Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma

项目总结/摘要 这项研究的目的是了解为什么大脑皮层创伤往往会导致阵发性活动。 在头部损伤后24小时内，高达80%的穿透伤患者显示临床癫痫发作。 这种急性发作往往会引发癫痫亚阈值过程导致自发的， 反复发作并最终导致癫痫。我们建议研究创伤的电生理特征- 在体内、体外和计算模型的慢性实验中诱导癫痫发生， 与实验紧密联系而发展起来的。癫痫发生原因的主要假设是， 我们将测试的是，创伤相关的慢性活动阻滞可能激活稳态可塑性机制 上调去极化影响（如兴奋性内在传导和突触传导）， 下调超极化（如抑制电导）。在异常情况下， 创伤性皮质，这可能会造成不稳定的平衡，导致阵发性癫痫发作。多站点局部字段 潜在的记录（多达64个通道）将被用于测试侵入性脑外伤造成的假设， 不均匀的兴奋不足和兴奋过度的皮层区域，这些区域的相互作用增加了 癫痫发作的可能性。内稳态可塑性在癫痫发生中作用的直接证据将 通过测量minis，突触反应性，轴突分支，内在细胞 特性和多位点焦点场电位。将在中期（天）内进行测量 长期（周）。体内电生理半慢性和慢性实验，体外实验 将在拉瓦尔进行慢性去传入皮质切片以及形态学研究 大学（加拿大）。研究增加癫痫发作可能性的条件的数据 将在索尔克研究所使用独立成分分析（伊卡）进行研究， 在加州大学滨江，将其纳入了皮质神经元和网络的霍奇金-赫胥黎型模型。目标 计算模型的一个目的是探索大脑皮层中发生的所有变化之间的相互作用， 在癫痫发生过程中体内，并预测可以预防癫痫发作的干预措施。设计 这些干预措施将基于可以进一步发展的治疗人类的方法， 临床环境中的创伤性癫痫。

Project Summary/Abstract The goal of this research is to understand why cerebral cortical trauma often leads to paroxysmal activity. Within 24 hours following head injury, up to 80% of patients with penetrating wounds display clinical seizures. Such acute seizures often initiate epileptogenesisthe subthreshold processes that lead to spontaneous, recurring seizures and ultimately to epilepsy. We propose to study the electrophysiological features of trauma- induced epileptogenesis in chronic experiments in vivo, in vitro and with computational models that will be developed in close contact with the experiments. The primary hypothesis for the cause of epileptogenesis that we will test is that trauma-related chronic blockade of activity may activate homeostatic plasticity mechanisms that upregulate depolarizing influences (such as excitatory intrinsic and synaptic conductances) and downregulate hyperpolarizing ones (such as inhibitory conductances). Under the abnormal conditions found in traumatized cortex, this may create an unstable balance that leads to paroxysmal seizures. Multisite local field potential recordings (up to 64 channels) will be used to test the hypothesis that invasive brain trauma creates heterogeneous under- and overexcited cortical areas and that interaction of these areas increases the likelihood of seizure occurrence. Direct evidence for the role of homeostatic plasticity in the epileptogenesis will be obtained by measuring changes in minis, synaptic responsiveness, axonal arborization, intrinsic cellular properties, and multisite focal field potentials. Measurement will be performed over the medium-term (days) and long-term (weeks). In vivo electrophysiological semichronic and chronic experiments, in vitro experiments from chronically deafferented cortical slices as well as morphological studies will be performed at Laval University (Canada). Data from studying the conditions that increase the likelihood of seizure development after brain trauma will be studied using Independent Component Analysis (ICA) at the Salk Institute and will be incorporated into Hodgkin-Huxley type models of cortical neurons and networks at the UC Riverside. The goal of the computational models is to explore the interplay between all of the changes that occur in the cortex in vivo during epileptogenesis and to make predictions for interventions that could prevent seizures. The design of these interventions will be based on approaches that could be further developed to treat humans with trauma-induced epilepsy in clinical settings.