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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：
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.

项目总结/文摘