CEREBELLAR FUNCTION IN TREMOR

项目摘要/摘要 震颤是最常见的运动障碍。它损害了自愿行动，因为它导致强烈的 走路、吃饭和说话时都会发抖。摇晃是重复的，而且是高度有节奏的，因为 受影响的身体部位来回“摆动”。振荡频率是震颤的一个重要特征； 帕金森氏病、肌张力障碍和特发性震颤(ET)都有明显的震颤。因为 震颤障碍有神经学基础，它意味着特定的大脑振荡驱动身体 以相同的频率振荡。然而，目前仍不清楚中枢神经系统中 振荡开始了，而导致连接的大脑区域振荡的过程仍然存在 未知。在最常见的病理性震颤形式ET中，后脑运动区 小脑被认为是异常活动的主要来源。但是，如何 小脑活动异常导致振荡运动一直是测试的挑战。这在很大程度上 因为缺乏合适的动物模型。为了解决这个问题，我们识别了一只老鼠 显示ET核心特征的遗传模型。我们已经产生了令人信服的初步数据 研究表明，浦肯野细胞基因Car8的缺失会导致一种类似ET的震颤，类似于人类 病情的频率，进展与年龄，以及对酒精的反应。在这里，我们将扩大 在这项工作中，通过检验Car8功能丧失会导致小脑振荡的假设 推动丘脑皮质环路中的催眠活动。在我们的第一个目标中，我们将追踪4- 12赫兹震颤活动时从小脑到下橄榄、丘脑和运动皮质 老鼠。因此，我们将确定对ET病理生理学有贡献的主要脑振荡器。在……里面 我们的第二个目标是，我们通过测试基因和光基因是否存在，来确定震颤的细胞来源 改变蒲肯野细胞的放电可以调节Car8小鼠的震颤。因为小脑抑制性中间神经元 也与ET有关，我们还将测试是否调节它们的活动对Purkinje细胞产生影响 震颤。本实验将研究本地电路布线如何影响网络范围的振荡。下一首 我们将利用小脑核团与运动的其他部分的强大连接。 系统，加上脑深部刺激(DBS)的效果。在我们的第三个目标中，我们将使用Car8小鼠 以测试小脑核团是否为DBS的有效靶点。我们假设导演 DBS到小脑核团将防止病理性振荡的传播远离源头。 Car8作为临床前模型的实用性显示了揭示其机制的希望 星展银行很管用。我们的研究对人类健康很重要，因为我们引入了一个多学科的 一种研究各种震颤的方法，这些震颤的定义、诊断和治疗都具有挑战性。

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.