The brainstem-based pedunculopontine nucleus (PPN) traditionally associates with motor function, but undergoes extensive degeneration during Parkinson's disease (PD), which correlates with axial motor deficits. PPN-deep brain stimulation (DBS) can alleviate certain symptoms, but its mechanism(s) of action remains unknown. We previously characterized rats hemi-intranigrally injected with the proteasomal inhibitor lactacystin, as an accurate preclinical model of PD. Here we used a combination of chemogenetics with positron emission tomography imaging for in vivo interrogation of discrete neural networks in this rat model of PD. Stimulation of excitatory designer receptors exclusively activated by designer drugs expressed within PPN cholinergic neurons activated residual nigrostriatal dopaminergic neurons to produce profound motor recovery, which correlated with striatal dopamine efflux as well as restored dopamine receptor 1- and dopamine receptor 2-based medium spiny neuron activity, as was ascertained with c-Fos-based immunohistochemistry and stereological cell counts. By revealing that the improved axial-related motor functions seen in PD patients receiving PPN-DBS may be due to stimulation of remaining PPN cholinergic neurons interacting with dopaminergic ones in both the substantia nigra pars compacta and the striatum, our data strongly favor the PPN cholinergic-midbrain dopaminergic connectome as mechanism for PPN-DBS's therapeutic effects. These findings have implications for refining PPN-DBS as a promising treatment modality available to PD patients.

中文翻译：

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桥脚胆碱能神经元的 DREADD 激活可逆转帕金森病大鼠的运动缺陷并恢复纹状体多巴胺信号传导。


基于脑干的桥脚核（PPN）传统上与运动功能相关，但在帕金森病（PD）期间经历了广泛的退化，这与轴向运动缺陷相关。 PPN-深部脑刺激（DBS）可以缓解某些症状，但其作用机制仍不清楚。我们之前对半黑体内注射蛋白酶体抑制剂乳胞素的大鼠进行了表征，作为准确的 PD 临床前模型。在这里，我们将化学遗传学与正电子发射断层扫描成像相结合，对 PD 大鼠模型中的离散神经网络进行体内询问。刺激仅由 PPN 胆碱能神经元内表达的设计药物激活的兴奋性设计受体激活残留的黑质纹状体多巴胺能神经元，产生深度运动恢复，这与纹状体多巴胺流出以及恢复的基于多巴胺受体 1 和多巴胺受体 2 的中型多巴胺神经元活性相关，正如通过基于 c-Fos 的免疫组织化学和体视细胞计数所确定的那样。通过揭示接受 PPN-DBS 的 PD 患者中轴相关运动功能的改善可能是由于刺激剩余的 PPN 胆碱能神经元与黑质致密部和纹状体中的多巴胺能神经元相互作用，我们的数据强烈支持 PPN 胆碱能神经元-中脑多巴胺能连接组作为 PPN-DBS 治疗作用的机制。这些发现对于改进 PPN-DBS 作为一种可供 PD 患者使用的有前景的治疗方式具有重要意义。