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.

项目概要 癫痫诊断和针对患者的治疗策略的基础依赖于检测 脑电图记录中的刻板模式。这些模式需要同步的大脑活动，因为电 信号是相加的，因此当未对准时波峰和波谷会相互抵消。尽管存在这种联系，但角色 癫痫机制中的神经元同步性尚不清楚。我正在寻求测试是否存在并且 失神性癫痫中广泛神经元同步的起源并测试它是否在失神性癫痫中具有因果作用 癫痫发作的一代。失神发作具有突然发作的双侧同步尖波放电 （SWD）大脑广泛区域的脑电图模式。这些癫痫发作取决于皮质和 丘脑网络，但我们不知道皮质和丘脑同步放电的广泛程度 发生的情况，涉及哪些大脑结构，或者之间是否存在同步的直接因果作用 皮质和丘脑缺席时癫痫发作的产​​生或维持。理解的基本原则 网络节点之间的同步性如下：两个节点之间的相似度越大 振荡频率越高，它们就越容易同步。我的中心假设是协调变化 放电频率达到共同频率会促进皮质丘脑同步，从而产生癫痫发作。在目标 1 中我 寻求测量和扰动发射率以测试发射率是否直接收敛到共同速率 促进他们的同步。我将使用多个高密度硅探针来测量群体发射 缺席前和缺席期间皮质和丘脑各个目标脑区的比率 癫痫发作。随后，利用化学遗传学，我将迫使给定目标区域内的神经元子集 以不兼容的发射频率开火，我预测这将阻止其在全球范围内招募 癫痫发作期间同步放电。在目标 2 中，我试图测试皮质丘脑同步的因果作用 失神时癫痫发作。我将用盐视紫红质诱导的反弹放电以光遗传学方式启动癫痫发作 如之前所做的那样，丘脑皮层神经元，然后使用视紫红质通道的闭环激活 在相应的皮质丘脑输入轴突中表达。这将为丘脑提供皮质输入 定义相对于 SWD 的相位和频率，测试皮质同步和/或特定 丘脑的相对频率调节癫痫发作的诱发或持续时间。这部作品将首次 证明同步神经元放电的广泛存在和皮质丘脑的因果作用 同步失神发作的产生。该项目将在两位的指导下进行 导师Huguenard博士指导实验方面的训练，Ganguli博士指导理论， 计算和分析技术。通过这种综合方法以及广泛的机构和 在斯坦福大学的专业支持下，我将培养一套非常独特的技能来开始我自己的实验室。