Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
Invicro, Hammersmith Hospital Campus, Imperial College London, London, W12 0NN, UK.
Neurotherapeutics. 2020 Jul;17(3):1120-1141. doi: 10.1007/s13311-019-00830-4.
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.
基于脑桥的脚桥核（PPN）传统上与运动功能相关，但在帕金森病（PD）中会发生广泛的退化，这与轴性运动缺陷有关。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。我们之前对用蛋白酶体抑制剂乳胞素半侧脑内注射的大鼠进行了特征描述，作为 PD 的一种准确的临床前模型。在这里，我们使用化学遗传学与正电子发射断层扫描成像相结合，对该 PD 大鼠模型中的离散神经网络进行了体内研究。刺激仅在 PPN 胆碱能神经元中表达的兴奋性设计受体，专门激活设计药物，可激活残余的黑质纹状体多巴胺能神经元，从而产生显著的运动恢复，这与纹状体多巴胺外排以及恢复多巴胺受体 1 和多巴胺受体 2 为基础的中型多棘神经元活动相关，这是通过 c-Fos 免疫组织化学和立体学细胞计数来确定的。我们的数据表明，接受 PPN-DBS 的 PD 患者改善的与轴相关的运动功能可能是由于刺激残余的 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所致，这强烈支持 PPN 胆碱能-中脑多巴胺连接组作为 PPN-DBS 治疗效果的机制。这些发现对完善 PPN-DBS 作为 PD 患者的一种有前途的治疗方式具有重要意义。
