Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis

创伤诱发癫痫发生的多尺度建模和大规模记录

基本信息

批准号：
10229375
负责人：
TERRENCE J SEJNOWSKI
金额：
$ 60.16万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2018-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229375
关键词：
Acute Affect Age American Anatomy Animals Area Astrocytes Brain Canada Cell Compartmentation Cellular Morphology Cellular Structures Cerebrum Chronic Clinical Computer Models Craniocerebral Trauma Cyclic AMP Data Deafferentation procedure Development Direct Costs Electric Stimulation Electrophysiology (science)Elements Epilepsy Epileptogenesis Equilibrium Facilities and Administrative Costs Felis catus Foundations Goals Hodgkin-Huxley model Hour Human In Vitro Institutes Intervention Laboratories Lead Letters Long-Term Effects Measurement Methods Modeling Morphology Mus Neocortex Neurons Outcome Pathologic Pathology Pathway interactions Patients Pattern Penetrating Wounds Pharmacogenetics Physiological Preparation Prevention Process Property Recovery Regulation Reporting Research Seizures Signal Transduction Slice Synapses Synaptic Potentials TNF gene Techniques Testing Trauma Traumatic Brain Injury Universities Up-Regulation age related base biophysical properties cell type cost design experimental study in vivo intervention effect ion dynamics juvenile animal mature animal multi-electrode arrays multi-scale modeling network models neuronal excitability optogenetics prevent simulation therapy design

项目摘要

Project Summary/Abstract The goal of this research is to understand why cerebral cortical trauma often leads to seizures and to propose interventions that may reduce or prevent trauma-induced epileptogenesis. Within 24 hours following head injury, up to 80% of patients with penetrating wounds display clinical seizures. Such acute seizures often initiate epileptogenesis―the subthreshold processes that lead to spontaneous, recurring seizures and ultimately to epilepsy. The primary hypotheses of this project are: 1) Trauma-related chronic blockade of activity activates homeostatic plasticity mechanisms that upregulate depolarizing influences (such as excitatory intrinsic and synaptic conductances) and downregulate hyperpolarizing ones (such as inhibitory conductances); in traumatized cortex, this may create an unstable balance of excitation and inhibition that leads to paroxysmal seizures; 2) The effect of the pathological homeostatic changes is age dependent with older animals being more prone to seizures; 3) External interventions designed to prevent decrease of activity after trauma reduce the likelihood of epileptic seizures. Importantly, rather than focus on the ways to treat epilepsies after epileptogenesis is complete, this proposal aims to develop new techniques that can interfere with a process of epileptogenesis itself. Following past experiments with cats in the Timofeev laboratory, a well-established undercut model of cortical deafferenation will be used to induce seizures in mice experiments in vivo and in vitro. Measurement will be performed over the medium-term (days) and long-term (weeks). Interventions will be explored that can prevent epileptogenesis using pharmocogenetic stimulation to block homeostatic changes. In vivo electrophysiological semichronic and chronic experiments will be performed at Laval University (Canada). In vitro experiments from deafferented cortical slices will be conducted at Laval University and UCSD. Necessary data on the astrocyte properties will be provided by the collaborators (Dr. Nedergaard, Univ of Rochester). Experimental data will be analyzed at The Salk Institute and UCSD and will be incorporated into large-scale network models of the neocortex, implementing subcellular, circuit and network level properties, at the Salk Institute and UCSD. The computational models allow the interplay between all of the changes that occur in the cortex in vivo during epileptogenesis to be simulated to identify the critical mechanisms and to make predictions for intervention strategies that could prevent epileptogenesis.

项目概要/摘要这项研究的目的是了解为什么脑皮质创伤经常导致癫痫发作，并提出建议头部受伤后 24 小时内可减少或预防创伤诱发的癫痫发生的干预措施。高达 80% 的穿透伤患者经常出现此类急性癫痫发作。启动癫痫发生——导致自发性、反复发作的阈下过程该项目的主要假设是：1）与创伤相关的慢性阻断。活动激活稳态可塑性机制，上调去极化影响（例如兴奋性内在和突触电导）并下调超极化电导（例如抑制性电导）电导）；在受创伤的皮层中，这可能会造成兴奋和抑制的不稳定平衡导致阵发性癫痫发作；2) 病理性稳态变化的影响取决于年龄年长的动物更容易癫痫发作；3) 旨在防止活动减少的外部干预措施重要的是，创伤后减少癫痫发作的可能性，而不是关注治疗方法。癫痫发生完成后的癫痫，该提案旨在开发可以干扰癫痫发生的新技术继蒂莫费耶夫实验室过去对猫进行的实验之后，癫痫发生的过程本身也有一个过程。完善的皮质传入神经阻滞底切模型将用于在小鼠实验中诱导癫痫发作体内和体外测量将在中期（几天）和长期（几周）内进行。将探索通过药物遗传学刺激来阻止癫痫发生的干预措施体内电生理学半慢性和慢性实验将在拉瓦尔大学（加拿大）将在拉瓦尔进行不同皮质切片的体外实验。大学和加州大学圣地亚哥分校的合作者将提供有关星形胶质细胞特性的必要数据（Dr. Nedergaard，罗切斯特大学）的实验数据将在索尔克研究所和加州大学圣地亚哥分校进行分析。被纳入新皮质的大规模网络模型中，实现亚细胞、电路和索尔克研究所和加州大学圣地亚哥分校的网络级属性允许相互作用。在癫痫发生过程中体内皮质发生的所有变化之间进行模拟以确定关键机制并对可以预防癫痫发生的干预策略做出预测。