BACKGROUND Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre(+) transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients. RESULTS In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO), dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait, sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by CNO administration, consistent with upregulated neuronal activation in this defined neuronal population. CONCLUSIONS Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons alleviates parkinsonian motor symptoms.

中文翻译：

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胆碱能脚桥神经元的药物遗传学刺激可逆转帕金森病大鼠模型的运动缺陷。


背景晚期帕金森病（PD）患者经常出现中轴症状，包括对多巴胺能药物反应不佳的姿势和步态困难。尽管高度异质性大脑结构桥脚核 (PPN) 的深部脑刺激 (DBS) 可以改善此类症状，但负责临床益处的潜在神经元基质在很大程度上仍然未知，从而阻碍了 DBS 干预措施的优化。胆碱乙酰转移酶 (ChAT)::Cre(+) 转基因大鼠通过黑质内、单半球立体定向施用泛素蛋白酶体系统抑制剂乳胞素与仅由设计药物 (DREADD) 激活的设计受体相结合，进行假损伤或呈现帕金森病，以激活被盖脚桥核 (PPTg) 的胆碱能神经元，大鼠相当于人类 PPN。我们之前已经证明，lactacystin 大鼠模型准确地反映了 PD 的各个方面，包括 PPTg 胆碱能神经元的部分丧失，类似于晚期 PD 患者死后大脑中看到的情况。结果在这篇手稿中，我们表明，通过外周给予同源 DREADD 配体氯氮平-N-氧化物（CNO），短暂激活 PD 大鼠乳胞素模型中剩余的 PPTg 胆碱能神经元，显着改善了运动症状，正如评估的那样通过测量姿势不稳定性、步态、感觉运动整合、前肢运动不能和一般运动活动的行为测试。体内电生理记录显示，在 CNO 诱导的激活过程中，PPTg 假定的胆碱能神经元的尖峰活性增加。 PPTg 的 DREADD 过表达 ChAT 免疫阳性 (ChAT+) 神经元中的 c-Fos 表达也因 CNO 给药而增加，这与该定义的神经元群体中神经元激活的上调一致。结论 总体而言，这些发现提供了证据表明 PPN 胆碱能神经元的功能调节可减轻帕金森运动症状。