CEREBELLAR FUNCTION IN TREMOR

项目总结/摘要 震颤是最常见的运动障碍。它通过引起强烈的 走路、吃饭和说话时发抖。震动是重复的，而且有很高的节奏， 受影响的身体部位来回“摆动”。振荡频率是震颤的定义特征; 在帕金森病、肌张力障碍和特发性震颤（ET）中发现了不同的震颤。因为 震颤障碍具有神经学基础，这意味着特定的脑振荡驱动身体 以相同的频率振荡。然而，仍然不清楚在中枢神经系统中， 振荡开始，导致相连的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， 被认为是异常活动的主要来源。但如何 异常的小脑活动导致振荡运动已经具有挑战性的测试。这主要是 因为缺乏合适的动物模型。为了解决这个问题，我们发现了一种老鼠， 表现出ET核心特征的遗传模型。我们得到了令人信服的初步数据 这表明浦肯野细胞基因Car 8的缺失会导致类似ET的震颤， 在其频率，随着年龄的进展和对酒精的反应性条件。在这里，我们将扩大 通过测试Car 8功能丧失导致小脑振荡的假设， 驱动丘脑皮层回路的震颤活动。在我们的第一个目标中，我们将追踪4- 12 Hz震颤振荡从小脑到下橄榄核，丘脑和运动皮层在活动 小鼠因此，我们将确定主要的大脑振荡器，有助于ET病理生理。在 我们的第二个目标，我们通过测试遗传学和光遗传学是否确定震颤的细胞起源， 改变浦肯野细胞放电调节Car 8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对浦肯野细胞的活性影响 震颤本实验将讨论本地电路布线如何影响网络范围的振荡。下 我们将利用小脑核团与运动神经其余部分的强大连接， 系统，加上脑深部电刺激（DBS）的疗效。在我们的第三个目标中，我们将使用Car 8小鼠 以测试小脑核是否是DBS的有效靶点。我们假设， 脑深部电刺激小脑核将防止病理性振荡从源头扩散。 Car 8作为临床前模型的实用性显示出了揭示其机制的希望， DBS工作。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 方法来研究广泛的震颤，所有具有挑战性的定义，诊断和治疗。

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.