Cerebellar Circuitry in the Pathophysiology of Tremor

项目摘要/摘要 震颤是最常见的运动障碍，通常高度致残。这些有节奏的动作是如何 都是由异常的大脑回路产生的，目前仍知之甚少。在震颤障碍中，必不可少的 震颤是震颤最常见、最典型的疾病。最近的尸检人类病理学 研究表明，ET可能是一种小脑突触病理疾病。具体地说，有一种异常 ET患者小脑皮质攀升纤维与浦肯野细胞之间的突触形成。 为了进一步研究这种PC突触病理和震颤之间的病理生理学，我们建立了一个 具有ET样PC突触病理的小鼠模型，并发现该小鼠模型发展与年龄相关的动力学 对扑米酮、心得安和酒精有反应的震颤，类似于ET患者。然而，详细的 病理生理学仍不清楚。因此，我们提出了一系列实验来研究它们之间的关系 在这个新的小鼠模型中，PC突触病理、PC生理和震颤之间的关系。在具体目标1中，我们将 在我们新的震颤小鼠模型中使用光遗传学方法抑制PC活动，并观察震颤 可能会被压制。此外，我们还将在不同的频率和频率下增强PC的光遗传活性 观察这种手法是否会在野生型小鼠身上造成震颤。在具体目标2中，我们将确定如何 PC突触病理与PC退行性改变相互作用，这可能调制震颤特征 (频率和幅度)和相应的小脑生理学在我们的震颤小鼠模型中 发作和震颤进展。在特定目标3中，我们将操纵控制PC突触的分子 组织以明确具体的PC突触病理和PC生理学如何调节震颤。我们有 开发了研究解剖PC突触组织并同时记录PC反应的方法 在震颤期间自由移动的小鼠，这将使我们能够详细检查PC如何活动 与震颤特征有关。因此，我们的研究将为震颤的病理生理学提供重要的见解。

PROJECT SUMMARY/ ABSTRACT Tremor is the most common movement disorder and is often highly disabling. How these rhythmic movements are generated from the abnormal brain circuitry is still poorly understood. Among tremor disorders, essential tremor (ET) is the most common and a prototypical disorder for tremor. Recent postmortem human pathology studies have shown that ET might be a disease of cerebellar synaptic pathology. Specifically, there is abnormal synaptic formation between climbing fibers (CFs) and Purkinje cells (PCs) in the cerebellar cortex of ET patients. To further investigate the pathophysiology between this PC synaptic pathology and tremor, we established a mouse model with ET-like PC synaptic pathology and found that this mouse model develops age-related kinetic tremor that responds to primidone, propranolol, and alcohol, similar to ET patients. However, the detailed pathophysiology remains obscure. Therefore, we propose a series of experiments to study the relationship between PC synaptic pathology, PC physiology and tremor in this novel mouse model. In Specific Aim 1, we will use optogenetic approaches to inhibit PC activities in our novel tremor mouse model and observe whether tremor could be suppressed. In addition, we will optogenetically enhance PC activities at different frequencies and observe whether this manipulation will create tremor in wild type mice. In Specific Aim 2, we will determine how the PC synaptic pathology interacts with PC degenerative changes, which could modulate tremor characteristics (frequency and amplitude) and the corresponding cerebellar physiology in our tremor mouse model during tremor onset and tremor progression. In Specific Aim 3, we will manipulate molecules controlling PC synaptic organization to pinpoint how specific PC synaptic pathology and PC physiology can regulate tremor. We have developed methods to study anatomical PC synaptic organization and to simultaneously record PC responses during tremor in freely moving mice, which will allow us to perform detailed examination of how the PC activity relates to tremor characteristics. Our study will thus provide important insights into the pathophysiology of tremor.