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：
9789979
负责人：
TERRENCE J SEJNOWSKI
金额：
$ 61.75万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789979
关键词：
Acute Affect Age American Anatomy Animals Area Astrocytes Brain Canada Cell Compartmentation Cellular Morphology Cellular Structures Cerebrum Chronic Clinical Computer Simulation 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脑皮质创伤经常导致癫痫发作和提案可以减少或预防创伤引起的癫痫发生的干预措施。在头部后24小时内受伤，多达80％的穿透伤口患者表现出临床癫痫发作。这样的急性癫痫发作启动癫痫发生 - 导致发重，反复癫痫发作和的子阈值过程最终要进行癫痫。该项目的主要假设是：1）与创伤相关的慢性封锁活性激活了上调分推性影响的体内平衡可塑性机制（例如兴奋性固有和突触电导）并下调过度的电导（例如抑制性电导）；在创伤性皮质中，这可能会产生不稳定的兴奋和抑制平衡导致阵发性癫痫发作； 2）病理稳态变化的影响是年龄的依赖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措施创伤后减少了癫痫发作的可能性。重要的是，而不是专注于治疗的方式癫痫发生后的癫痫发作，该提案旨在开发可能干扰的新技术随着癫痫发生本身的过程。在过去对Timofeev实验室中的猫进行了实验之后，良好成熟的皮质死亡模型将用于诱导小鼠实验中的癫痫发作体内和体外。测量将在中期（天）和长期（周）中进行。将探索可以防止使用药物遗传学刺激阻止癫痫发生的干预措施稳态变化。体内电生理学分类和慢性实验将在拉瓦尔大学（加拿大）。将在Laval上进行脱皮皮质切片的体外实验大学和UCSD。合作者将提供有关星形胶质细胞特性的必要数据（Dr. 罗切斯特大学Nedergaard）。实验数据将在Salk Institute和UCSD上进行分析，并将被整合到新皮层的大规模网络模型中，实施亚细胞，电路和 Salk Institute和UCSD的网络级别属性。计算模型允许相互作用在癫痫发生期间皮质中发生的所有变化之间发生，以识别关键机制并为可以预防癫痫发生的干预策略做出预测。