Pathophysiology of Dystonia

肌张力障碍的病理生理学

• 批准号: 8696829
• 负责人: Mark S Baron
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696829
• 关键词: Animal Model; Basal Ganglia; Beds; Binding; Brain; Cell Nucleus; Data; Dyskinetic syndrome; Dystonia; Fiber; Functional disorder; Ganglia; Globus Pallidus; Goals; Gunn Rats; Human; Icterus; Investigation; Knowledge; Lesion; Measures; Methodology; Microelectrodes; Modeling; Motor Cortex; Motor Manifestations; Movement; Movement Disorders; Muscle; Neurons; Output; Parkinson Disease; Pathway interactions; Pattern; Physiological; Posture; Rattus; Research Personnel; Research Proposals; Role; Sedation procedure; Severities; Signal Transduction; Stroke; Structure of subthalamic nucleus; Techniques; Terminology; Testing; Thalamic Nuclei; Thalamic structure; Veterans; Work; base; design; endopeduncular nucleus; extracellular; ibotenate; improved; novel; prevent

DESCRIPTION (provided by applicant): The proposed study "Pathophysiology of dystonia" was designed with the goal of improving our understanding of dystonia and ultimately, developing improved therapies for this devastating condition. Dystonia is the third most common movement disorder and is characterized by ineffective, twisting movements and contorted postures. Experts in the field are increasingly recognizing that pathological alterations in discharge patterned activity are likely to be the key to understanding dystonia; yet, to date, this had not been systematically investigated previously in animal models of dystonia. Largely because little is known about the underlying pathophysiology of dystonia and because of a lack of adequate animal models, no therapies have even been introduced specifically to treat dystonia. Here we propose to conduct a systematic investigation of dystonia in the jaundiced Gunn rat model. Our group has worked extensively to advance the Gunn rat model to be able to induce reliable dystonia. Moreover, we have developed a number of methodological advances towards the proposed comprehensive investigation of the underlying pathophysiology of dystonia. Our preliminarily data demonstrate highly synchronized movement-related alterations in neuronal discharge activity in basal ganglia nuclei, including pauses in the globus pallidus (GP) and bursts in the entopeduncular nucleus (EP) in dystonic Gunn rats. In the ventrolateral (VL) thalamus, which receives the principal outputs from the basal ganglia, we discovered the discharge activity to be dominated by rhythmical burst activity. This unexpected pattern is normally thought to be reserved for higher order corticothalomocortical neurons and is distinct from the tonic mode normally used by thalamic relay neurons to transmit detail oriented signals to the cortex. From these preliminary findings, our overarching hypothesis is that dystonia is caused by exaggerated silencing of neuronal discharge activity in GP leading to excessive and abnormal basal ganglia outflow drive to the motor cortex via the thalamus. Our specific aims (SAs) will test this hypothesis: SA 1., to determine the relationship between abnormally patterned multi-neuronal discharge activity in single basal ganglia and thalamic nuclei and the motor manifestations of dystonia, SA 2., to establish which discharge alterations in intrinsic basal ganglia nuclei are essential and to delineate the temporal relation of the pathological signaling between these basal ganglia nuclei, and SA 3., to define the physiological abnormalities along the pallidal- thalamic outflow pathway that ultimately contribute to abnormal cortical signaling in dystonia. In SA 1, we will record extracellular discharge activity from large numbers of neurons in single basal ganglia nuclei (GP, EP, and the subthalamic nucleus (STN)) and VL, while simultaneously examining electromyographic activity (EMG) from multiple muscles in normal and dystonic Gunn rats; in SA 2, we will simultaneously record in GP, STN and EP and collect EMG activity before and after placing fiber-sparing ibotenate lesions in GP and STN; and in SA 3, we will simultaneously record in EP, VL and primary motor cortex (MC) and collect EMG activity before and after placing lesions in EP and VL. We are confident that the findings from the proposed studies will broaden our understanding of the physiological bases for many forms of dystonia and, in so doing, reveal new targets for mechanistically-based approaches to treating dystonia. Further, our proposal is anticipated to contribute new basic knowledge of the role of the basal ganglia and thalamus and challenge current basal ganglia thalamocortical models.

描述（由申请人提供）： 拟议的研究“肌张力障碍的病理生理学”旨在提高我们对肌张力障碍的理解，并最终开发针对这种破坏性病症的改进疗法。肌张力障碍是第三种最常见的运动障碍，其特征是无效的扭转运动和扭曲的姿势。该领域的专家越来越认识到放电模式活动的病理改变可能是理解肌张力障碍的关键。然而，迄今为止，此前尚未在肌张力障碍动物模型中对此进行过系统研究。主要是因为对肌张力障碍的潜在病理生理学知之甚少，并且由于缺乏足够的动物模型，甚至还没有专门用于治疗肌张力障碍的疗法。在这里，我们建议对黄疸冈恩大鼠模型中的肌张力障碍进行系统研究。我们的小组进行了广泛的工作来改进冈恩大鼠模型，使其能够诱导可靠的肌张力障碍。此外，我们在对肌张力障碍的潜在病理生理学进行全面研究方面取得了一些方法学进展。 我们的初步数据表明，基底节核中神经元放电活动存在高度同步的运动相关变化，包括肌张力障碍 Gunn 大鼠苍白球 (GP) 的暂停和内脚核 (EP) 的爆发。在接受基底神经节主要输出的腹外侧（VL）丘脑中，我们发现放电活动以节律性爆发活动为主。这种意想不到的模式通常被认为是为高阶皮质丘脑皮质神经元保留的，并且与丘脑中继神经元通常使用的将细节导向信号传输到皮质的强直模式不同。根据这些初步发现，我们的总体假设是肌张力障碍是由于 GP 中神经元放电活动过度沉默导致基底神经节通过丘脑流向运动皮层的过度和异常的流出驱动而引起的。我们的具体目标（SA）将检验这一假设：SA 1.，确定单个基底节和丘脑核中异常模式的多神经元放电活动与肌张力障碍的运动表现之间的关系，SA 2.，确定哪些放电改变内在基底神经节核中的 3.苍白球-丘脑流出通路的生理异常最终导致肌张力障碍的皮质信号异常。在 SA 1 中，我们将记录单个基底节核（GP、EP 和底丘脑核 (STN)）和 VL 中大量神经元的细胞外放电活动，同时检查正常和不同状态下多个肌肉的肌电活动 (EMG)。肌张力障碍冈恩大鼠；在SA 2中，我们将同时记录GP、STN和EP，并收集在GP和STN中放置纤维保留的鹅膏菌病灶之前和之后的EMG活动；在 SA 3 中，我们将同时记录 EP、VL 和初级运动皮层 (MC)，并收集 EP 和 VL 放置病灶前后的 EMG 活动。我们相信，拟议研究的结果将拓宽我们对多种肌张力障碍的生理基础的理解，并由此揭示基于机械的治疗肌张力障碍的方法的新目标。此外，我们的建议预计将贡献有关基底神经节和丘脑作用的新基础知识，并挑战当前的基底神经节丘脑皮质模型。