CEREBELLAR FUNCTION IN TREMOR

震颤时的小脑功能

• 批准号: 9977296
• 负责人: Roy Vincent Sillitoe
• 金额: $ 33.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977296
• 关键词: Address; Affect; Affinity; Age; Alcohols; Animal Model; Area; Ataxia; Back; Behavior; Binding Proteins; Body part; Brain; Brain region; Calcium Signaling; Cell physiology; Cerebellar Nuclei; Cerebellum; Cerebral cortex; Chronic; Data; Deep Brain Stimulation; Devices; Diagnosis; Disease; Disease model; Dystonia; Eating; Electrophysiology (science); Essential Tremor; Exhibits; Fire - disasters; Frequencies; Functional disorder; Genes; Genetic; Genetic Models; Health; Homologous Gene; Human; ITPR1 gene; Impairment; Inferior; Interneurons; Lead; Locomotion; Measures; Motion; Motor; Motor Cortex; Movement Disorders; Mus; Muscle; Muscle function; Mutant Strains Mice; Mutation; Neuraxis; Neurologic; Neurons; Olives - dietary; Output; Parkinson Disease; Pathologic; Pattern; Periodicity; Physiologic pulse; Physiology; Pre-Clinical Model; Process; Purkinje Cells; Research; Rest; Signal Transduction; Source; Spinocerebellar Ataxias; Structure; System; Testing; Thalamic structure; Therapeutic; Tremor; Walking; Wireless Technology; Work; experimental study; hindbrain; human model; imaging study; in vivo; interdisciplinary approach; millisecond; motor function improvement; mouse genetics; mouse model; mutant; neuromechanism; neuroregulation; optogenetics; prevent; receptor; therapeutic evaluation

PROJECT SUMMARY/ABSTRACT Tremor is the most common movement disorder. It impairs voluntary actions by causing intense shaking during walking, eating, and speaking. The shaking is repetitive and highly rhythmic as the affected body parts “oscillate” back and forth. Oscillation frequency is a defining feature of tremor; distinct tremors are found in Parkinson's disease, dystonia, and essential tremor (ET). Because tremor disorders have a neurological basis, it implies that specific brain oscillations drive the body to oscillate at the same frequency. However, it is still not clear where in the central nervous system the oscillations begin, and the processes that lead to oscillations in the connected brain regions remain unknown. In ET, which is the most prevalent form of pathological tremor, a hindbrain motor region called the cerebellum has been heavily implicated as the major source of abnormal activity. But, how abnormal cerebellar activity leads to oscillating motions has been challenging to test. This is largely because of the lack of an appropriate animal model. To address this problem, we identified a mouse genetic model that exhibits the core features of ET. We have generated compelling preliminary data showing that the loss of a Purkinje cell gene, Car8, causes an ET-like tremor that mimics the human condition in its frequency, progression with age, and responsiveness to alcohol. Here, we will expand on this work by testing the hypothesis that loss of Car8 function causes cerebellar oscillations that drive tremorgenic activity in the thalamocortical circuit. In our first aim, we will trace the path of the 4- 12Hz tremor oscillations from the cerebellum to the inferior olive, thalamus, and motor cortex in active mice. We will therefore identify the major brain oscillators that contribute to ET pathophysiology. In our second aim, we define the cellular origin of the tremor by testing if genetically and optogenetically altering Purkinje cell firing modulates tremor in Car8 mice. Because cerebellar inhibitory interneurons are also implicated in ET, we will also test if modulating their activity onto Purkinje cells influences tremor. This experiment will address how local circuit wiring impacts network-wide oscillations. Next we will take advantage of the robust connectivity of the cerebellar nuclei with the rest of the motor system, plus the efficacy of deep brain stimulation (DBS). In our third aim, we will use the Car8 mice to test whether the cerebellar nuclei are an effective target for DBS. We hypothesize that directing the DBS to the cerebellar nuclei will prevent the spread of pathological oscillations away from the source. The utility of Car8 as a preclinical model shows promise towards uncovering the mechanisms for how DBS works. Our research has importance to human health because we introduce a multi-disciplinary approach to study a broad spectrum of tremors that are all challenging to define, diagnose, and treat.

项目摘要/摘要 震颤是最常见的运动障碍。它通过造成强烈的强烈而损害自愿行动 在步行，进食和说话期间摇晃。摇晃是重复的，高度有节奏的 受影响的身体部位来回“振荡”。振荡频率是Tremorim的定义特征； 在帕金森氏病，肌张力障碍和本质震颤（ET）中发现了不同的震颤。因为 震颤障碍具有神经系统基础，这意味着特定的脑振荡将身体驱动到 以相同的频率振荡。但是，尚不清楚中枢神经系统中的何处 振荡开始，导致连接大脑区域振荡的过程仍然存在 未知。在ET中，这是病理性震颤的最普遍形式，是后脑运动区域 称为小脑已被严重牵涉到异常活性的主要来源。但是，怎么样 小脑活性异常导致振荡动作受到挑战。这很大程度上 由于缺乏合适的动物模型。为了解决这个问题，我们确定了一只鼠标 具有ET的核心特征的遗传模型。我们已经生成了引人入胜的初步数据 表明purkinje细胞基因car8的丧失会导致类似人类的Et样树 其频率，随着年龄的增长和对酒精的反应性的条件。在这里，我们将扩展 在这项工作中测试CAR8功能的损失导致小脑振荡的假设， 在丘脑皮质回路中驱动震颤活性。在我们的第一个目标中，我们将追踪4-的道路 从小脑到下橄榄，丘脑和运动皮层的12Hz震颤振荡 老鼠。因此，我们将确定有助于ET病理生理学的主要脑振荡器。在 我们的第二个目标，我们通过测试遗传和光学测试来定义树的细胞起源 更改Purkinje电池发射会调节CAR8小鼠中的树。因为小脑抑制性中间神经元 也已在ET中实施，我们还将测试是否将其活性调节到Purkinje细胞上 震颤。该实验将解决本地电路接线如何影响网络范围的振荡。下一个 我们将利用小脑核与电动机的其余部分的强大连通性 系统，加深脑刺激（DBS）的效率。在我们的第三个目标中，我们将使用CAR8小鼠 测试小脑核是否是DBS的有效靶标。我们假设指导 到小脑核的DBS将防止病理振荡从源头传播。 CAR8作为临床前模型的实用性显示出有望揭示如何揭示如何的机制 DBS起作用。我们的研究对人类健康具有重要意义，因为我们引入了多学科 研究各种震颤的方法，这些震颤都挑战了定义，诊断和治疗。