Mechanisms and Control of Thalamocortical Synchrony in Absence Epilepsy

失神癫痫丘脑皮质同步性的机制和控制

• 批准号: 10534110
• 负责人: Jacob M Hull
• 金额: $ 3.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534110
• 关键词: Absence Epilepsy; Area; Axon; Behavior; Bilateral; Binding; Brain; Cell Nucleus; Characteristics; Clinical; Communication; Conscious; Cortical Synchronization; Dependovirus; Detection; Diagnosis; Disease; Electrodes; Electroencephalography; Epilepsy; Evolution; Fiber; Fiber Optics; Fire - disasters; Foundations; Frequencies; Generations; Genetic; Halorhodopsins; Hyperactivity; Impairment; Institution; Intuition; Knowledge; Laboratories; Maintenance; Mathematics; Measures; Mentors; Modeling; Mus; Neurons; Operative Surgical Procedures; Opsin; Output; Patients; Pattern; Phase; Population; Probability; Rattus; Rodent; Role; SCN8A gene; Sampling; Seizures; Signal Transduction; Silicon; Site; Somatosensory Cortex; Stereotyping; Structure; Synapses; Target Populations; Techniques; Testing; Thalamic Nuclei; Thalamic structure; Time; Training; Transfection; Work; association cortex; density; designer receptors exclusively activated by designer drugs; improved; individualized medicine; loss of function; mouse model; neural; optical fiber; optogenetics; recruit; response; skills; treatment strategy

Project Summary The foundation of epilepsy diagnosis and patient-tailored treatment strategies relies on the detection of stereotyped patterns in EEG recordings. These patterns require synchronous brain activity because electrical signals are additive, and thus peaks and troughs cancel when misaligned. Despite this connection, the role of neuronal synchrony in epilepsy mechanisms is surprisingly unclear. I am seeking to test for the presence and origin of widespread neuronal synchronization in absence epilepsy and test if it has a causal role in absence seizure generation. Absence seizures have an abrupt onset of bilaterally synchronous spike wave discharge (SWD) EEG pattern across widespread areas of the brain. These seizures depend on both cortical and thalamic networks but we do not know to what degree widespread cortical and thalamic synchronous firing occurs, which brain structures are involved, or if there is any direct causal role of synchronization between cortex and thalamus in absence seizure generation or maintenance. A fundamental principle for understanding synchronization between network nodes is the following: the greater the similarity between the two nodes in oscillation frequencies, the more readily they synchronize. My central hypothesis is that coordinated changes in firing rates to a common frequency promotes corticothalamic synchronization, generating seizures. In aim 1 I seek to measure and perturb firing rates to test whether firing rate convergences to a common rate directly promote their synchronization. I will use multiple high density silicon probes to measure the population firing rates of various target brain areas in the cortex and thalamus in the times leading up to and during absence seizures. Subsequently, using chemogenetics, I will force a subset of neurons within a given target region to fire at an incompatible firing frequency, which I predict will preclude its recruitment into this otherwise globally synchronous firing during a seizure. In aim 2, I seek to test for a causal role of corticothalamic synchronization in absence seizures. I will initiate seizures optogenetically with halorhodopsin induced rebound firing in thalamocortical neurons as has been done previously, and then use closed loop activation of channelrhodopsin expressed in the corresponding corticothalamic input axons. This will provide cortical input to the thalamus at defined phases and frequencies relative to the SWDs, testing whether cortical synchronization and/or specific relative frequencies with thalamus regulates seizure induction or duration. This work will for the first time demonstrate both the widespread presence of synchronous neuronal firing and a causal role of corticothalamic synchronization in absence seizure generation. This project will be performed under the guidance of two mentors, Dr. Huguenard guiding training in experimental aspects and Dr. Ganguli guiding theoretical, computational, and analysis techniques. With this combined approach along with extensive institution and professional support at Stanford, I will develop a highly unique skillset with which to begin my own laboratory.

项目摘要 癫痫诊断和患者定制治疗策略的基础依赖于对癫痫的检测。 脑电图记录中的模式化模式这些模式需要同步的大脑活动， 信号是相加的，因此当未对准时峰和谷抵消。尽管有这种联系， 癫痫机制中的神经元同步性令人惊讶地不清楚。我想测试一下 失神癫痫中广泛神经元同步的起源和测试它是否在失神癫痫中起因果作用 癫痫发作一代。失神发作突然出现双侧同步棘波放电 (SWD)脑电图模式遍布大脑的各个区域。这些癫痫发作取决于皮质和 但我们不知道广泛的皮层和丘脑同步放电的程度 发生，哪些大脑结构参与，或者是否有任何直接的因果关系之间的同步作用， 皮质和丘脑在失神发作的产生或维持。理解的基本原则 网络节点之间的同步如下： 振荡频率越高，它们就越容易同步。我的核心假设是协调的变化 在放电率的共同频率促进皮质丘脑同步，产生癫痫发作。在目标1 I中 试图测量和扰动点火率，以测试点火率是否直接收敛到公共速率 促进他们的同步。我将使用多个高密度硅探针来测量群体放电 在缺席之前和缺席期间，皮质和丘脑中各种目标脑区的比率 癫痫发作随后，使用化学遗传学，我将迫使给定目标区域内的一部分神经元， 以不兼容的发射频率发射，我预测这将阻止它在全球范围内招募 癫痫发作时的同步放电在目标2中，我试图测试皮质丘脑同步化的因果作用 在失神发作中我将用盐视紫红质诱导的反弹放电启动癫痫发作， 丘脑皮质神经元，如先前所做的，然后使用通道视紫红质的闭环激活 在相应的皮质丘脑输入轴突中表达。这将为丘脑提供皮层输入， 定义相对于SWD的相位和频率，测试皮质同步和/或特定 与丘脑的相对频率调节癫痫发作的诱导或持续时间。这项工作将首次 证明了同步神经元放电的广泛存在和皮质丘脑的因果作用， 同步在缺席发作的产生。该项目将在两个指导下进行 导师，Huguenard博士指导实验方面的培训，Ganguli博士指导理论， 计算和分析技术。通过这种结合的方法，沿着广泛的机构和 在斯坦福大学的专业支持下，我将发展一套非常独特的技能，开始我自己的实验室。