The role of the centromedian and pedunculopontine nuclei in motor function during naïve, parkinsonian and DBS conditions

摘要 帕金森病(PD)是第二种最常见的神经退行性疾病，影响多达 占工业化国家人口的3%。这种疾病的晚期患者可以参与其中 不同的治疗方法，包括脑深部刺激(DBS)。这种特殊的疗法可以改善糖尿病的症状 震颤、运动迟缓、运动迟缓和四肢僵硬，然而，有一个未得到满足的需求，即增加 这种疗法对步态功能障碍的疗效，这种疾病的一种症状可以显著减少 患者的生活质量。最近，人们对深部脑刺激的新靶点感兴趣。 来解决这个赤字问题。两个大脑区域，中脑运动区(MLR)和中央中线- 丘脑束旁核(CM-Pf)参与了丘脑束旁核的启动、停止或消失。 在不断变化的感觉环境中调节运动和选择新的运动动作， 分别进行了临床试验，结果喜忧参半。而这些核团在运动中的作用 功能已在文献中阐明，尚不清楚这些核的信号如何从 天真到帕金森状态，以及基底节中的DBS如何进一步干扰它们的放电。的总目标是 这个项目是为了了解帕金森病发作后这些结构中的放电变化。 人类灵长类MPTP-PD的模型以及DBS如何针对传统的DBS目标，如 丘脑底核和苍白球内侧核，加重或促进它们的信号传递。目标1 这项建议将记录在自然步态期间的MLR，并表征射击变化和 帕金森综合症和不同的DBS刺激所见的行为变化。Aim 2将包括相同的内容 方法，但在CM，而且将包括研究MLR-CM的电路动力学通过 在这些结构中同时记录。初步数据已经验证了行为范式和 应用DBS后，步态变量发生了明显的变化。这项提案的结果将阐明 正常步态功能中MLR和CM的机制及其电生理变化 发生在帕金森症和DBS发作之后。这将在这些文件中提供急需的信息 临床上无法从帕金森病患者身上收集到的结构，并将提供线索 关于如何改进目前的DBS治疗。

ABSTRACT Parkinson's Disease (PD) is the second most common neurodegenerative disease and affects up to 3% of the population in industrialized countries. Patients in the advanced stages of the disease can partake in different therapies, including deep brain stimulation (DBS). This particular therapy can ameliorate symptoms of tremor, bradykinesia, akinesia and rigidity of the limbs, however, there is an unmet need to increase the effectiveness of this therapy on gait dysfunction, a symptom of the disease that can drastically reduce the quality-of-life of patients. Recently, there has been interest in novel targets for deep brain stimulation in order to address this deficit. Two brain areas, the mesencephalic locomotor region (MLR) and the centromedian- parafascicular nucleus of the thalamus (CM-Pf) have been identified as involved in initiation, halting or modulating locomotion and selecting new motor actions in the context of changing sensory environments, respectively, and clinical trials have been conducted with mixed results. While the roles of these nuclei in motor function have been illustrated in the literature, it is unknown how the signaling of these nuclei change from a naïve to parkinsonian state and how DBS in the basal ganglia further perturbs their firing. The overall goal of this project is to understand the firing changes in these structures after parkinsonian onset in a non- human primate MPTP-model of PD and how DBS targeting traditional DBS targets, such as the subthalamic nucleus and globus pallidus internus, exacerbates or facilitates their signaling. Aim 1 of this proposal will be to record from the MLR during naturalistic gait and characterize firing changes and behavioral changes seen with parkinsonism and different DBS stimulation. Aim 2 will include the same methods, but in CM, and furthermore, it will include studying the circuit dynamics of MLR-CM through simultaneous recording in these structures. Preliminary data has validated the behavioral paradigm and changes in gait variables can be seen after DBS application. The results of this proposal will elucidate the mechanisms of the MLR and CM in normal gait function and the electrophysiological changes that occur after parkinsonism and DBS onset. This will provide much-needed information in these structures that cannot be gleaned from PD patients in the clinic and, furthermore, it will provide clues on how to improve current DBS therapy.