & Wotu Tian & Lisa Chang & Jinghong Ma & Jifeng Guo & Jieqiong Tan & Ao Dong & Kaikai He & Jingheng Zhou & Resat Cinar & Junbing Wu & Armando G. Salinas & Lixin Su, 2022. "Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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