A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments.
A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments.
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DOI：
10.1016/j.expneurol.2015.04.023
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发表时间：
2015-09
影响因子：
5.3
通讯作者：
Honig MG
中科院分区：
文献类型：
--
作者：
del Mar N;von Buttlar X;Yu AS;Guley NH;Reiner A;Honig MG
弥漫性轴索损伤被认为是轻度脑外伤引起的功能障碍的基础。为了研究轴突是如何被创伤性事件（如车祸、福尔斯、体育活动或爆炸性爆炸）损伤的，我们利用了脊髓及其广泛的白色物质束。我们开发了一种小鼠脊髓损伤的闭体模型，其中针对下胸椎水平的高压空气冲击在脊髓实质内产生拉伸力、压缩力和剪切力，从而引起广泛的轴突损伤。细胞骨架完整性的标志物显示，脊髓轴突表现出三种不同的病理：微管断裂，神经丝压实，钙蛋白酶介导的血影蛋白分解。皮质脊髓束的背侧轴突主要表现为微管断裂，而所有三种病理现象在侧部和腹侧白色物质中均常见。个别轴突通常表现出只有一个的三种病理在爆炸伤后的第一个24小时，这表明不同的扰动启动彼此独立。在爆炸后的最初几天，神经丝致密化经常伴随着自噬，随后是退化轴突的碎片化。TuJ1免疫标记和YFP报告基因标记的小鼠均显示比βAPP免疫标记更广泛的微管断裂，这引起了对这种评估轴突损伤的标准方法的敏感性的怀疑。虽然运动缺陷是轻微的，很大程度上是短暂的，运动功能的某些方面逐渐恶化了几个星期，这表明一个低水平的轴突变性继续过去的初始波。我们的模型可以帮助进一步了解如何干预最初的轴突损伤最终导致轴突变性的过程，以改善创伤性损伤后的结果。重要的是，我们对广泛轴突损伤的发现也提醒我们，反复的创伤可能对大脑和脊髓产生累积的不良后果。
Diffuse axonal injury is thought to be the basis of the functional impairments stemming from mild traumatic brain injury. To examine how axons are damaged by traumatic events, such as motor vehicle accidents, falls, sports activities, or explosive blasts, we have taken advantage of the spinal cord with its extensive white matter tracts. We developed a closed-body model of spinal cord injury in mice whereby high-pressure air blasts targeted to lower thoracic vertebral levels produce tensile, compressive, and shear forces within the parenchyma of the spinal cord and thereby cause extensive axonal injury. Markers of cytoskeletal integrity showed that spinal cord axons exhibited three distinct pathologies: microtubule breakage, neurofilament compaction, and calpain-mediated spectrin breakdown. The dorsally situated axons of the corticospinal tract primarily exhibited microtubule breakage, whereas all three pathologies were common in the lateral and ventral white matter. Individual axons typically demonstrated only one of the three pathologies during the first 24 h after blast injury, suggesting that the different perturbations are initiated independently of one another. For the first few days after blast, neurofilament compaction was frequently accompanied by autophagy, and subsequent to that, by the fragmentation of degenerating axons. TuJ1 immunolabeling and mice with YFP-reporter labeling each revealed more extensive microtubule breakage than did βAPP immunolabeling, raising doubts about the sensitivity of this standard approach for assessing axonal injury. Although motor deficits were mild and largely transient, some aspects of motor function gradually worsened over several weeks, suggesting that a low level of axonal degeneration continued past the initial wave. Our model can help provide further insight into how to intervene in the processes by which initial axonal damage culminates in axonal degeneration, to improve outcomes after traumatic injury. Importantly, our findings of extensive axonal injury also caution that repeated trauma is likely to have cumulative adverse consequences for both brain and spinal cord.