IMPULSE CONDUCTION BLOCK IN INJURED CENTRAL AXONS

受伤中央轴突中的脉冲传导阻滞

基本信息

批准号：
2460597
负责人：
ANDREW R BLIGHT
金额：
$ 18.26万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-15 至 1998-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2460597
关键词：
action potentials aminopyridines electrophysiology guinea pigs histology mathematical model myelination nervous system regeneration neural conduction neural inhibition neurophysiology nonhuman therapy evaluation potassium channel spinal cord injury

项目摘要

The goal of this project is to examine the relation between partial remyelination in the injured nervous system and the clinically significant problem of action potential conduction block. These studies will be performed in a guinea pig model of chronic spinal cord injury and will involve intracellular recording from myelinated nerve fibers within strips of spinal cord white matter isolated in artificial media. The physiological responses and conduction properties of these fibers will be recorded and related to the characteristics of their myelin sheaths, as determined by intracellular injection of the marker biocytin and subsequent morphologic reconstruction from serial sections. This information will be used to explore the relation between morphological and physiological changes using computer based mathematical models of action potential conduction. A broader survey of the range of myelination deficits in these white matter tracts will also be performed by conventional means of osmium tetroxide fixation and teasing apart of single fibers. A particular goal of this study will be to identify differences between axons that respond and those that do not respond to the application of 4- aminopyridine (4-AP) with a change in the temperature of conduction block or of frequency-response characteristics. Previous experiments have shown that 4-AP, a potassium channel blocking drug, can restore conduction of impulses in some axons of chronically injured spinal cord that otherwise fail to conduct at physiological temperature. The same drug has also been shown to improve neurologic function in animals and human subjects with chronic spinal cord injury, and may prove to be a useful symptomatic treatment, particularly in some cases of incomplete spinal cord injury. It is important to understand the cell physiological basis of these responses, in order to optimize this approach to reducing functional deficits following injury to the nervous system. The experiments will address the potential role of a number of factors in the relation between changes in the myelination of central axons and their conduction characteristics. These include the dimensions of node and internode, with attendant effects on impedance matching; changes in the resting potential of the nerve fiber and their influence on excitability; alterations in the accumulation of extracellular potassium as a result of action potential transmission; and direct involvement of internodal ion channels exposed to large electrical potential transients as a result of dramatic reductions of myelin sheath thickness. A mathematical model of the myelinated axon will be used to explore the possible interaction between these factors and the blockade of voltage-dependent potassium channels, equivalent to the effects of CAP and other drugs.

该项目的目的是检查部分之间的关系受伤的神经系统和临床意义动作问题潜在传导阻滞。这些研究将是在慢性脊髓损伤的豚鼠模型中进行，将涉及条带中髓神经纤维的细胞内记录在人工培养基中孤立的脊髓白质的。这这些纤维的生理反应和传导特性将是记录并与其髓鞘的特征有关通过细胞内注射标记物生物细胞和随后从序列切片进行的形态重建。这信息将用于探索形态学与使用基于计算机的数学模型的生理变化潜在传导。对髓鞘范围的更广泛的调查这些白质区的缺陷也将由常规的四氧化osmium固定和取笑单纤维。这项研究的特定目标是确定响应的轴突和那些不响应4-的应用的轴突氨基吡啶（4-AP），温度变化或频率响应特性。以前的实验已显示 4-AP是一种钾通道阻断药物，可以恢复在某些长期受伤的脊髓轴突中冲动，否则无法在生理温度下进行。同样的药物也是证明可以改善动物和人类受试者的神经功能慢性脊髓损伤，可能被证明是有用的症状治疗，特别是在某些情况下脊髓损伤不完全。它了解这些细胞生理基础很重要响应，以优化这种降低功能的方法神经系统受伤后的缺陷。实验将解决许多因素在中央轴突的髓鞘变化及其它们的关系传导特征。这些包括节点的尺寸和节间，对阻抗匹配产生影响；变化神经纤维的静止潜力及其对兴奋性的影响；由于动作电位传输；并直接参与节间离子由于髓鞘厚度的急剧减少。一个数学模型髓鞘的轴突将用于探索可能的相互作用在这些因素与电压依赖性钾的阻塞之间通道，相当于CAP和其他药物的影响。