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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：
10468022
负责人：
TERRENCE J SEJNOWSKI
金额：
$ 58.89万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468022
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.

项目摘要/摘要这项研究的目的是了解为什么大脑皮层损伤经常导致癫痫发作，并提出可减少或防止外伤性癫痫发生的干预措施。在事故发生后24小时内在穿透伤患者中，高达80%的患者表现为临床癫痫发作。这种急性癫痫发作经常引发癫痫-阈值以下的过程，导致自发性、复发性癫痫发作和最终导致癫痫。该项目的主要假设是：1)创伤相关的慢性阻断活动激活体内平衡可塑性机制，从而上调去极化影响(如兴奋性内源性和突触电导)和下调超极化(如抑制性电导)；在受创伤的皮层，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)病理内稳态改变的影响与年龄有关年龄较大的动物更容易癫痫发作；3)旨在防止活动减少的外部干预创伤后减少癫痫发作的可能性。重要的是，不要把注意力集中在治疗的方法上在癫痫发生完成后，这项提议旨在开发新的技术，可以干预伴随着癫痫发生本身的过程。继过去在蒂莫费耶夫实验室进行的猫实验后，已建立的皮层去传入的下切模型将被用来在小鼠实验中诱导癫痫发作在体内和体外。将在中期(天)和长期(周)进行测量。将探索可利用致病刺激阻断癫痫发生的干预措施。动态平衡的变化。在活体电生理学、半时间和慢性实验将在拉瓦尔大学(加拿大)。去传入皮层脑片的体外实验将在拉瓦尔进行大学和加州大学圣迭戈分校。合作者将提供有关星形胶质细胞特性的必要数据(Dr。内德加德，罗切斯特大学)。实验数据将在索尔克研究所和加州大学洛杉矶分校进行分析，并将结合到新大脑皮层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迭戈分校的网络级属性。计算模型允许相互作用在癫痫发生期间体内皮层发生的所有变化之间进行模拟，以确定关键机制，并对可防止癫痫发生的干预策略作出预测。