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

• 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
• 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

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.

项目总结/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一种 共济失调的标志，一种运动协调性差的疾病。然而，越来越多的共识认为， 传统上被认为是回路障碍的疾病，如震颤和肌张力障碍，也可能涉及小脑， 退化这一争论部分是由于技术上的限制。目前的人类成像技术缺乏 单细胞分辨率必须揭示局部细胞损失，死后研究仅告知终末状态 疾病和遭受组织样本的稀缺，特别是来自肌张力障碍患者的组织样本。与此同时，啮齿动物 这项研究表明，浦肯野细胞的丧失对行为有不同的影响，尽管这些研究通常涉及到 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是困难的。为了解决这些挑战，我们使用了一种遗传小鼠模型， 以时间精确性启动浦肯野细胞特异性死亡。初步数据显示成人型浦肯野病毒 细胞死亡引起进行性运动功能障碍，其转变为共济失调、震颤和肌张力障碍。这 一项提案检验了浦肯野细胞丢失驱动进行性功能变化的假设， 运动行为小脑的不同区域控制不同的行为。因此，第一个目标测试 成人型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。的电池 行为测试将跟踪运动功能障碍是如何出现的，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退化而变化。的 第二个目标是测试浦肯野细胞的逐渐丧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回路的其他部分。体内电生理记录 来自经历变性诱导的运动缺陷的清醒小鼠的小脑核的细胞将用于 确定浦肯野细胞丢失如何动态地塑造神经元功能障碍。此外，这一目标将决定 脑深部电刺激对运动功能障碍的小脑核的有益作用是否成立 在浦肯野细胞丧失期间。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， 震颤和肌张力障碍以及对回路的单一损伤可产生不同后果的机制 运动功能。研究员培训计划包括设计和执行这些实验，分析 数据，并在一个支持性的，资源丰富的培训环境中编写和展示工作。