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

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.