Geneva Foundation, Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States of America; Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States of America.
Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States of America.
Exp Neurol. 2021 Jan;335:113516. doi: 10.1016/j.expneurol.2020.113516. Epub 2020 Oct 22.
The degree of brain injury is the governing factor for the magnitude of the patient's psycho- and physiological deficits post-injury, and the associated long-term consequences. The present scaling method used to segregate the patients among mild, moderate and severe phases of traumatic brain injury (TBI) has major limitations; however, a more continuous stratification of TBI is still elusive. With the anticipation that differentiating molecular markers could be the backbone of a robust method to triage TBI, we used a modified closed-head injury (CHI) Marmarou model with two impact heights (IH). By definition, IH directly correlates with the impact force causing TBI. In our modified CHI model, the rat skull was fitted with a helmet to permit a diffuse axonal injury. With the frontal cortex as the focal point of injury, the adjacent brain regions (hippocampus, HC and cerebellum, CB) were susceptible to diffuse secondary shock injury. At 8 days post injury (po.i.), rats impacted by 120 cm IH (IH) took a longer time to find an escape route in the Barnes maze as compared to those impacted by 100 cm IH (IH). Using a time-resolved interrogation of the transcriptomic landscape of HC and CB tissues, we mined those genes that altered their regulations in correlation with the variable IHs. At 14 days po.i., when all rats demonstrated nearly normal visuomotor performance, the bio-functional analysis suggested an advanced healing mechanism in the HC of IH group. In contrast, the HC of IH group displayed a delayed healing with evidence of active cell death networks. Combining whole genome rat microarrays with behavioral analysis provided the insight of neuroprotective signals that could be the foundation of the next generation triage for TBI patients.
脑损伤程度是决定患者受伤后心理和生理缺陷以及相关长期后果严重程度的主要因素。目前用于将患者分为轻度、中度和重度创伤性脑损伤（TBI）阶段的分级方法存在重大局限性；然而，更连续的 TBI 分层仍然难以实现。由于预期区分分子标志物可能是一种强大的 TBI 分诊方法的基础，我们使用了一种改良的闭合性颅脑损伤（CHI）Marmarou 模型，该模型有两种撞击高度（IH）。根据定义，IH 直接与引起 TBI 的撞击力相关。在我们的改良 CHI 模型中，大鼠颅骨配有头盔以允许弥漫性轴索损伤。以额皮质为损伤焦点，相邻的脑区（海马体、HC 和小脑、CB）易受弥漫性二次冲击损伤。在受伤后 8 天（po.i.），与撞击 100 cm IH（IH）的大鼠相比，撞击 120 cm IH（IH）的大鼠在 Barnes 迷宫中找到逃生路线的时间更长。使用对 HC 和 CB 组织转录组景观的时间分辨询问，我们挖掘了那些与可变 IH 相关改变其调节的基因。在受伤后 14 天（po.i.），当所有大鼠表现出几乎正常的视觉运动表现时，生物功能分析表明 IH 组 HC 中存在先进的愈合机制。相比之下，IH 组的 HC 显示出延迟的愈合迹象，有活跃的细胞死亡网络的证据。将全基因组大鼠微阵列与行为分析相结合，提供了神经保护信号的见解，这些信号可能成为 TBI 患者下一代分诊的基础。
