Mechanisms of Epileptogenesis

描述（由申请人提供）： 难治性癫痫仍然是一个重要的问题，内侧颞叶癫痫（MTLE），也称为慢性边缘癫痫（CLE），是一种常见的癫痫综合征，往往是难治性的。虽然我们对与癫痫发作的各个阶段相关的几个大脑区域了解很多，但对这些特定区域在癫痫发作的起始中所起的特定作用，或者它们如何与癫痫发作回路的其他可能组件相互作用，却知之甚少。了解这些信息对于理解边缘系统癫痫的病理生理学和靶向治疗至关重要。为了研究这一问题，必须在完整的系统中研究缉获情况。在这个项目中，我们建议评估的几个候选电路和区域的作用，在边缘癫痫发作的启动和推广：三突触的丘脑-内嗅环和内侧背侧丘脑核-边缘电路。具体来说，我们将测试的假设，一个或两个是在癫痫发作的开始和癫痫发作的蔓延到大脑的其他部分的关键因素。我们还将研究是否有可能通过刺激这些部位的传入神经来调节癫痫发作。在项目结束时，我们将确定边缘癫痫发作演变的关键控制点，以及利用这些点改进治疗的可能方法。公共卫生相关性：在这个应用程序中，我们建议检查网络的相互作用，在边缘癫痫发作的启动和泛化。虽然参与癫痫发作的大脑区域是众所周知的，但不同部分如何参与以及它们如何相互作用还不清楚。这些信息对于识别治疗目标和指导未来研究癫痫发作回路的关键要素至关重要。我们将使用几种体内癫痫发作模型，包括自发性边缘癫痫发作模型，以梳理出完整神经系统中每个癫痫发作阶段的各种组成部分。

DESCRIPTION (provided by applicant): Intractable epilepsy remains a significant problem, and mesial temporal lobe epilepsy (MTLE), also known as chronic limbic epilepsy (CLE), is a common epilepsy syndrome that is frequently intractable. Although much is known about several regions of the brain that are associated with various stages of the seizures, little is known about the specific roles these particular regions play in the initiation of seizures, or how they interact with the other likely components of the seizure circuits. Knowing this information is essential for understanding the pathophysiology of limbic epilepsy and for targeting therapy. To examine this issue, seizures have to be studied in intact systems. In this project we propose to evaluate the roles of several candidate circuits and regions in the initiation and generalization of limbic seizures: the trisynaptic hippocampal-entorhinal loop and the medial dorsal thalamic nucleus-limbic circuits. Specifically we will test the hypotheses that one or both are key elements in the initiation of the seizures and the spread of seizures to other parts of the brain. We will also examine whether it is possible to modulate seizures by stimulation of afferents to these sites. At the end of the project we will have identified key control points in the evolution of limbic seizures and possible ways to use these points for improved therapies. PUBLIC HEALTH RELEVANCE: In this application we are proposing to examine the network interactions that underlie seizure initiation and generalization in limbic epilepsy. Although the brain regions that are involved in seizures are well known, how the different parts get involved and how they interact with one another is not well understood. This information is essential for the identification of targets for therapy and for directing future research to the key elements of the seizure circuits. We will use several in vivo seizure models, including a model with spontaneous limbic seizures to tease out the various components of each seizure stage in an intact nervous system.