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，通常是难治性的。尽管我们对大脑中与癫痫发作不同阶段相关的几个区域了解甚多，但对这些特定区域在癫痫发作中所起的具体作用，以及它们如何与癫痫发作回路的其他可能组成部分相互作用知之甚少。了解这些信息对于理解边缘癫痫的病理生理学和靶向治疗是必不可少的。为了研究这个问题，癫痫发作必须在完整的系统中进行研究。在这个项目中，我们建议评估几个候选回路和区域在边缘癫痫发作的启动和推广中的作用：三突触海马-内鼻环和内侧背丘脑核-边缘回路。具体来说，我们将测试一种或两种假设，即一种或两种是癫痫发作的关键因素，以及癫痫发作扩散到大脑其他部位的关键因素。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过程中的关键控制点，以及利用这些控制点改进治疗方法的可能方法。公共卫生相关性：在这项应用中，我们建议研究边缘癫痫发作开始和普遍化的基础网络相互作用。虽然大脑中与癫痫发作有关的区域是众所周知的，但不同的部分是如何参与的，以及它们是如何相互作用的，我们还不太清楚。这些信息对于确定治疗目标和指导未来研究癫痫回路的关键要素至关重要。我们将使用几种体内发作模型，包括一个自发边缘发作模型，以梳理出完整神经系统中每个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.