Adult-onset Purkinje cell loss in cerebellar dysfunction

小脑功能障碍中成人发病的浦肯野细胞丢失

基本信息

批准号：
10676782
负责人：
Sarah Donofrio
金额：
$ 5.02万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676782
关键词：
Accelerometer Address Adult Affect Anatomy Animal Model Architecture Ataxia Automobile Driving Autopsy Behavior Behavioral Brain imaging Categories Cause of Death Cell Death Cells Cerebellar Ataxia Cerebellar Diseases Cerebellar Nuclei Cerebellar degeneration Cerebellum Cessation of life Clinical Consensus Data Deep Brain Stimulation Defect Deterioration Development Developmental Gene Disease Dystonia Electromyography Electrophysiology (science)Environment Essential Tremor Fellowship Genetic Goals Human Human Pathology Imaging Techniques Immunohistochemistry Individual Label Laboratories Lead Link Measures Modeling Molecular Motor Mus Muscle Contraction Mutation Nerve Degeneration Neuroanatomy Neuronal Dysfunction Output Pathologic Pathology Patients Pattern Periodicity Phenotype Posture Purkinje Cells Research Personnel Resolution Resources Rodent Role Shapes Symptoms Testing Tissue Sample Training Tremor Work Writing awake behavior test behavioral outcome cell type comorbidity design end stage disease experience experimental study functional outcomes human imaging immunohistochemical markers in vivo motor behavior motor disorder mouse genetics mouse model nervous system disorder neural optogenetics response targeted treatment time use

项目摘要

PROJECT SUMMARY/ABSTRACT Neurodegeneration underlies many major neurological diseases. Cerebellar Purkinje cell degeneration is a hallmark of ataxia, a disorder that entails poor motor coordination. However, a growing consensus argues that conditions traditionally thought of as circuit disorders, such as tremor and dystonia, may also involve cerebellar degeneration. This debate is due in part to technical limitations. Current human imaging techniques lack the single-cell resolution necessary to reveal localized cell loss, and postmortem studies only inform the end-state of disease and suffer from a scarcity of tissue samples, particularly from dystonia patients. Meanwhile, rodent work suggests that Purkinje cell loss has diverse effects on behavior, although these studies often involve the disruption of multiple cell types and prolonged developmental deficits, which make directly attributing behavioral outcomes to Purkinje cell death difficult. To address these challenges, we use a genetic mouse model that initiates Purkinje cell-specific death with temporal precision. Preliminary data suggests that adult-onset Purkinje cell death causes progressive motor dysfunction that transitions through ataxia, tremor, and dystonia. This proposal tests the hypothesis that Purkinje cell loss drives progressive functional changes that uniquely impact motor behavior. Different regions of the cerebellum control distinct behaviors. Therefore, the first aim tests whether adult-onset Purkinje cell loss causes behavioral defects depending on the region affected. A battery of behavioral tests will track how motor dysfunction emerges, and immunohistochemistry and neural tracing will reveal how cerebellar circuit architecture changes with degeneration and motor function deterioration. The second aim tests how progressive Purkinje cell loss impacts the firing activity of the cerebellar nuclei, which receive Purkinje cell input and project to other parts of the motor circuit. In vivo electrophysiological recordings from the cerebellar nuclei of awake mice experiencing degeneration-induced motor defects will be used to determine how Purkinje cell loss dynamically shapes neuronal dysfunction. In addition, this aim will determine whether the beneficial effects of deep brain stimulation to the cerebellar nuclei in motor dysfunction hold true during Purkinje cell loss. The completion of these aims will define the impact of Purkinje cell death in ataxia, tremor, and dystonia and the mechanisms by which a single insult to a circuit can exert diverse consequences on motor function. The fellowship training plan includes designing and performing these experiments, analyzing the data, and writing and presenting the work in a supportive, resource-filled training environment.

项目概要/摘要神经变性是许多主要神经系统疾病的基础。小脑浦肯野细胞变性是共济失调的标志，一种导致运动协调不良的疾病。然而，越来越多的共识认为传统上被认为是回路疾病的病症，例如震颤和肌张力障碍，也可能涉及小脑退化。这场争论的部分原因是技术限制。目前的人类成像技术缺乏揭示局部细胞损失所需的单细胞分辨率，而尸检研究只能告知最终状态疾病并缺乏组织样本，尤其是肌张力障碍患者的组织样本。与此同时，啮齿动物研究表明，浦肯野细胞损失对行为有多种影响，尽管这些研究通常涉及多种细胞类型的破坏和长期的发育缺陷，这使得直接归因于行为浦肯野细胞死亡的结果很困难。为了应对这些挑战，我们使用基因小鼠模型以时间精度启动浦肯野细胞特异性死亡。初步数据表明，成人发病的浦肯野病细胞死亡会导致进行性运动功能障碍，进而导致共济失调、震颤和肌张力障碍。这该提案测试了浦肯野细胞损失导致渐进性功能变化的假设，这些变化独特地影响运动行为。小脑的不同区域控制着不同的行为。因此，第一个目标测试成人发病的浦肯野细胞丢失是否会导致行为缺陷取决于受影响的区域。一块电池行为测试将追踪运动功能障碍如何出现，免疫组织化学和神经追踪将揭示小脑回路结构如何随着退化和运动功能恶化而变化。这第二个目标测试进行性浦肯野细胞丢失如何影响小脑核的放电活动，接收浦肯野细胞输入并投射到运动电路的其他部分。体内电生理记录来自经历退化引起的运动缺陷的清醒小鼠的小脑核将被用于确定浦肯野细胞损失如何动态地影响神经元功能障碍。此外，这个目标将决定深部脑刺激对小脑核对运动功能障碍的有益作用是否成立浦肯野细胞丢失期间。这些目标的完成将确定浦肯野细胞死亡对共济失调的影响，震颤、肌张力障碍以及对电路的一次损伤可能产生不同后果的机制关于运动功能。奖学金培训计划包括设计和执行这些实验、分析数据，并在支持性的、资源丰富的培训环境中撰写和展示工作。