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

项目概要/摘要 这项研究的目的是了解为什么大脑皮层创伤经常导致癫痫发作，并提出 可能减少或预防创伤诱导的癫痫发生的干预措施。24小时内，头部 在创伤中，高达80%的穿透伤患者显示临床癫痫发作。这种急性发作通常 引发癫痫发生-导致自发性反复发作的阈下过程， 最终导致癫痫。本研究的主要假设是：1）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（如兴奋性 内源性和突触传导）和下调超极化（如抑制性 电导）;在受创伤的皮层中，这可能会产生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与年龄有关， 老年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 减少癫痫发作的可能性。重要的是，与其关注治疗方法， 癫痫后癫痫是完整的，这项建议旨在开发新的技术，可以干扰 癫痫本身就是一个过程。在过去的实验中，猫在阿格菲耶夫实验室， 在小鼠实验中，将使用一种成熟的皮质去传入的底切模型来诱导癫痫发作 在体内和体外。将在中期（天）和长期（周）进行测量。 将探索可以预防癫痫发生的干预措施，使用药物发生刺激来阻断 稳态变化体内电生理学半慢性和慢性实验将在 拉瓦尔大学（加拿大）。将在拉瓦尔进行去传入皮质切片的体外实验 大学和UCSD。有关星形胶质细胞特性的必要数据将由合作者提供（Dr. Nedergaard，Univ of罗切斯特）。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， 被纳入新皮层的大规模网络模型，实现亚细胞，电路和 网络级属性，在索尔克研究所和加州大学圣地亚哥分校。计算模型允许相互作用 在癫痫发生过程中在体内皮层发生的所有变化之间进行模拟，以确定癫痫发生的可能性。 关键机制，并预测可以预防癫痫发生的干预策略。

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.