Molecularly distinct striatonigral neuron subtypes differentially regulate locomotion

Jie Dong, Lupeng Wang, Breanna T. Sullivan, Lixin Sun, Victor M. Martinez Smith, Lisa Chang, Jinhui Ding, Weidong Le, Charles R. Gerfen and Huaibin Cai ()
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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
Charles R. Gerfen: National Institutes of Health
Huaibin Cai: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58007-x

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