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：
8318223
负责人：
TERRENCE J SEJNOWSKI
金额：
$ 38万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318223
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 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 abstracting 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

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.

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阵发性活动。头部受伤后 24 小时内，高达 80% 的穿透伤患者会出现临床癫痫发作。这种急性癫痫发作通常会引发癫痫发生，即导致自发性癫痫发作的阈下过程，反复发作，最终导致癫痫。我们建议研究创伤的电生理学特征在体内、体外和计算模型的慢性实验中诱导癫痫发生与实验密切联系而发展起来的。癫痫发生原因的主要假设是我们将测试的是，与创伤相关的慢性活动阻断可能会激活稳态可塑性机制上调去极化影响（例如兴奋性内在电导和突触电导）和下调超极化（例如抑制电导）。在发现异常情况下皮质受到创伤，这可能会造成不稳定的平衡，导致阵发性癫痫发作。多站点本地字段潜在的录音（最多 64 个通道）将用于测试侵入性脑外伤造成的假设异质的低兴奋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。稳态可塑性在癫痫发生中作用的直接证据将通过测量迷你、突触反应性、轴突分枝、内在细胞的变化来获得特性和多位点焦场电位。测量将在中期（天）内进行和长期（几周）。体内电生理半慢性和慢性实验、体外实验来自长期传入神经缺失的皮质切片以及形态学研究将在拉瓦尔进行大学（加拿大）。研究增加癫痫发作可能性的条件的数据索尔克研究所将使用独立成分分析 (ICA) 对脑外伤后的情况进行研究，并将纳入加州大学河滨分校的霍奇金-赫胥黎型皮层神经元和网络模型。目标计算模型的目的是探索皮层中发生的所有变化之间的相互作用癫痫发生期间的体内情况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开发的方法来治疗人类临床环境中创伤诱发的癫痫。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Local origin of slow EEG waves during sleep.

睡眠期间脑电图慢波的局部起源。

DOI：
10.7868/s0044467713010139
发表时间：
2013
期刊：
Zhurnal vysshei nervnoi deiatelnosti imeni I P Pavlova
影响因子：
0
作者：
Timofeev,Igor
通讯作者：
Timofeev,Igor

Selective memory generalization by spatial patterning of protein synthesis.

DOI：
10.1016/j.neuron.2014.02.028
发表时间：
2014-04-16
期刊：
Neuron
影响因子：
16.2
作者：
O'Donnell C;Sejnowski TJ
通讯作者：
Sejnowski TJ

Gap junctions and epileptic seizures--two sides of the same coin?

DOI：
10.1371/journal.pone.0020572
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Volman V;Perc M;Bazhenov M
通讯作者：
Bazhenov M

Spike-rate coding and spike-time coding are affected oppositely by different adaptation mechanisms.

DOI：
10.1523/jneurosci.1792-08.2008
发表时间：
2008-12-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Prescott SA;Sejnowski TJ
通讯作者：
Sejnowski TJ