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.

概括 根据当前的模型，解释了巴萨神经节在电机和非运动功能中的参与 在隔离的低音神经节 - 丘脑皮层环中的信息处理中。这些模型预测 帕金森氏病（PD）中这种纹状体多巴胺的损失最终导致“运动”中的异常处理 丘脑皮质网络和感觉运动的深脑刺激（DBS）的抗帕金森氏症效应 内部球体pallidus（GPI）被解释为与运动相关的丘脑神经元的释放。 抑制GPI输入。但是，最近的证据表明，低音神经节输出，特别是 GPI对Pedunculopontine Nucus（PPN）的大规模投射也可能与正常行为和 帕金森主义。这是对PPN的操作会影响肢体运动和姿势调整，PPN 激活在猴子中具有反帕金森的影响，PPN的DBS可以改善某些灾难 PD患者。 PPN是一个高度异构的大脑区域，引起广泛的上升，并且 下降项目。我们对PPN的GPI项目的解剖目标缺乏了解，以及 GPI-PPN途径激活对PPN活性的影响限制了我们对正常作用的理解 GPI-PPN的相互作用及其在PD的病理生理中的作用，特别是在私人中。拟议的研究目的 因此，要检查GPI和PPN之间的功能连接性（目标1和2），请确定是否是否 这些网络的解剖学和生理学在帕金森州发生了变化（目标2和3），以及如何如何 GPI-DBS改变了GPI接收PPN神经元的点火率和模式，以及局部现场潜在活动 PPN（目标3）。这些研究将以正常和MPTP处理的帕金森猴进行 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，以开发或完善针对PPN或IT的替代疗法 治疗PD或其他基底神经节疾病的预测。