Dong Jie, Wang Lupeng, Sullivan Breanna T, Sun Lixin, Martinez Smith Victor M, Chang Lisa, Ding Jinhui, Le Weidong, Gerfen Charles R, Cai Huaibin
Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Nat Commun. 2025 Mar 19;16(1):2710. doi: 10.1038/s41467-025-58007-x.
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.
传统上认为促进运动的黑质纹状体神经元包含具有不同转录组特征的多种亚型。然而，它们对运动调节的具体贡献仍未完全了解。利用基因标记物Kremen1和Calb1，我们在小鼠模型中证明，Kremen1和Calb1黑质纹状体神经元对运动产生相反的影响。Kremen1神经元在运动开始时激活延迟，但在运动结束时活动增加。相比之下，Calb1神经元在运动开始时早期激活，在运动结束时活动减少。对Kremen1神经元进行光遗传学激活会抑制正在进行的运动，而激活Calb1神经元则会促进运动。与Calb1神经元相比，激活Kremen1神经元导致多巴胺释放的减少幅度更大，随后出现刺激后反弹。相反，激活Calb1神经元会引发多巴胺释放的初始增加。此外，在醛脱氢酶1a1黑质纹状体多巴胺能神经元（DANs）中对GABA-B受体Gabbr1进行基因敲低会降低DAN抑制作用，并完全消除Kremen1神经元的运动抑制作用。总之，这些发现揭示了黑质纹状体神经元亚型内一种细胞类型特异性机制：Calb1神经元促进运动，而Kremen1神经元通过GABBR1受体抑制醛脱氢酶1a1 DAN活性来终止正在进行的运动。
