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: 9404759
• 负责人: Yoland Smith
• 金额: $ 53.51万
• 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/9404759
• 关键词: 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; Posture; 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.

概括 根据当前模型，解释了基底神经节参与运动和非运动功能 在分离的基底神经节-丘脑皮质环路中的信息处理的背景下。这些模型预测 帕金森病 (PD) 中纹状体多巴胺的丧失最终导致“运动”处理异常 丘脑皮质网络，以及感觉运动深部脑刺激 (DBS) 的抗帕金森病作用 内部苍白球（GPi）被解释为运动相关丘脑神经元从过度活跃中释放出来 抑制性 GPi 输入。然而，最近的证据表明，下降的基底神经节输出，特别是 GPi 大量投射到桥脚核 (PPN)，也可能与正常行为和 帕金森症。因此，PPN 的操作会影响肢体运动和姿势调整，PPN PPN 激活对猴子具有抗帕金森病作用，PPN 的 DBS 可以改善某些猴子的步态障碍 帕金森病患者。 PPN 是一个高度异质的大脑区域，导致广泛的上行和 下降的预测。我们缺乏对 GPi 投影到 PPN 的解剖目标的了解，以及 GPi-PPN 通路激活对 PPN 活性的影响限制了我们对 GPi-PPN 通路正常作用的理解。 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。拟议的研究目标 因此，要检查 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 GPi 接收 PPN 神经元的放电率和模式，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结合。知识点 需要从这些研究中获得的成果来开发或完善针对 PPN 或其靶点的抗帕金森病疗法 PD 或其他基底神经节疾病的治疗预测。