MECHANISMS OF EPILEPTOGENESIS

癫痫是一种慢性神经系统疾病，影响着美国约1%的人口。虽然通常很容易用药物治疗，但约25-30%的癫痫患者在接受多种药物治疗后仍会反复发作。一种非常常见的难以控制的人类癫痫是内侧颞叶癫痫综合征，它涉及到海马体、内嗅皮层和杏仁核等边缘结构。了解这种情况的病理生理基础对于改进治疗方法的发展至关重要。人体研究表明，癫痫发作的过程可能涉及多个部位。在这种情况下，癫痫发作通常同时发生在几个边缘部位。这些观察结果提高了癫痫发作可能部分通过皮层下机制触发的可能性，该机制输入到多个边缘结构。直到最近，随着几种新的边缘癫痫大鼠模型的发展，这一想法才得以验证，这些模型与人类的情况相似。这些边缘癫痫模型的特点是自发发作以及脑电图上的边缘病理和发作生理学与人类状态（内侧颞叶癫痫）在形态学上相似。已完成或即将完成的工作表明，所有被证明参与癫痫发作的边缘部位对刺激都有过度兴奋的反应。更重要的是，我们最近发现，丘脑中线核对这些区域（杏仁核、海马体和内嗅皮层）有显著的兴奋性输入。我们还发现丘脑中线核参与并可能调节边缘系统的癫痫发作活动。这些观察结果表明，这些丘脑区域可能在癫痫发作的开始和调节中起重要作用。在本项目中，我们拟评估丘脑中线核在边缘癫痫发作和癫痫中的作用，以回答以下问题：1)丘脑中线核在边缘癫痫发作和癫痫中起什么作用，以回答以下问题：2)丘脑中线核与其边缘靶点之间的相互作用在边缘癫痫中是如何改变的？3)慢性边缘癫痫时丘脑中线核的生理变化是怎样的？这些实验将结合几种大鼠边缘癫痫模型（包括慢性边缘癫痫）的体外和体内生理学来研究这些问题，这是了解该区域在边缘癫痫中的作用的第一步。这些结果将为这些条件下的网络变化提供新的见解和依据。

Epilepsy is a chronic neurological condition that affects about 1% of the population in the United States. Although it is usually readily treatable with medications, about 25-30% of epileptic patients continue to experience recurrent seizures in spite of multiple drug therapy. A very common form of difficult to control human epilepsy is the mesial temporal lope epilepsy syndrome, which involves limbic structures such as the hippocampus, entorhinal cortex and amygdala. Understanding the pathophysiological basis for this condition is essential for the development of improved treatments. Human studies have suggested that the process of seizure initiation may involve multiple sites. In these situations the seizures often begin simultaneously at several of the limbic sites. These observations raise the possibility that seizure onset may be triggered in part through a subcortical mechanism that has input to multiple limbic structures. Testing this idea has not been possible until recently with the development of several new rat models of limbic epilepsy that have similarities to the human condition. These limbic epilepsy models are characterized by spontaneous seizures as well as limbic pathology and seizure physiology on EEG that are morphologically similar to the human condition (mesial temporal lobe epilepsy). Work completed or nearing completion has suggested that all of the limbic sites demonstrated to participate in seizure onset have hyperexcitable responses to stimulation. More importantly, we have recently discovered that the midline thalamic nuclei have significant excitatory input to these areas (amygdala, hippocampus and entorhinal cortex). We have also found that the midline thalamic nuclei participate in, and may regulate, the seizure activity in the limbic system. These observations suggest that these thalamic regions may have an important role in seizure initiation and modulation. In this project we propose to evaluate the role of the midline thalamic nuclei in limbic seizures and epilepsy to answer the following questions: 1) What role does the midline thalamic nuclei play in limbic seizures and epilepsy to answer the following questions: 2) How are the interactions between the midline thalamic nuclei and its limbic targets altered in limbic epilepsy? 3) How is the physiology of the midline thalamic nuclei changed in chronic limbic epilepsy? These experiments will combine in vitro and in vivo physiology of several rat models of limbic seizures, including chronic limbic seizures, to examine these issues, which are the first steps to understanding the role of this region in limbic epilepsy. These results will provide new insights into the network changes and basis for these conditions.