CEREBELLAR FUNCTION IN TREMOR

震颤时的小脑功能

基本信息

批准号：
10459139
负责人：
Roy Vincent Sillitoe
金额：
$ 16万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

项目摘要

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.

项目概要/摘要震颤是最常见的运动障碍，它会引起强烈的自主行动。走路、吃饭和说话时颤抖颤抖是重复性的，并且有很强的节奏性。受影响的身体部位来回“振动”，振动频率是震颤的一个明显特征。帕金森病、肌张力障碍和特发性震颤 (ET) 中存在明显的震颤。震颤症有神经学基础，这意味着特定的大脑振荡会驱动身体然而，目前尚不清楚中枢神经系统中的哪个位置。振荡开始，导致相连大脑区域振荡的过程仍然存在在 ET 中，这是最常见的病理性震颤，是后脑运动区。被称为小脑的大脑被认为是异常活动的主要来源。异常的小脑活动导致振荡运动一直难以测试。由于缺乏合适的动物模型，为了解决这个问题，我们确定了一种小鼠。展示 ET 核心特征的遗传模型我们已经生成了令人信服的初步数据。表明浦肯野细胞基因 Car8 的缺失会导致模仿人类的 ET 样震颤在这里，我们将扩展其频率、随年龄的进展以及对酒精的反应。在这项工作中，我们测试了 Car8 功能丧失会导致小脑振荡的假设，驱动丘脑皮质回路中的震颤活动在我们的第一个目标中，我们将追踪 4- 的路径。活动时从小脑到下橄榄、丘脑和运动皮层的 12Hz 震颤振荡因此，我们将确定导致 ET 病理生理学的主要脑振荡器。我们的第二个目标是，通过测试遗传和光遗传学是否可以确定震颤的细胞起源改变浦肯野细胞放电可调节 Car8 小鼠的震颤，因为小脑抑制性中间神经元。也与 ET 有关，我们还将测试调节它们对浦肯野细胞的活性是否会产生影响接下来，该实验将解决局部电路布线如何影响网络范围的振荡。我们将利用小脑核与运动其余部分的强大连接系统，加上深部脑刺激 (DBS) 的功效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 的有效目标。对小脑核进行 DBS 将防止病理振荡远离源头传播。 Car8 作为临床前模型的实用性显示出揭示其机制的希望 DBS 的研究对人类健康具有重要意义，因为我们引入了多学科。研究广泛的震颤的方法，这些震颤的定义、诊断和治疗都具有挑战性。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cerebellar Lobulus Simplex and Crus I Differentially Represent Phase and Phase Difference of Prefrontal Cortical and Hippocampal Oscillations.

小脑单纯叶和小腿 I 不同地代表前额皮质和海马振荡的相位和相位差。

DOI：
发表时间：
2019
期刊：
影响因子：
8.8
作者：
McAfee, Samuel S;Liu, Yu;Sillitoe, Roy V;Heck, Detlef H
通讯作者：
Heck, Detlef H

Insights into cerebellar development and connectivity.

对小脑发育和连接的见解。

DOI：
发表时间：
2019
期刊：
影响因子：
2.5
作者：
Beckinghausen, Jaclyn;Sillitoe, Roy V
通讯作者：
Sillitoe, Roy V

In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy.

杜氏肌营养不良症 mdx 小鼠模型体内小脑回路功能受到破坏。

DOI：
发表时间：
2019-12-09
期刊：
影响因子：
4.3
作者：
Stay, Trace L;Miterko, Lauren N;Arancillo, Marife;Lin, Tao;Sillitoe, Roy V
通讯作者：
Sillitoe, Roy V

Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper [corrected].

小脑模块及其作为小脑操作处理单元的作用：共识文件[已更正]。

DOI：
发表时间：
2018-10
期刊：
影响因子：
0
作者：
Apps, Richard;Hawkes, Richard;Aoki, Sho;Bengtsson, Fredrik;Brown, Amanda M;Chen, Gang;Ebner, Timothy J;Isope, Philippe;Jörntell, Henrik;Lackey, Elizabeth P;Lawrenson, Charlotte;Lumb, Bridget;Schonewille, Martijn;Sillitoe, Roy V;Spaeth, Ludov
通讯作者：
Spaeth, Ludov

Genetically eliminating Purkinje neuron GABAergic neurotransmission increases their response gain to vestibular motion.

从基因上消除浦肯野神经元 GABA 能神经传递增加了它们对前庭运动的反应增益。