Pathophysiology of the Pedunculopontine Nucleus in Parkinson's Disease

帕金森病桥脚核的病理生理学

• 批准号: 9975917
• 负责人: Yoland Smith
• 金额: $ 52.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975917
• 关键词: 3-Dimensional; Affect; Anatomy; Animals; Antiparkinson Agents; Axon; Basal Ganglia; Basal Ganglia Diseases; Behavior; Brain Stem; Brain region; Cell Nucleus; Cells; Cervical spinal cord structure; Corpus striatum structure; Deep Brain Stimulation; Development; Dopamine; Electron Microscopy; Electrons; Face; Felis catus; Frequencies; Functional disorder; Gait abnormality; Globus Pallidus; Glutamates; Homologous Gene; Human; Invaded; Knowledge; Light; Literature; Location; MPTP Poisoning; Macaca mulatta; Methods; Microscopic; Modeling; Monkeys; Morphology; Motor; Motor Manifestations; Movement; Neurons; Opsin; Output; Parkinson Disease; Parkinsonian Disorders; Partner in relationship; Pathway interactions; Patients; Pattern; Pharmacology; Physiological; Physiology; Population Heterogeneity; Postural adjustments; Primates; Procedures; Prosencephalon; Reticular Formation; Rodent; Role; Salvelinus; Scanning Electron Microscopy; Spinal Cord; Substantia nigra structure; Subthalamic structure; Synapses; Testing; Thalamic structure; base; cholinergic neuron; endopeduncular nucleus; experimental study; information processing; insight; limb movement; motor control; optogenetics; pars compacta; predictive modeling; response; targeted treatment

SUMMARY According to current models, the involvement of the basal ganglia in motor and non-motor functions is explained in the context of information processing in segregated basal ganglia-thalamocortical loops. These models predict that striatal dopamine loss in Parkinson’s disease (PD) eventually leads to abnormal processing in the “motor” thalamocortical network, and the antiparkinsonian effects of deep brain stimulation (DBS) of the sensorimotor internal globus pallidus (GPi) is explained as a release of movement-related thalamic neurons from overactive inhibitory GPi inputs. However, recent evidence suggests that descending basal ganglia output, specifically the massive projection of GPi to the pedunculopontine nucleus (PPN), may also be relevant for normal behavior and parkinsonism. Thus, manipulations of the PPN influence limb movements and postural adjustments, PPN activation has antiparkinsonian effects in monkeys, and DBS of the PPN ameliorates gait disturbances in some PD patients. The PPN is a highly heterogeneous brain region that gives rise to widespread ascending and descending projections. Our lack of knowledge of the anatomical targets of GPi projections to the PPN, and the effects of activation of the GPi-PPN pathway on PPN activity limits our understanding of the normal role of the GPi-PPN interaction and its role in the pathophysiology of PD, particularly in primates. The proposed studies aim therefore to examine the functional connectivity between the GPi and the PPN (aims 1 and 2), determine whether the anatomy and physiology of these networks are altered in the parkinsonian state (aims 2 and 3), and how GPi-DBS alters firing rates and patterns of GPi-receiving PPN neurons, as well as local field potential activity in the PPN (aim 3). These studies will be done in normal and MPTP-treated parkinsonian monkeys, using a combination of state-of-the-art optogenetic, anatomical and electron microscopy procedures. The knowledge gained from these studies is needed to develop or refine antiparkinsonian therapies that target the PPN or its projections for treatment of PD or other basal ganglia disorders.

摘要 根据目前的模型，解释了基底节参与运动和非运动功能。 在分离的基底节-丘脑皮质环的信息处理的背景下。这些模型预测 帕金森氏病患者的纹状体多巴胺丢失最终导致“运动”的异常处理。 丘脑皮质网络和感觉运动脑深部刺激(DBS)的抗帕金森病效应 内侧苍白球(GPI)被解释为运动相关的丘脑神经元从过度活动中释放出来 抑制GPI输入。然而，最近的证据表明，下降的基底节输出，特别是 GPI向桥脑脚核(PPN)的大量投射也可能与正常行为和 帕金森症。因此，PPN的操作影响肢体运动和姿势调整 激活PPN对猴子有抗帕金森病的作用，而PPN的DBS可以改善某些人的步态障碍 帕金森病患者。PPN是一个高度异质性的大脑区域，它引起广泛的上升和 下降的投影。我们对GPI投射到PPN的解剖靶点缺乏了解，以及 GPI-PPN通路的激活对PPN活性的影响限制了我们对PPN的正常作用的理解 GPI-PPN相互作用及其在帕金森病病理生理学中的作用，特别是在灵长类动物中。建议的研究目的 因此，要检查GPI和PPN之间的功能连接性(目标1和2)，请确定是否 这些网络的解剖和生理学在帕金森状态下发生了改变(目标2和3)，以及如何改变 GPI-DBS改变GPI受体PPN神经元的放电频率和模式，以及局部场电位活动 PPN(目标3)。这些研究将在正常和MPTP治疗的帕金森病猴子身上进行，使用一种 结合了最先进的光遗传学、解剖学和电子显微镜程序。《知识》 需要从这些研究中获得，以开发或改进针对PPN或其 帕金森病或其他基底节疾病的治疗预测。