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

• 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
• 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

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.

项目摘要/摘要 震颤是世界上最常见的神经系统运动障碍，影响了超过1000万人 仅美国。以非自愿的，无法控制的振荡运动的特征，震颤是 使患者衰弱，并且在任何年龄的性别中，都可以从遗传或特发性起源中出现。震颤 人们认为病理涉及小脑等运动脑中心，但特定细胞的身份 活动模式和震颤的分子机制仍然是一个谜。为了研究这些未知数，我 开发了一种使用处方药的研究树的方法 小脑途径和驱动树的电路活动模式，希望揭示潜在的治疗 目标。普萘洛尔是一种已连续规定的β-肾上腺素受体阻滞剂（或β受体阻滞剂） 自1965年以来，对于患者作为震颤的一线治疗方法。尽管其震颤的神经机制是 尚不理解，普罗诺洛尔在震颤患者中的高效率使其成为理想和独特的工具 震颤病理研究。由越来越广泛的文献所暗示的小脑电路的动机 活动异常可能会导致震颤，我对暴露了强大通用的小鼠给了普萘洛尔 震颤的形式，发现不仅普萘洛尔在消除震颤表型方面非常有效，而且还 在普萘洛尔的主动震颤降低过程中，小脑活性发生了显着改变。在遗传的小鼠中 震颤，已知Purkinje细胞以更高的发射速度更加不规则地发射。使用体内电 - 生理学，我发现普萘洛尔大大降低了遗传震颤小鼠的浦肯野细胞发射率。 此外，这种降低率的持续时间与树木严重程度降低的持续时间相关。一次 足够的时间过去了，从系统中消除了普萘洛尔，浦肯野的速率恢复到了震颤 水平，震颤表型也恢复了。我的数据提出了一个有趣的假设，即发射异常 小脑电路中的钥匙单元的模式，例如Purkinje细胞，其活性模式很容易通过 普萘洛尔是大脑震颤病理学的核心。为了检验这一假设，我产生了两个目标 进一步发现树下的小脑功能，使用普萘洛尔作为测试的机械工具 小脑在颤音中的分子遗传特性（AIM 1），并剖析Purkinje细胞活性的作用 在产生和减少震颤时（AIM 2）。对于这两个目标，我都将使用遗传十字来创建针对目标的小鼠 小脑环和小脑神经元的体内电生理记录中基因的操纵 行为动物。这些目标的完成将要求重新评估未解决和辩论的理论 试图解释震颤是如何在中枢神经系统中开始的，并给出了关键的见解 处方最常的树毒在患者中真正起作用。关于神经电路的知识的可用性 潜在的树病理学将为基于药物和替代方案的巨大进步提供机会 震颤的治疗方法，例如基于大脑刺激的治疗，并最终使我们更接近未来的治疗方法。