Inhibitory single neuron control of human epilepsy

人类癫痫的抑制性单神经元控制

基本信息

批准号：
8649376
负责人：
Omar Jamil Ahmed
金额：
$ 5.39万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8649376
关键词：
Action Potentials Adverse effects Affect American Animal Model Animals Area Basic Science Behavior Brain Brain region Cells Clinical Clinical Research Data Data Analyses Data Set Devices Electrocorticogram Electroencephalography Epilepsy Fire - disasters Focal Seizure Genetic Research Goals Hand Human Human Activities Individual Interneurons Intervention Intractable Epilepsy Knowledge Lead Learning Link Magnetic Resonance Imaging Mentors Methods Mus Neocortex Neurologic Neurons Operative Surgical Procedures Partial Epilepsies Patients Phase Play Process Research Role Runaway Seizures Signal Transduction Single Seizures Slice Source Stereotyping Sum Surgeon Techniques Testing Time Training Travel Work brain cell career design effective therapy excitatory neuron human data in vivo inhibitory neuron mouse model neocortical novel optogenetics prevent public health relevance skills theories

项目摘要

DESCRIPTION (provided by applicant): Epilepsy is an often debilitating neurological condition affecting 3 million Americans and more than 50 million people across the globe. Despite several decades of excellent clinical, genetic and basic research and the existence of dozens of animal models and hypotheses, the mechanisms underlying human focal epilepsy are still not understood. To achieve the "no seizures, no side effects" goal of epilepsy research, we need to first answer a set of fundamental questions: how do focal seizures start, how do they spread, and how do they terminate? In particular, what roles do different subsets of neurons - inhibitory vs excitatory - play in the progression of human seizures? Intracranial electrocorticogram (ECoG) recordings in patients with intractable epilepsy are used to localize the brain region where seizures originate. ECoG signals represent the summed activity of thousands of neurons, and have revealed many important macroscopic features of seizures. However, many of the mechanistic predictions arising from animal models of epilepsy are at the level of individual neurons, and cannot be tested using ECoG alone. Here, specially designed recording techniques and devices are used to safely record the simultaneous activity of hundreds of individual neurons during seizures directly in patients with pharmacoresistant focal epilepsy. It i then possible to selectively identify human inhibitory neurons and ask how they control seizures. Many animal and slice studies state that decreased inhibition leads to seizures. However, many others state that increased inhibition is necessary to synchronize activity before a seizure can occur. Direct recordings of these inhibitory interneurons from humans present a unique opportunity to resolve this debate. By carefully identifying human inhibitory interneurons it is possible to characterize how they behave during all phases of human seizures. The activity of these human inhibitory interneurons can then be compared to that of different kinds of excitatory cells. The activity of inihibitory neurons can then also be manipulated optogenetically in mouse models of epilepsy to confirm that the human observations linking inhibitory neuron activity and seizure intensity are causal, and not just correlative. This can point the field towards novel pharmacological, surgical and predictive therapies for epilepsy that specifically target particular neuronal subtypes.

描述（由申请人提供）：癫痫病通常是一种令人衰弱的神经系统状况，影响了300万美国人和全球超过5000万人。尽管有数十年的出色临床，遗传和基础研究以及数十种动物模型和假设的存在，但仍不了解人类局灶性癫痫的机制。为了实现癫痫研究的“没有癫痫发作，没有副作用”的目标，我们需要首先回答一组基本问题：焦点癫痫发作如何开始，它们如何传播以及如何终止？特别是，神经元的不同子集（抑制性与兴奋性）在人类癫痫发作的进展中起什么作用？顽固性癫痫患者的颅内皮质图（ECOG）记录用于定位癫痫发作的大脑区域。 ECOG信号代表了数千个神经元的求和活性，并揭示了许多癫痫发作的重要宏观特征。但是，癫痫动物模型引起的许多机械预测都处于单个神经元的水平，不能单独使用ECOG进行测试。在这里，专门设计的记录技术和设备用于在癫痫发作过程中安全记录数百个单个神经元的同时活性，直接在药剂敏感的局灶性癫痫患者中。然后，我有可能选择性地识别人类抑制性神经元并询问它们如何控制癫痫发作。许多动物和切片研究指出，降低抑制作用会导致癫痫发作。但是，许多其他人指出，在发生癫痫发作之前同步活动是必要的。这些抑制性中间神经元的直接记录为解决这一辩论提供了独特的机会。通过仔细识别人类抑制性神经元，可以表征它们在人类癫痫发作的所有阶段中的行为。然后可以将这些人类抑制性中间神经元的活性与不同种类的兴奋性细胞的活性进行比较。然后，在小鼠癫痫模型中也可以通过光遗传来操纵非抑制性神经元的活性，以确认将抑制性神经元活性和癫痫发作强度联系起来的人类观察结果是因果关系，而不仅仅是相关。这可以将领域指向癫痫的新型药理，外科和预测疗法，该疗法专门针对特定神经元亚型。