Neurophysiological mechanisms underlying parkinsonian motor signs

 描述（由申请人提供）：本研究的目的是确定帕金森病发作时苍白球丘脑皮质运动回路关键节点内和节点之间发生的特定神经生理学变化，以及这些变化如何随着运动体征变得越来越严重而演变。这将通过在相同猴中使用连续低剂量给予神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP），同时记录和比较在静止时和正常、轻度、中度和重度帕金森病阶段运动期间基底神经节丘脑-皮质运动回路中多个节点的神经元群体的活动来完成。将被检查的结构包括初级和辅助运动皮质、运动前皮质、苍白球的内部和外部段（分别为GPi和GPe）、丘脑底核（subthalamic nucleus，简称ENA）和运动丘脑，包括腹前肌、腹外侧肌口部和腹后外侧肌口部。特定ims 1和2将分别表征在动物静止时以及在被动运动和执行训练的运动任务期间，基底神经节-皮层和丘脑-皮层区域上的同步振荡、爆发模式、感受野特性和相位振幅耦合的变化。具体目标2将通过应用离散的、纤维保留的病变进一步检查运动丘脑亚核在运动迟缓/运动不能、僵硬和震颤的发展中的不同作用。具体目标3将使用苍白球丘脑皮质回路的LFP记录来表征苍白球、丘脑、运动丘脑与PMC、SMA和MC之间的有效连接的变化，作为帕金森病状态的函数。通过检查PD不同阶段的休息和运动时有效连接变化的方向和强度，我们将能够阐明PD的类型、位置和运动方式。 以及随着帕金森病运动体征的发展和严重程度的进展，有效连接性变化的演变。更好地了解单个电机电路的作用和类型 对这些回路中发生的生理变化以及它们如何与个体运动信号的发展相关的研究将为开发新的靶点和技术治疗提供理论基础，这些技术治疗包括脑深部刺激、经颅电刺激和基因治疗，旨在恢复基底神经节丘脑回路中更正常的活动模式。

 DESCRIPTION (provided by applicant): The goal of this study is to identify the specific neurophysiological changes that occur within and across key nodal points of the pallidothalamocortical motor circuit with the onset of Parkinson's disease and how these evolve as motor signs become increasingly more severe. This will be done by simultaneously recording and comparing the activity from populations of neurons across multiple nodal points in the basal ganglia thalamo-cortical motor circuit at rest and during movement during normal, mild, moderate and severe stages of parkinsonism in the same monkeys using sequential, low dose administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Structures that will be examined include the primary and supplementary motor cortices, the premotor cortex, the internal and external segments of the globus pallidus (GPi and GPe, respectively), the subthalamic nucleus (STN), and the motor thalamus including ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis. Specific ims 1 and 2 will characterize changes in synchronized oscillations, bursting patterns, receptive field properties and phase amplitude coupling across basal ganglia- cortical and thalamo-cortical regions, respectively, with the animal at rest and during both passive movement and the performance of a trained motor task. Specific aim 2 will further examine the differential role of subnuclei of the motor thalamus in the development of bradykinesia/akinesia, rigidity and tremor through the application of discrete, fiber-sparing lesions. Specific aim 3 will use LFP recordings across the pallidothalamocortical circuit to characterize changes in effective connectivity between the pallidum, STN, motor thalamus and PMC, SMA and MC as a function of parkinsonian state. By examining the direction and strength of changes in effective connectivity at rest and during movement at different stages of PD we will be able to clarify the type, location and evolution of changes in effective connectivity as parkinsonian motor signs develop and progress in severity. A better understanding of the role of individual motor circuits and the types of physiological changes that occur within these circuits and how they relate to the development of individual motor signs will provide the rationale for the development of new targets, and technology therapies such as deep brain stimulation, transcranial electrical stimulation and gene therapy that are directed at restoring a more normal pattern of activity in the basal ganglia thalamic circuit.