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

桥脚被盖核（PPN）与帕金森病（PD）有关：胆碱能神经元的进行性丧失，而来自白球、丘脑下核和黑质网状带的输入改变了PPN的代谢活性。最重要的是，低频深部脑刺激（DBS）在PPN中具有治疗效果。步态和姿势的不稳定性得到改善，一些认知障碍也得到改善。这有力地表明，PPN在PD中的作用比以前认为的更重要。该项目将探索PPN在帕金森病中的作用：我们将创建一个体内啮齿动物模型来评估PPN刺激对帕金森病的行为影响。迫切需要这样做：(i)关于DBS与PPN的位置存在争议。这些电极真的在PPN中吗？如果是的话，PPN内最有效的位置是什么？（ii）哪些职能将受益？我们将测试运动和认知能力：人们认为PPN具有运动功能，但最近的数据显示它在学习中也有作用。由于这些结构在进化过程中高度保守，啮齿类动物的PPN和基底神经节是其他物种的良好模型。为了创建相关的啮齿动物PD模型，我们将使用新型药物，尿紧张素ii -白喉毒素（diptx - ii）选择性PPN胆碱能神经元，制造部分双侧病变。在相同的大鼠中，我们将用6-羟多巴胺制造双侧黑质致密部多巴胺（DA）神经元病变。我们将测试运动（步态、运动、反应时间）和认知表现（学习、记忆），在受损大鼠中使用PPN电极（大鼠和/或实验者控制）和适当的对照。电极在PPN内和周围的位置将系统地变化。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（使用即时早期基因表达测量）。

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.