Mechanisms and Control of Thalamocortical Synchrony in Absence Epilepsy

项目摘要 癫痫诊断和患者个体化治疗策略的基础依赖于对 脑电记录中的刻板印象。这些模式需要同步的大脑活动，因为电信号 信号是相加的，因此当未对准时，峰和谷相互抵消。尽管有这种联系，但 令人惊讶的是，癫痫机制中的神经元同步性尚不清楚。我正在努力测试它的存在 失神癫痫中广泛神经元同步化的起源及其在失神中是否具有因果作用 癫痫的产生。失神发作具有双侧同步棘波放电的突然发作 (SWD)大脑广泛区域的脑电模式。这些癫痫发作依赖于皮质和 丘脑网络，但我们不知道在多大程度上广泛的皮质和丘脑的同步放电 发生，哪些大脑结构参与，或是否有任何直接的因果作用之间的同步 大脑皮质和丘脑缺乏性癫痫的产生或维持。理解的一个基本原则 网络节点之间的同步如下：中的两个节点之间的相似性越大 振荡频率越容易同步。我的中心假设是协调的变化 相同频率的放电频率会促进皮质丘脑的同步化，产生癫痫发作。在目标1中，我 寻求测量和扰动射速，以测试射速是否直接收敛到共同射速 促进它们的同步。我将使用多个高密度硅探测器来测量粒子数 缺勤前和缺勤期间大脑皮质和丘脑各靶区的比率 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神经元子集 以不兼容的发射频率开火，我预测这将排除它在全球范围内的招募 癫痫发作时的同步射击。在目标2中，我试图测试皮质-丘脑同步化的因果作用 在缺席的情况下癫痫发作。我将用卤视紫红质诱导的反弹放电在光遗传学上启动癫痫发作 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。这将为丘脑提供皮质输入 定义相对于SWD的相位和频率，测试皮质同步和/或特异性 丘脑的相对频率调节癫痫的诱发或持续时间。这项工作将是第一次 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 失神发作发生的同步性。这个项目将在两个人的指导下进行 导师，胡格纳德博士指导实验方面的训练，甘古利博士指导理论， 计算和分析技术。通过这种结合的方法以及广泛的机构和 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，用来开始我自己的实验室。

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.