Inhibitory single neuron control of human epilepsy

人类癫痫的抑制性单神经元控制

• 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
• 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

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）：癫痫是一种经常使人衰弱的神经系统疾病，影响300万美国人和地球仪的5000多万人。尽管几十年来进行了出色的临床、遗传和基础研究，并存在数十种动物模型和假说，但人类局灶性癫痫的潜在机制仍不清楚。为了实现癫痫研究的“无癫痫发作，无副作用”的目标，我们需要首先回答一系列基本问题：局灶性癫痫发作如何开始，如何传播，以及如何终止？特别是，不同的神经元亚群--抑制性与兴奋性--在人类癫痫发作的进展中起着什么样的作用？难治性癫痫患者的颅内皮层电图（ECoG）记录用于定位癫痫发作起源的大脑区域。ECoG信号代表了数千个神经元的活动总和，并揭示了癫痫发作的许多重要宏观特征。然而，许多来自癫痫动物模型的机制预测是在单个神经元的水平上，并且不能单独使用ECoG进行测试。在这里，专门设计的记录技术和设备被用来安全地记录数百个单独的神经元在癫痫发作期间的同时活动，直接在耐药性局灶性癫痫患者。然后，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表明，抑制作用减弱会导致癫痫发作。然而，许多其他国家的国家，增加抑制是必要的同步活动之前，癫痫发作可以发生。直接记录这些来自人类的抑制性中间神经元为解决这一争论提供了一个独特的机会。通过仔细识别人类抑制性中间神经元，可以描述它们在人类癫痫发作的所有阶段中的行为。这些人类抑制性中间神经元的活性可以与不同种类的兴奋性细胞的活性进行比较。然后，抑制性神经元的活性也可以在癫痫小鼠模型中进行光遗传学操纵，以证实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，而不仅仅是相关的。这可以将该领域指向针对癫痫的新的药理学，外科手术和预测疗法，这些疗法专门针对特定的 神经元亚型