Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma

皮质创伤引发癫痫发生的内在机制和突触机制

基本信息

批准号：
8144893
负责人：
TERRENCE J SEJNOWSKI
金额：
$ 38.58万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144893
关键词：
Acute Affect Area Behavioral Canada Cell Culture Techniques Cells Cephalic Cerebrum Chronic Clinical Computer Simulation Coupled Craniocerebral Trauma Croatia Data Deafferentation procedure Development Electric Stimulation Employee Strikes Epilepsy Epileptogenesis Equilibrium Event Evolution Experimental Models Felis catus Foundations Frequencies Goals Head Health Hippocampus (Brain)Hodgkin Disease Hour Human In Vitro Institutes Intervention Journals Lead Lesion Manuscripts Measurement Measures Modeling Monograph N-Methylaspartate Neocortex Neurons Patients Pattern Peer Review Penetrating Wounds Peripheral Physiological Predisposition Process Property Publications Publishing Pyramidal Cells REM Sleep Research Role Seizures Site Sleep Slice Slow-Wave Sleep Staging Structure Synapses Synaptic plasticity Techniques Testing Time Trauma Traumatic Brain Injury United States National Institutes of Health Universities Up-Regulation Vietnam War awake axonal sprouting base deprivation design gray matter in vivo independent component analysis neocortical neuronal excitability prevent public health relevance research study simulation success synaptic inhibition therapy design vigilance white matter

项目摘要

DESCRIPTION (provided by applicant): 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 epileptogenesis the 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. PUBLIC HEALTH RELEVANCE: Within 24 hours up to 80% of patients with penetrating head wounds display clinical seizures. Following the Vietnam and Croatia wars, approximately 50% of patients with penetrating cranial wounds developed epilepsy characterized by recurring seizures 10-15 years later. Understanding and preventing epileptogenesis is a central problem in epilepsy research.

描述（由申请人提供）：这项研究的目的是了解为什么脑皮质创伤通常会导致阵发性活性。头部受伤后24小时内，多达80％的穿透伤口患者显示出临床癫痫发作。这种急性癫痫发作通常会引发癫痫发生的亚阈值过程，导致自发，反复癫痫发作并最终导致癫痫。我们建议在体内，体外和计算模型中研究创伤诱导的癫痫发生的电生理特征，这些计算模型将与实验密切接触。我们将检验的癫痫生成原因的主要假设是，与创伤相关的慢性封锁活性可能会激活稳态可塑性机制，从而上调去极化影响（例如兴奋性内在电导和突触电导率）并下调超极化的影响（例如抑制性电导率）。在受创伤性皮质的异常条件下，这可能会产生不稳定的平衡，从而导致阵发性癫痫发作。多站点的局部现场潜在记录（最多64个通道）将用于检验以下假设：侵入性脑创伤会产生异质性下和过度兴奋的皮质区域，并且这些区域的相互作用增加了癫痫发作的可能性。直接证据表明，将通过测量微型的变化，突触反应能力，轴突木器化，固有的细胞特性和多站点局灶性场电位来获得稳态可塑性在癫痫发生中的作用。测量将在中期（天）和长期（周）中进行。体内电生理学的半复杂和慢性实验，将在加拿大的Laval University（加拿大）进行长期脱落皮质切片的体外实验以及形态学研究。研究脑创伤后增加癫痫发育可能性的条件的数据将使用Salk Institute的独立成分分析（ICA）研究，并将纳入UC Riverside的皮质神经元和网络的Hodgkin-Huxley类型模型中。计算模型的目的是探索癫痫发生过程中体内皮质中发生的所有变化之间的相互作用，并对可能阻止癫痫发作的干预措施进行预测。这些干预措施的设计将基于可以进一步开发的方法，以治疗临床环境中创伤引起的癫痫病的人。公共卫生相关性：在24小时内，多达80％的穿透性头部伤口患者显示出临床癫痫发作。在越南和克罗地亚战争之后，大约50％的穿透性颅伤口患者出现了癫痫病，其特征是10 - 15年后反复发生癫痫发作。理解和预防癫痫发生是癫痫研究中的一个核心问题。