Mechanisms of Epileptogenesis

描述(申请人提供)：顽固性癫痫仍然是一个重要的问题，内侧颞叶癫痫(MTLE)，也被称为慢性边缘癫痫(CLE)，是一种常见的癫痫综合征，通常是难治性的。虽然人们对大脑中与癫痫发作不同阶段相关的几个区域知之甚少，但对于这些特定区域在癫痫发作的启动中所起的具体作用，或者它们如何与癫痫发作回路的其他可能组成部分相互作用，人们知之甚少。了解这些信息对于了解边缘癫痫的病理生理学和靶向治疗至关重要。为了审查这一问题，必须在完整的系统中研究癫痫发作。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的起始和泛化中的作用：三突触海马-内嗅环和丘脑内侧背核-边缘回路。具体地说，我们将检验这样的假设，即一个或两个都是癫痫发作的启动和癫痫发作扩散到大脑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来调节癫痫发作。在项目结束时，我们将确定边缘癫痫演变中的关键控制点，以及使用这些控制点改进治疗的可能方法。公共卫生相关性：在这项应用中，我们建议检查边缘癫痫发作启动和泛化的基础网络相互作用。虽然参与癫痫发作的大脑区域是众所周知的，但不同的部分是如何参与的，以及它们如何相互作用还不是很清楚。这一信息对于确定治疗目标和指导今后对癫痫发作回路关键要素的研究至关重要。我们将使用几个活体癫痫模型，包括一个自发边缘癫痫的模型，以梳理出完整神经系统中每个癫痫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.