Pathophysiology of Dystonia

描述（由申请人提供）： 拟议的研究“肌张力障碍的病理生理学”的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的疾病开发更好的治疗方法。肌张力障碍是第三种最常见的运动障碍，其特征是无效的、扭曲的运动和扭曲的姿势。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，这还没有在肌张力障碍的动物模型中进行系统的研究。然而，由于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，甚至没有专门用于治疗肌张力障碍的疗法。在这里，我们建议在黄疸古恩大鼠模型进行系统的调查肌张力障碍。我们的小组已经广泛地工作，以促进古恩大鼠模型能够诱导可靠的肌张力障碍。此外，我们在方法上取得了许多进展，以全面研究肌张力障碍的潜在病理生理学。 我们的初步数据表明，高度同步的运动相关的改变，在基底节核神经元放电活动，包括暂停苍白球（GP）和爆发在脚内核（EP）在张力障碍古恩大鼠。在腹外侧（VL）丘脑，从基底神经节接收的主要输出，我们发现的放电活动是由有节奏的爆发活动为主。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用于将细节导向信号传输到皮质的紧张模式不同。从这些初步的发现，我们的总体假设是，肌张力障碍是由过度沉默的神经元放电活动在GP导致过度和异常的基底神经节流出驱动通过丘脑到运动皮层。我们的特定目标（SA）将测试这一假设：SA 1.，为了确定单个基底神经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.，建立内在基底神经节核中哪些放电改变是必需的，并描绘这些基底神经节核与SA 3之间的病理信号传导的时间关系，以确定沿着苍白球-丘脑流出通路的生理异常，这些异常最终导致肌张力障碍中的异常皮质信号传导。在SA 1中，我们将记录单个基底节核团中大量神经元的细胞外放电活动（GP、EP和丘脑底核（EEP））和VL，同时检测正常和肌张力障碍古恩大鼠多块肌肉的肌电图活动（EMG）;在SA 2中，我们将同时记录GP、EEG和EP，并在GP和EEG中放置保留纤维鹅膏肌损伤前后收集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放置损伤前后的EMG活动。我们相信，拟议研究的结果将拓宽我们对许多形式肌张力障碍的生理基础的理解，并在此过程中揭示基于机械方法治疗肌张力障碍的新目标。此外，我们的建议预计将有助于新的基础知识的作用，基底神经节和丘脑和挑战目前的基底神经节丘脑皮质模型。

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.