From the Department of Surgery, Division of Trauma and Critical Care (N.K.D., N.T.L., G.B., A.Y., E.J.L.), and Regenerative Medicine Institute (J.O., N.C., O.S.), Cedars-Sinai Medical Center, Los Angeles, California.
J Trauma Acute Care Surg. 2020 Nov;89(5):955-961. doi: 10.1097/TA.0000000000002811.
How recurrent traumatic brain injury (rTBI) alters brain function years after insult is largely unknown. This study aims to characterize the mechanistic cause for long-term brain deterioration following rTBI using a rat model.
Eighteen Sprague-Dawley wild-type rats underwent bilateral rTBI using a direct skull impact device or sham treatment, once per week for 5 weeks, and were euthanized 56 weeks after the first injury. Weekly rotarod performance measured motor deficits. Beam walk and grip strength were also assessed. Brain tissue were stained and volume was computed using Stereo Investigator's Cavalieri Estimator. The L5 cortical layer proximal to the injury site was microdissected and submitted for sequencing with count analyzed using R "DESeq2" and "GOStats." Brain-derived neurotrophic factor (BDNF) levels were determined using enzyme-linked immunosorbent assay.
Rotarod data demonstrated permanent deficits 1 year after rTBI. Decreased beam walk performance and grip strength was noted among rTBI rodents. Recurrent traumatic brain injury led to thinner cortex and thinner corpus callosum, enlarged ventricles, and differential expression of 72 genes (25 upregulated, 47 downregulated) including dysregulation of those associated with TBI (BDNF, NR4A1/2/3, Arc, and Egr) and downregulation in pathways associated with neuroprotection and neuroplasticity. Over the course of the study, BDNF levels decreased in both rTBI and sham rodents, and at each time point, the decrease in BDNF was more pronounced after rTBI.
Recurrent traumatic brain injury causes significant long-term alteration in brain health leading to permanent motor deficits, cortical and corpus callosum thinning, and expansion of the lateral ventricles. Gene expression and BDNF analysis suggest a significant drop in pathways associated with neuroplasticity and neuroprotection. Although rTBI may not cause immediate neurological abnormalities, continued brain deterioration occurs after the initial trauma in part due to a decline in genes associated with neuroplasticity and neuroprotection.
多次创伤性脑损伤（rTBI）在损伤后多年如何改变大脑功能在很大程度上尚不清楚。本研究旨在使用大鼠模型来描述 rTBI 后长期脑恶化的机制原因。
18 只 Sprague-Dawley 野生型大鼠使用直接颅骨冲击装置或假手术每周进行一次 rTBI，共 5 周，并在第一次损伤后 56 周处死。每周进行旋转棒测试以测量运动缺陷。还评估了束棒行走和握力。使用立体学 Investigator 的 Cavalieri 估计器对脑组织进行染色和体积计算。损伤部位附近的 L5 皮质层被微解剖并进行测序，使用 R“DESeq2”和“GOStats”进行计数分析。使用酶联免疫吸附试验测定脑源性神经营养因子（BDNF）水平。
旋转棒数据表明 rTBI 后 1 年存在永久性缺陷。rTBI 啮齿动物的束棒行走表现和握力下降。反复性创伤性脑损伤导致皮质变薄、胼胝体变薄、脑室扩大以及 72 个基因的差异表达（25 个上调，47 个下调），包括与 TBI 相关基因（BDNF、NR4A1/2/3、Arc 和 Egr）的失调以及与神经保护和神经可塑性相关的通路下调。在研究过程中，rTBI 和假手术啮齿动物的 BDNF 水平均下降，并且在每个时间点，rTBI 后 BDNF 的下降更为明显。
反复性创伤性脑损伤会导致大脑健康的显著长期改变，导致永久性运动缺陷、皮质和胼胝体变薄以及侧脑室扩张。基因表达和 BDNF 分析表明，与神经可塑性和神经保护相关的通路显著下降。尽管 rTBI 可能不会立即引起神经异常，但在初始创伤后仍会发生持续的脑恶化，部分原因是与神经可塑性和神经保护相关的基因下降。
