Cognitive Deficits After Experimental Febrile Seizures: Neurobiology & Biomarkers

实验性热性惊厥后的认知缺陷：神经生物学

基本信息

批准号：
9912854
负责人：
Tallie Z. Baram
金额：
$ 51.23万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912854
关键词：
Action Potentials Address Adult Affect Affinity Attention Behavior Binding Biological Biological Markers Brain Diseases Cells ChIP-seq Child Childhood Chromatin Chronic Code Cognition Cognitive Cognitive deficits Complex Coupled Defect Development Diffusion Magnetic Resonance Imaging Dimensions Disease Epilepsy Exhibits Experimental Models Febrile Convulsions Fever Functional Magnetic Resonance Imaging Future Gene Expression Gene Family Genes Genetic Genetic Transcription Health Hippocampus (Brain)Impaired cognition Impairment Individual Inflammatory Injury Intervention Laboratories Laboratory Research Learning Learning Disorders Life Measures Mediating Memory Memory Disorders Memory impairment Methods Modeling Molecular Neurobiology Neurons Play Population Positioning Attribute Probability Public Health Pyramidal Cells Quality of life Rattus Recording of previous events Resolution Rest Rodent Model Role Seizures Status Epilepticus Structure Temporal Lobe Epilepsy Testing Therapeutic Translating Translations United States National Academy of Sciences childhood epilepsy cognitive function comorbidity dentate gyrus executive function experimental study functional restoration granule cell improved improved functioning innovation insight multidisciplinary novel prevent tool transcription factor transcriptome sequencing

项目摘要

Project Summary Epilepsy is a complex disorder which involves much more than seizures. It may also be accompanied by a range of associated comorbid health conditions with significant health and quality of life implications as emphasized by the National Academy of Science-sponsored Committee on the Public Health Dimensions of the Epilepsies.1 Our research laboratories have generated a rodent model of experimental febrile status epilepticus (eFSE), which provokes both temporal lobe epilepsy-like seizures and cognitive deficits, thereby providing a powerful tool to probe the mechanisms underlying these conditions. Following eFSE, rats exhibit significant deficits in the active avoidance test—a test of spatial cognition—and show altered hippocampal oscillatory activity and abnormal temporal coding of action potentials when compared with controls. Recently, we identified some of the mechanisms underlying epilepsy-promoting functional changes in the hippocampal network provoked by eFSE. Specifically, we observed coordinated transcriptionally-regulated changes in the expression of multiple genes governing neuronal behavior which resulted from eFSE-induced up-regulated expression and function of the neuron-restrictive silencing factor (NRSF). Remarkably, our preliminary studies indicate that both the cognitive deficits and the neuronal discoordination can be prevented by blocking NRSF following status epilepticus. While the therapeutic implications of our findings are exciting, it is not yet known how eFSE-induced abnormal NRSF activities contribute to disruption of gene expression and maturation of specific cell populations throughout the circuit affected by eFSE. This proposal aims to determine the biological underpinnings of eFSE-induced cognitive deficits at the molecular, single cell and circuit levels, and to establish how NRSF-blockade reverses these deficits. In addition, we will determine if NRSF is involved in memory problems associated with other developmental seizures as this will be a requisite for translation of our discoveries. The proposed multidisciplinary, multidimensional and cutting-edge experiments will address the mechanisms involved in eFSE-induced memory disorders and establish how such disorders can be reversed through genetic methods. These studies will also provide novel insights into mechanisms of memory-circuit maturation and have a potential major impact on a large population of children with febrile status epilepticus.

项目概要癫痫是一种复杂的疾病，不仅仅涉及癫痫发作，它还可能伴有癫痫发作。一系列对健康和生活质量有重大影响的相关合并症健康状况，例如美国国家科学院主办的公共卫生维度委员会强调癫痫.1 我们的研究实验室已经建立了实验性发热状态的啮齿动物模型癫痫（eFSE），它会引起颞叶癫痫样癫痫发作和认知缺陷，从而大鼠在 eFSE 后表现出一种强大的工具来探究这些病症的机制。主动回避测试（空间认知测试）中存在显着缺陷，并显示海马体最近，与对照组相比，振荡活动和动作电位异常时间编码。我们确定了海马体中癫痫促进功能变化的一些机制具体来说，我们观察到转录协调调节的变化。 eFSE 诱导的上调导致控制神经行为的多个基因的表达值得注意的是，我们的初步研究表明神经元限制性沉默因子（NRSF）的表达和功能。表明认知缺陷和神经失调可以通过阻断 NRSF 来预防虽然我们的研究结果的治疗意义令人兴奋，但目前尚不清楚。 eFSE 诱导的异常 NRSF 活性如何导致基因表达破坏和成熟该提案旨在确定整个电路中受 eFSE 影响的特定细胞群。在分子、单细胞和回路水平上研究 eFSE 诱导的认知缺陷的基础，并确定 NRSF 封锁如何扭转这些赤字。此外，我们将确定 NRSF 是否参与其中。与其他发育性癫痫发作相关的记忆问题，因为这将是翻译我们的拟议的多学科、多维度和前沿实验将解决这些问题。 eFSE 诱发的记忆障碍的机制，并确定如何逆转此类障碍通过遗传方法，这些研究还将为记忆回路的机制提供新的见解。成熟并对大量患有发热性癫痫持续状态的儿童产生潜在的重大影响。