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“肌张力障碍病理生理学”的设计目的是提高我们对肌张力障碍的理解，并最终为这种毁灭性疾病开发改善的疗法。肌张力障碍是第三种常见的运动障碍，其特征是无效，扭曲运动和扭曲的姿势。该领域的专家越来越认识到出院活动活动中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进行系统的研究。很大程度上是因为对肌张力障碍的潜在病理生理学知之甚少，并且由于缺乏适当的动物模型，因此甚至没有专门引入疗法来治疗肌张力障碍。在这里，我们建议对黄疸的Gunn大鼠模型进行系统研究。我们的小组已广泛努力推进Gunn Rat模型，以诱导可靠的肌张力障碍。此外，我们已经在对肌张力障碍基础病理生理学的拟议综合研究方面发展了许多方法上的进步。 我们的初步数据表明，基底神经节核中神经元排出活性的高度同步运动相关变化，包括palludus pallidus（GP）（GP）的暂停以及长门质核中肠核（EP）中的爆发。在接收基底神经节的主要输出的腹外侧（VL）丘脑中，我们发现出院活性由节奏爆发活动主导。通常认为这种意外的模式是为高阶皮质皮质皮质神经元保留的，并且与通常由丘脑中继神经元使用的滋补模式不同，以将面向细节的信号传输到皮层。从这些初步发现中，我们的总体假设是肌张力障碍是由GP中神经元排放活性夸大引起的，导致过度和异常的基底神经节流出通过丘脑流向运动皮层。我们的具体目的（SAS）将检验以下假设：SA 1.，确定单个基底神经节和丘脑核中异常的多模式多神经元排放活性与肌张力障碍的运动表现，SA 2.确定在核心神经核的基本基础上的基本构和这些基本的基本构成，这些核的基础是构成的基础，这些基本是构成的，这些核心是构成的，这些核心是构成的。 3.，定义沿苍白的丘脑流出途径的生理异常，最终导致肌张力障碍的皮质信号传导。在SA 1中，我们将记录单个基底神经节核（GP，EP和丘脑下核（STN））和VL中的大量神经元的细胞外排出活性，同时检查正常和肌张力肌的多个肌肉的肌电图活性（EMG）；在SA 2中，我们将同时记录GP，STN和EP，并在将纤维分配的依Nibotenate病变放置在GP和STN中之前和之后收集EMG活动；在SA 3中，我们将同时记录EP，VL和原发性运动皮层（MC），并在将EP和VL的病变放置之前和之后收集EMG活性。我们相信，提出的研究的发现将扩大我们对许多形式的肌张力障碍生理碱基的理解，并且在这样做的过程中，揭示了基于机械的方法治疗肌张力障碍的新目标。此外，我们预计我们的建议将对基底神经节和丘脑的作用有了新的基础知识，并挑战了当前的基底神经神经皮层模型。