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

摘要 帕金森病（PD）是第二常见的神经退行性疾病， 占工业化国家人口的3%。在疾病的晚期阶段的患者可以参加 不同的治疗方法，包括脑深部电刺激（DBS）。这种特殊的疗法可以改善 然而，对于增加运动障碍、震颤、运动迟缓、运动不能和肢体僵硬的治疗， 这种疗法对步态功能障碍的有效性，这种疾病的症状可以大大减少 患者的生活质量。最近，人们对深部脑刺激的新靶点产生了兴趣， 来弥补这一赤字。两个大脑区域，中脑运动区（MLR）和中央- 丘脑束旁核（CM-Pf）已被确定为参与启动，停止或 在变化的感觉环境中调节运动和选择新的运动动作， 临床试验结果喜忧参半。虽然这些核团在运动中的作用 功能已经在文献中说明，但这些核的信号传导如何从一个核改变为一个核， 帕金森病状态以及基底神经节中的DBS如何进一步干扰其放电。的总目标 这个项目是为了了解在非帕金森病发作后， 人类灵长类动物MPTP-PD模型以及DBS如何靶向传统DBS靶点，如 丘脑底核和苍白球内，加剧或促进其信号传导。目标1 该建议将在自然步态期间从MLR记录并表征放电变化， 帕金森综合征和不同DBS刺激所见的行为变化。目标2将包括相同的 方法，但在CM中，此外，它将包括研究MLR-CM的电路动态， 在这些结构中同时记录。初步数据验证了行为模式， 在DBS应用后可以看到步态变量的变化。该提案的结果将阐明 MLR和CM在正常步态功能中的机制以及 发生在帕金森症和DBS发作后。这将提供急需的信息， 这些结构不能从临床上的PD患者中收集，此外，它将提供线索 关于如何改进目前的DBS疗法。

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.