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”旨在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改进的治疗方法。肌张力障碍是第三种最常见的运动障碍，其特征是无效、扭曲的运动和扭曲的姿势。该领域的专家越来越多地认识到，放电模式活动的病理变化可能是了解肌张力障碍的关键；然而，到目前为止，这一点之前还没有在肌张力障碍的动物模型中进行系统的研究。这在很大程度上是因为人们对肌张力障碍的基本病理生理学知之甚少，而且由于缺乏适当的动物模型，甚至没有专门用于治疗肌张力障碍的治疗方法。在这里，我们建议对黄褐性Gunn大鼠模型的肌张力障碍进行系统的研究。我们的团队已经进行了广泛的工作，以改进Gunn大鼠模型，使其能够诱导可靠的肌张力障碍。此外，我们已经制定了一些方法学的进展，以拟议的全面调查潜在的肌张力障碍的病理生理学。我们的初步数据显示，在Gunn营养不良大鼠，基底节核团神经元放电活动的高度同步化变化，包括苍白球(GP)的停顿和内侧丘脑核(EP)的爆发。在接受基底节主要输出的丘脑腹外侧部，我们发现放电活动主要由节律性爆发活动主导。这种意想不到的模式通常被认为是为高级皮质丘脑皮质神经元保留的，不同于丘脑中继神经元通常使用的紧张模式，以向皮质传递面向细节的信号。根据这些初步发现，我们的主要假设是，肌张力障碍是由于GP中神经元放电活动的过度沉默导致过度和异常的基底节流出驱动通过丘脑进入运动皮质所致。我们的特定目标(SA)将验证这一假说：SA 1.确定单个基底节和丘脑核团异常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.确定哪些固有基底节核团的放电变化是必需的，并描绘这些基底节核团与SA 3之间的病理信号的时间关系，确定苍白球-丘脑流出通路上最终导致肌张力障碍的皮质信号异常的生理异常。在SA 1中，我们将记录单个基底节核(GP、EP和丘脑底核(STN)和VL的大量神经元的细胞外放电活动，同时检测正常和营养不良Gunn大鼠多块肌肉的肌电活动；在SA 2中，我们将同时记录GP、STN和EP中的大量神经元的细胞外放电活动，并采集在GP和STN中放置纤维保留的ibotenate病变前后的EMG活动；在SA 3中，我们将同时在EP、VL和初级运动皮质(MC)中记录EMG活动，并收集在EP和VL中放置病变前后的EMG活动。我们相信，拟议研究的结果将扩大我们对多种形式肌张力障碍的生理基础的理解，并由此揭示基于机械方法治疗肌张力障碍的新靶点。此外，我们的提案有望对基底节和丘脑的作用提供新的基础知识，并挑战现有的基底节丘脑皮质模型。

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.