Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310030, China.
Neurosci Bull. 2022 Jan;38(1):1-15. doi: 10.1007/s12264-021-00775-9. Epub 2021 Oct 11.
Parkinson's disease (PD) is the second most common and fastest-growing neurodegenerative disorder. In recent years, it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis. However, little is known about whether and how the caudal zona incerta (ZIc) regulates parkinsonian motor symptoms. Here, we showed that specific glutamatergic but not GABAergic ZIc neurons regulated these symptoms. ZIc neuronal activation induced time-locked parkinsonian motor symptoms. In mouse models of PD, the ZIc neurons were hyperactive and inhibition of their activity ameliorated the motor deficits. ZIc neurons monosynaptically projected to the substantia nigra pars reticulata. Incerta-nigral circuit activation induced parkinsonian motor symptoms. Together, our findings provide a direct link between the ZIc, its glutamatergic neurons, and parkinsonian motor symptoms for the first time, help to better understand the mechanisms of PD, and supply a new important potential therapeutic target for PD.
帕金森病（PD）是第二常见和增长最快的神经退行性疾病。近年来，人们已经认识到除了多巴胺和基底神经节以外的神经递质和神经元系统也与 PD 的发病机制有关。然而，人们对于尾状核下区（ZIc）是否以及如何调节帕金森运动症状知之甚少。在这里，我们发现特定的谷氨酸能但不是 GABA 能 ZIc 神经元调节这些症状。ZIc 神经元的激活诱导与时间锁定的帕金森运动症状。在 PD 的小鼠模型中，ZIc 神经元过度活跃，抑制其活性可改善运动缺陷。ZIc 神经元单突触投射到黑质网状部。ZIc-黑质回路的激活诱导帕金森运动症状。总之，我们的研究结果首次为 ZIc 及其谷氨酸能神经元与帕金森运动症状之间提供了直接联系，有助于更好地理解 PD 的机制，并为 PD 提供了一个新的重要潜在治疗靶点。
