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: 10213844
• 负责人: Yoland Smith
• 金额: $ 48.69万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213844
• 关键词: 3-Dimensional; Affect; Anatomy; 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; parkinsonian animal; parkinsonian non-human primate; 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.

总结 根据目前的模型，基底神经节参与运动和非运动功能的解释 在分离的基底神经节-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（PD）中纹状体多巴胺的丢失最终会导致“运动”中的异常处理， 丘脑皮质网络，以及感觉运动脑深部电刺激（DBS）的抗帕金森病作用 内苍白球（GPi）被解释为运动相关的丘脑神经元从过度活跃的释放 抑制性GPi输入。然而，最近的证据表明，基底神经节输出下降，特别是 GPi向脚桥核（PPN）的大量投射也可能与正常行为有关， 帕金森综合征因此，PPN的操作影响肢体运动和姿势调整， 激活在猴子中具有抗帕金森病作用，PPN的DBS改善了一些猴子的步态障碍。 PD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 下降投影我们对GPi投射到PPN的解剖靶点缺乏了解， GPi-PPN通路的激活对PPN活性的影响限制了我们对PPN正常作用的理解， GPi-PPN相互作用及其在PD病理生理学中的作用，特别是在灵长类动物中。拟议的研究旨在 因此，为了检查GPi和PPN之间的功能连接（目标1和2），确定是否 这些网络的解剖学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改变了GPi接收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治疗的帕金森病猴中进行，使用 最先进的光遗传学、解剖学和电子显微镜程序的组合。知识 需要从这些研究中获得的信息来开发或改进靶向PPN或其 用于治疗PD或其他基底神经节疾病的预测。