ERANET NEURON 1: Establishing an in vivo rodent model to evaluate the behavioural effects of pedunculopontine stimulation in Parkinson’s disease

脚桥被盖核（PPN）参与帕金森病（PD）：存在胆碱能神经元的进行性损失，并且PPN代谢活性通过来自苍白球、丘脑底核和黑质网状核的改变的输入而改变。最重要的是，PPN中的低频脑深部电刺激（DBS）具有治疗益处。步态和姿势不稳定改善，有建议说，一些认知障碍也受益。这强烈表明PPN在PD中的作用比以前认为的更重要。本项目将探索PPN在PD中的作用：我们将创建一个体内啮齿动物模型，以评估PPN刺激在帕金森病条件下的行为效应。（i）关于DBS相对于PPN的位置存在争议。电极是否真的在PPN内，如果是，最有效的PPN内部位是什么？(ii)哪些功能将受益？我们将测试运动和认知能力：人们认为PPN具有运动功能，但最近的数据表明它在学习中发挥作用。由于这些结构在进化过程中高度保守，啮齿动物的PPN和基底神经节是其他物种的极好模型。为了建立一个相关的啮齿类动物PD模型，我们将使用新的药物，尾加压素II-白喉毒素（DIPtx-UII）选择性PPN胆碱能神经元的部分双边病变。用6-羟多巴胺损毁双侧黑质腹侧部多巴胺（DA）神经元。我们将测试运动（步态;运动;反应时间）和认知性能（学习、记忆）的变化。PPN内和周围的电极位置将系统地变化。这将使我们能够确定：（i）PPN DBS对运动和认知表现的影响;（ii）不同的电极位置是否对这些有不同的影响，以及病变和PPN DBS改变了哪些神经活动（使用立即早期基因表达测量）。

The pedunculopontine tegmental nucleus (PPN) is involved in Parkinson's disease (PD): there is progressive loss of cholinergic neurons and PPN metabolic activity is changed by altered inputs from pallidum, subthalamic nucleus and substantia nigra zona reticulata. Most importantly, low frequency deep brain stimulation (DBS) in the PPN has therapeutic benefits. Gait and postural instability improve, and there are suggestions that some cognitive impairments also benefit. This strongly suggests that the PPN has a more significant role in PD than previously thought. This project will explore the role of the PPN in PD: we will create an in vivo rodent model to evaluate the behavioural effects of PPN stimulation in Parkinsonian conditions. There is a pressing need to do this: (i) There is controversy about the location of DBS in relation to PPN. Are the electrodes truly in PPN, and if so, what is the most effective intra-PPN site? (ii) What functions will benefit? We will test motor and cognitive abilities: it is thought that PPN has motor functions, but recent data show that it has a role in learning. Because these structures have been highly conserved through evolution, the rodent PPN and basal ganglia are excellent models for other species. To create a relevant rodent PD model we will make partial bilateral lesions using the novel agent, urotensin II–diphtheria toxin (DIPtx-UII) selective for PPN cholinergic neurons. In the same rats, we will make bilateral lesions of substantia nigra pars compacta dopamine (DA) neurons with 6-hydroxydopamine. We will test motor (gait; locomotion; reaction time) and cognitive performance (learning, memory) inrats that bear lesions, in lesioned rats with PPN electrodes (over which the rats and/or experimenters have control), and appropriate controls. Electrode location in and around PPN will be systematically varied. This will enable us to determine: (i) the effects of PPN DBS on motor and cognitive performance; (ii) whether different electrode locations have differential effects on these, and what neural activity (measured using immediate early gene expression) is changed both by the lesions and by PPN DBS.