Cerebellar Circuitry in the Pathophysiology of Tremor

项目总结/摘要 震颤是最常见的运动障碍，往往是高度致残。这些有节奏的动作 是由异常的大脑回路产生的，我们仍然知之甚少。在震颤性疾病中， 震颤（ET）是最常见的并且是震颤的典型病症。最近的死后人类病理学 研究表明ET可能是一种小脑突触病理性疾病。具体来说， ET患者小脑皮质中爬行纤维（CF）和浦肯野细胞（PC）之间的突触形成。 为了进一步研究这种PC突触病理学和震颤之间的病理生理学，我们建立了一个 具有ET样PC突触病理学的小鼠模型，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，与ET患者相似。然而，详细 病理生理学仍不清楚。因此，我们提出了一系列的实验来研究这种关系 PC突触病理学，PC生理学和震颤之间的联系。具体目标1： 在我们的新型震颤小鼠模型中使用光遗传学方法抑制PC活性， 可以被压制。此外，我们将在不同频率下光遗传学增强PC活性， 观察这种操作是否会在野生型小鼠中产生震颤。在具体目标2中，我们将确定如何 PC突触病理与PC退行性变化相互作用，这可能调节震颤特征 （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在震颤期间 发作和震颤进展。在具体目标3中，我们将操纵控制PC突触的分子， 组织来确定特定的PC突触病理学和PC生理学如何调节震颤。我们有 开发了研究解剖PC突触组织和同时记录PC反应的方法 在自由活动的小鼠震颤期间，这将使我们能够详细检查PC活动如何 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.