Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de São Paulo, São Paulo 05508, Brazil.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101.
J Neurosci. 2021 May 26;41(21):4732-4747. doi: 10.1523/JNEUROSCI.2114-20.2021. Epub 2021 Apr 16.
Parkinson's disease (PD) is a neurodegenerative disorder anatomically characterized by a progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). Much less known, yet clinically very important, are the detrimental effects on breathing associated with this disease. Consistent with the human pathophysiology, the 6-hydroxydopamine hydrochloride (6-OHDA) rodent model of PD shows reduced respiratory frequency (f) and NK1r-immunoreactivity in the pre-Bötzinger complex (preBötC) and PHOX2B neurons in the retrotrapezoid nucleus (RTN). To unravel mechanisms that underlie bradypnea in PD, we employed a transgenic approach to label or stimulate specific neuron populations in various respiratory-related brainstem regions. PD mice were characterized by a pronounced decreased number of putatively rhythmically active excitatory neurons in the preBötC and adjacent ventral respiratory column (VRC). Specifically, the number of Dbx1 and Vglut neurons was reduced by 47.6% and 17.3%, respectively. By contrast, inhibitory Vgat neurons in the VRC, as well as neurons in other respiratory-related brainstem regions, showed relatively minimal or no signs of neuronal loss. Consistent with these anatomic observations, optogenetic experiments identified deficits in respiratory function that were specific to manipulations of excitatory (Dbx1/Vglut) neurons in the preBötC. We conclude that the decreased number of this critical population of respiratory neurons is an important contributor to the development of irregularities in inspiratory rhythm generation in this mouse model of PD. We found a decreased number of a specific population of medullary neurons which contributes to breathing abnormalities in a mouse model of Parkinson's disease (PD).
帕金森病（PD）是一种神经退行性疾病，其解剖学特征是黑质致密部（SNpc）中的多巴胺能神经元进行性丧失。但鲜为人知的是，与这种疾病相关的呼吸损害。与人的病理生理学一致，6-羟多巴胺盐酸盐（6-OHDA）PD 啮齿动物模型显示呼吸频率（f）降低和预前包钦格复合体（preBötC）中的 NK1r 免疫反应性和延髓背外侧核（RTN）中的 PHOX2B 神经元。为了阐明 PD 中呼吸缓慢的机制，我们采用了一种转基因方法来标记或刺激各种与呼吸相关的脑干区域中的特定神经元群体。PD 小鼠的特征是预前包钦格复合体和相邻的腹侧呼吸柱（VRC）中推测具有节律性的兴奋性神经元数量明显减少。具体而言，Dbx1 和 Vglut 神经元的数量分别减少了 47.6%和 17.3%。相比之下，VRC 中的抑制性 Vgat 神经元以及其他与呼吸相关的脑干区域中的神经元几乎没有或没有神经元丢失的迹象。与这些解剖学观察结果一致，光遗传学实验确定了呼吸功能的缺陷，这些缺陷是特异性的，针对的是 preBötC 中兴奋性（Dbx1/Vglut）神经元的操作。我们得出的结论是，这种关键呼吸神经元群体数量的减少是导致这种 PD 小鼠模型中吸气节律产生不规则的重要因素。我们发现一种特定的延髓神经元数量减少，这导致了帕金森病（PD）小鼠模型中呼吸异常。
