Hippocampal Network Structure and Function in Epilepsy

癫痫中的海马网络结构和功能

• 批准号: 6929906
• 负责人: Robert S Sloviter
• 金额: $ 45.64万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929906
• 关键词: biomarker; brain electrical activity; brain mapping; brain septal area; cell population study; dentate gyrus; disease /disorder model; electrodes; fluorescence microscopy; hippocampus; immunocytochemistry; immunoelectron microscopy; interneurons; laboratory rat; model design /development; mossy fiber; neural inhibition; neural plasticity; neural transmission; neuroanatomy; neurophysiology; neurotoxins; partial seizure; temporal lobe /cortex disorder

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is a common and devastating neurological disorder that is often resistant to treatment. Although spontaneous epileptic seizures are believed to arise from an altered circuit within the temporal lobe, the nature of the causal network defect remains unidentified. The proposed experimental studies have been designed to elucidate the normal functional and structural organization of the hippocampus, with particular emphasis on the lamellar organization of this epileptogenic brain region. One hypothesis suggests that hippocampal segments are functionally separated from adjacent segments by translamellar inhibitory mechanisms, and that the breakdown of inhibitory barriers causes the formation of hyperexcitable "supersegments." This hypothesis will be addressed in a series of studies designed to demonstrate translamellar inhibition electrophysiologically, to identify the neurons that form the longitudinal projections that establish and maintain translamellar inhibition, and to determine whether loss of vulnerable interneurons causes translamellar disinhibition. Other studies will address the role of septal neurons in establishing lamellar hippocampal function. A second hypothesis predicts that synaptic reorganization forms abnormal connections between normally unconnected excitatory hippocampal neurons and that these interconnections give rise to hippocampal seizure discharges. A series of parallel electrophysiological studies in awake, chronically implanted animals will describe for the first time whether spontaneous epileptic seizures arise from the hippocampus, and will utilize a molecular marker of excitation to identify the neurons that are discharging in the most commonly used epilepsy models. Continuous electrophysiological monitoring will also determine the behavior of hippocampal neuron populations before and after injury, before and after injury-induced synaptic reorganization, and before and after the development of spontaneous seizures. New preliminary data indicating that human patients may have a pre-existing region of focal disinhibition will be used to develop several new models of temporal lobe epilepsy. These studies, which utilize a newly developed neurotoxin that selectively removes inhibitory interneurons in a highly focal region, will address the possibility that new animal models that may more closely approximate the human condition may be useful for detecting new pharmacological treatments for what remains a frequently drug-resistant neurological disorder.

描述（由申请人提供）：颞叶癫痫是一种常见且具有破坏性的神经系统疾病，通常对治疗有抵抗力。尽管自发性癫痫发作被认为是由颞叶内的回路改变引起的，但因果网络缺陷的性质仍不清楚。拟议的实验研究旨在阐明海马体的正常功能和结构组织，特别强调该致癫痫脑区域的层状组织。一种假设表明，海马节段通过跨层抑制机制与相邻节段在功能上分开，并且抑制屏障的破坏导致过度兴奋的“超节段”的形成。这一假设将在一系列研究中得到解决，这些研究旨在从电生理学角度证明跨层抑制，识别形成建立和维持跨层抑制的纵向投影的神经元，并确定脆弱中间神经元的损失是否会导致跨层抑制去抑制。其他研究将探讨间隔神经元在建立层状海马功能中的作用。第二个假设预测，突触重组在通常不连接的兴奋性海马神经元之间形成异常连接，并且这些互连引起海马癫痫放电。对清醒、长期植入的动物进行的一系列平行电生理学研究将首次描述自发性癫痫发作是否由海马体引起，并将利用兴奋分子标记来识别最常用癫痫模型中放电的神经元。连续的电生理监测还将确定海马神经元群在损伤前后、损伤引起的突触重组前后以及自发性癫痫发作前后的行为。新的初步数据表明人类患者可能具有预先存在的局灶性去抑制区域，将用于开发几种新的颞叶癫痫模型。这些研究利用新开发的神经毒素，选择性地去除高度集中区域的抑制性中间神经元，将解决这样一种可能性：更接近人类状况的新动物模型可能有助于检测新的药物治疗方法，以治疗经常耐药的神经系统疾病。