Cerebellar modulation of seizures through the cerebello-thalamo-cortical pathway

小脑通过小脑-丘脑-皮质通路对癫痫发作的调节

• 批准号: 9909173
• 负责人: Jaclyn Beckinghausen
• 金额: $ 4.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909173
• 关键词: Ablation; Absence Epilepsy; Affect; Age; Alzheimer' s Disease; Anatomy; Animal Model; Area; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Brain; Brain Diseases; Brain region; Cell Nucleus; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Child; Clinic; Clinical; Clonus; Convulsions; Data; Deep Brain Stimulation; Disease; Disease Outbreaks; Drug Targeting; Drug resistance; Elderly; Electroencephalography; Electrophysiology (science); Epilepsy; Face; Forelimb; Frequencies; Functional disorder; Future; Ganglioglioma; Gender; Healthcare; Human; Injections; Interruption; Involuntary Movements; Lidocaine; Light; Literature; Maintenance; Measures; Mediating; Methods; Migraine; Modeling; Motor; Movement; Mus; Neurologic; Neurons; Neurophysiology - biologic function; Output; Pathology; Pathway interactions; Patients; Pattern; Periodicity; Pharmacology; Physiologic pulse; Physiological; Posture; Quality of life; Recovery; Reporting; Reproducibility; Risk Factors; Role; Seizures; Severities; Signal Transduction; Site; Source; Specificity; Stroke; Structure; Tail; Techniques; Testing; Thalamic Nuclei; Thalamic structure; Time; Tonic - clonic seizures; Training; Ventroposterior Medial Nucleus of the Thalamus; Viral; Work; base; comorbidity; design; driving behavior; effective therapy; experimental study; extracellular; human model; improved; in vivo; kainate; mouse model; nervous system disorder; neural circuit; novel; novel therapeutics; optogenetics; prevent; relating to nervous system; therapeutic target

PROJECT SUMMARY/ABSTRACT Seizures are a devastating and often fatal neurological condition that manifests as a standalone disease or as a comorbidity in other debilitating conditions. Unfortunately, treatments are often ineffective, in part because the neural origins of seizures are unclear. As a first step towards identifying seizure loci in the brain, I designed an optogenetic approach in mice that provides a versatile method for generating severe seizures. This approach allows me to test whether specific brain regions have the capacity to initiate seizures and interrogate the circuit mechanisms underlying seizure propagation and maintenance. The seizure model I generated is based on controlling the function of neural circuits in a brain region called the cerebellum, now considered the hub for all motor functions and a central target in a growing list of brain diseases. There is an extensive literature implicating cerebellar dysfunction in epilepsy: in particular, its output may drive the uncontrollable movements during seizures. Using optogenetics, I have identified a cerebellar receiving region of the thalamus, the ventral posteromedial nucleus (VPM), as a powerful region of seizure initiation. The VPM is a major point of convergence of cerebellar and basal ganglia circuitry and could therefore mediate involuntary movements in several diseases. Delivery of light pulses to the VPM in channelrhodopsin-expressing mice elicits immediate, reproducible seizures that begin with myoclonic forelimb movements that progress to severe full body convulsions. I tested the specificity of the VPM as the main locus driving the behavior by stimulating surrounding thalamic nuclei and did not observe obvious behavioral abnormalities. Furthermore, the duration and severity of these optogenetic induced seizures worsens upon repeated stimulation over days. Interestingly, these behaviors are reminiscent of clinical reports that human seizures worsen and become more frequent following the first outbreak. My data raise the intriguing hypothesis that a discrete pool of neurons in the VPM may be a fulcrum site for seizures, into which the cerebellum provides a powerful stimulatory role that controls seizure severity. To test this hypothesis, I will use mice to determine the features of seizure pathophysiology (Aim1), test how cerebellar circuits interact with the thalamus and other regions to generate seizures (Aim2), and uncover the cellular firing mechanisms that produce seizures (Aim3). The experiments in each aim will include state-of-the-art anatomical and in vivo physiological techniques. The completion of these aims will call for a reevaluation of subcortical structures in seizure genesis, especially since the cerebellum was one of the first targets for deep brain stimulation in the treatment of epilepsy. The availability of new therapeutic brain targets for drug-resistant epilepsy will provide alternate healthcare considerations for reducing the impact of severe seizures and improving the quality of life of affected patients.

项目总结/摘要 癫痫发作是一种毁灭性的，往往是致命的神经系统疾病，表现为一种独立的疾病， 合并其他衰弱性疾病。不幸的是，治疗往往无效，部分原因是 癫痫发作的神经起源尚不清楚。作为确定大脑中癫痫发作部位的第一步，我设计了 一种小鼠的光遗传学方法，提供了一种产生严重癫痫发作的通用方法。这 这种方法使我能够测试特定的大脑区域是否有能力启动癫痫发作和询问 癫痫传播和维持的电路机制。我生成的癫痫模型是 基于控制被称为小脑的大脑区域的神经回路的功能，现在被认为是 大脑是所有运动功能的中枢，也是越来越多的脑部疾病的中心目标。有一个广泛 癫痫患者小脑功能障碍的文献：特别是，它的输出可能会驱动无法控制的 癫痫发作时的运动利用光遗传学，我已经确定了丘脑的小脑接收区， 腹后内侧核（VPM），作为一个强大的癫痫发作启动区域。VPM是一个主要的问题， 小脑和基底神经节电路的会聚，因此可以介导不自主运动， 几种疾病。将光脉冲传递到表达通道视紫红质的小鼠的VPM中， 开始为肌阵挛性前肢运动的可重复性癫痫发作，进展为严重的全身性癫痫 抽搐我测试了VPM作为驱动行为的主要位点的特异性， 周围丘脑核，并没有观察到明显的行为异常。此外，持续时间 和这些光遗传学诱导的癫痫发作的严重程度。有趣的是， 这些行为让人联想到临床报告，人类癫痫发作恶化并变得更频繁 在第一次爆发之后。我的数据提出了一个有趣的假设，即VPM中有一个离散的神经元库 可能是癫痫发作的支点，小脑提供了强大的刺激作用， 癫痫严重程度。为了验证这一假设，我将使用小鼠来确定癫痫发作的病理生理学特征 （目标1），测试小脑回路如何与丘脑和其他区域相互作用以产生癫痫发作（目标2）， 并揭示产生癫痫发作的细胞放电机制（Aim 3）。每个目标的实验将 包括最先进解剖学和体内生理学技术。要实现这些目标， 重新评估癫痫发作发生中的皮质下结构，特别是因为小脑是癫痫发作的重要机制之一。 脑深部电刺激治疗癫痫的第一个目标。新的治疗大脑的可用性 耐药性癫痫的目标将提供替代的医疗保健考虑，以减少 严重癫痫发作和改善受影响患者的生活质量。