Uncovering cerebellar mechanisms of tremor using the efficacy of propranolol to test circuit function

利用普萘洛尔的功效测试回路功能揭示震颤的小脑机制

基本信息

批准号：
10326838
负责人：
Yi Zhou
金额：
$ 4.6万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2023-07-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326838
关键词：
Adrenergic beta-Antagonists Affect Age Alleles Animals Binding Body part Brain Brain region Cell Nucleus Cell physiology Cells Cerebellar Cortex Cerebellar Nuclei Cerebellum Clinical Treatment Consensus DNA Sequence Alteration Data Deep Brain Stimulation Development Drug Prescriptions Eating Electrophysiology (science)Epinephrine Essential Tremor Ethanol Exhibits Experimental Models FDA approved Fire - disasters Functional disorder Future Gender Generations Genes Genetic Genetic Crosses Genetic Models Goals Heart Human Immunohistochemistry Impairment Intention Tremor Knock-out Knockout Mice Knowledge Lead Literature Mediating Methods Molecular Molecular Genetics Molecular Target Monitor Motor Movement Movement Disorders Mus Mutant Strains Mice Neuraxis Neurologic Neurons Norepinephrine Output Pathology Pathway interactions Patients Pattern Periodicity Pharmaceutical Preparations Pharmacology Phenotype Physiology Plant Roots Play Property Propranolol Proteins Purkinje Cells Recording of previous events Reproducibility Role Series Severities Signal Transduction Source System Testing Time Tremor Walking Work alternative treatment base beta-adrenergic receptor brain abnormalities cellular targeting clinically relevant experience genetic approach genetic manipulation improved improved functioning in vivo insight interdisciplinary approach monitoring device motor control motor disorder mutant neural circuit neuromechanism neurotransmission optogenetics receptor reduce symptoms relating to nervous system social theories therapeutic target tool vesicular GABA transporter

项目摘要

PROJECT SUMMARY/ABSTRACT Tremor is the most common neurological movement disorder in the world, affecting over 10 million people in the U.S. alone. Characterized by involuntary, uncontrollable oscillating movements of body parts, tremor is debilitating to patients and can emerge at any age, in both genders, from genetic or idiopathic origins. Tremor pathology is thought to involve motor brain centers such as the cerebellum, but the identities of specific cellular activity patterns and molecular mechanisms underlying tremor remain a mystery. To study these unknowns, I developed a method of studying tremor using the prescription drug propranolol as a mechanistic tool to uncover cerebellar pathways and circuit activity patterns that drive tremor, with hopes of revealing potential therapeutic targets. Propranolol is a β-adrenergic receptor blocker (or beta-blocker) that has been continuously prescribed to patients as a first-line treatment for tremor since 1965. Though its neural mechanisms for tremor reduction are not yet understood, propranolol’s high rate of efficacy in tremor patients makes it an ideal and unique tool for the study of tremor pathology. Motivated by the increasingly extensive literature implicating that cerebellar circuit activity abnormalities may contribute to tremor, I administered propranolol to mice that exhibit a robust genetic form of tremor, and found that not only was propranolol highly effective in eliminating the tremor phenotype, but that cerebellar activity was significantly altered during propranolol’s active tremor reduction. In mice with genetic tremor, Purkinje cells are known to fire more irregularly and at a much higher firing rate. Using in vivo electro- physiology, I found that propranolol dramatically reduces Purkinje cell firing rate in mice with genetic tremor. Moreover, the duration of this reduced firing rate correlated with the duration of decreased tremor severity; once enough time had passed that propranolol was eliminated from the system, Purkinje rates returned to tremorgenic levels, and the tremor phenotype returned as well. My data raise the intriguing hypothesis that abnormal firing patterns of key cells in the cerebellar circuit, such as Purkinje cells whose activity patterns are readily altered by propranolol, are at the heart of tremor pathology in the brain. To test this hypothesis, I generated two aims to further uncover the cerebellar functions underlying tremor, using propranolol as a mechanistic tool to test the molecular genetic properties of the cerebellum in tremor (Aim 1), and to dissect the role of Purkinje cell activity in generating and reducing tremor (Aim 2). For both aims, I will use genetic crosses to create mice with targeted manipulations of genes in the cerebellar circuit and in vivo electrophysiology recordings of cerebellar neurons in behaving animals. The completion of these aims will call for a reevaluation of the unsolved and debated theories that attempt to explain how tremor begins in the central nervous system, as well as give key insights into how the most-prescribed tremor drug truly works in patients. The availability of knowledge about the neural circuitry underlying tremor pathology will provide opportunities for great advancements in both drug-based and alternative treatments for tremor, such as brain stimulation-based treatments, and ultimately lead us closer to a future cure.

项目概要/摘要震颤是世界上最常见的神经运动障碍，影响着全球超过 1000 万人。仅在美国，震颤的特点是身体部位不自主、无法控制的振荡运动。使患者衰弱，任何年龄、性别均可出现，由遗传性或特发性震颤引起。病理学被认为涉及小脑等运动脑中心，但特定细胞的身份震颤的活动模式和分子机制仍然是个谜，为了研究这些未知因素，我。开发了一种研究震颤的方法，使用处方药普萘洛尔作为机械工具来揭示驱动震颤的小脑通路和回路活动模式，希望揭示潜在的治疗方法普萘洛尔是一种持续服用的β-肾上腺素受体阻滞剂（或β-阻滞剂）。自 1965 年以来，它一直作为震颤的一线治疗方法提供给患者。尽管其减少震颤的神经机制尚不清楚目前尚不清楚，普萘洛尔对震颤患者的高疗效使其成为治疗震颤的理想且独特的工具。受到越来越多涉及小脑回路的文献的推动。活动异常可能会导致震颤，我给表现出强大遗传基因的小鼠注射了普萘洛尔形式的震颤，发现普萘洛尔不仅能够非常有效地消除震颤表型，而且在普萘洛尔的主动震颤减少过程中，遗传小鼠的小脑活动发生了显着改变。震颤时，已知浦肯野细胞的放电更加不规则，并且使用体内电的放电率更高。生理学方面，我发现普萘洛尔可显着降低遗传性震颤小鼠的浦肯野细胞放电率。此外，放电频率降低的持续时间与震颤严重程度降低的持续时间相关。经过足够的时间，普萘洛尔从系统中消除，浦肯野率恢复到震颤状态我的数据提出了一个有趣的假设：异常放电。小脑回路中关键细胞的模式，例如浦肯野细胞，其活动模式很容易通过普萘洛尔是大脑震颤病理学的核心，为了检验这一假设，我提出了两个目标：使用普萘洛尔作为机械工具来测试震颤的小脑功能，进一步揭示震颤背后的小脑功能小脑在震颤中的分子遗传特性（目标 1），并剖析浦肯野细胞活性的作用为了产生和减少震颤（目标 2），我将使用基因杂交来培育具有目标的小鼠。小脑回路中基因的操作和小脑神经元的体内电生理学记录行为动物的完成将需要重新评估尚未解决和争论的理论。试图解释震颤如何在中枢神经系统中开始，并提供关于震颤如何发生的关键见解最常用的震颤药物确实对患者有效。有关神经回路的知识的可用性。潜在的震颤病理学将为基于药物和替代疗法的巨大进步提供机会震颤的治疗方法，例如基于脑刺激的治疗方法，最终使我们更接近未来的治愈方法。