The Neural Injury Center, University of Montana, Missoula, MT 59812, United States.
School of Public and Community Health Sciences, University of Montana, Missoula, MT 59812, United States.
Exp Neurol. 2017 Nov;297:62-72. doi: 10.1016/j.expneurol.2017.07.015. Epub 2017 Jul 27.
Multiple mild traumatic brain injury (mmTBI), in certain cases, produces persistent symptoms. However, the molecular mechanisms underlying these symptoms remain unclear. Here, we demonstrate extended pathological changes in the rat brain following mmTBI. Using the lateral fluid percussion (LFP) technique we exposed adult male Wistar rats to a mild TBI (mTBI) once a week for four weeks and compared them to surgical shams. At 90days following the last TBI or sham procedure the animals were cognitively tested in the Morris Water Maze (MWM), euthanized, and the brains removed for immunohistochemistry. At 90days following the last mTBI, NRF-2 staining was significantly decreased in the hilus of the hippocampus and cortex on the injured side, but did not significantly differ from shams on the un-injured side. CD68 positive microglia were significantly increased in the ipsilateral corpus callosum, cortex, and internal capsule of injured animals. Reactive astrocytosis, determined by increased GFAP staining, was also evident in the corpus callosum, cortex, internal capsule and thalamus on the injured side. Interestingly, the corpus callosum thickness at the midline was decreased in injured animals and had evident demyelination when compared to sham animals. Despite these findings, there were no significant differences in neurological assessments at 90days following the last injury. In MWM testing there were not significant differences in the training phase, the time spent in the thigmotaxia zone, or the target quadrant during the probe trial. However, there were significant differences between shams and injured animals in platform zone crossings during the probe trial. These results demonstrate that repetitive head trauma may produce persistent, long-term pathological alterations in brain architecture that may be difficult to detect using standard cognitive and neurological assessments.
多次轻度创伤性脑损伤（mmTBI）在某些情况下会产生持续的症状。然而，这些症状的分子机制尚不清楚。在这里，我们展示了大鼠脑在 mmTBI 后的长期病理变化。我们使用侧方流体冲击（LFP）技术，每周对成年雄性 Wistar 大鼠进行一次轻度 TBI（mTBI），并将其与手术假手术进行比较。在最后一次 TBI 或假手术 90 天后，对动物进行 Morris 水迷宫（MWM）认知测试，处死动物，取出大脑进行免疫组织化学分析。在最后一次 mTBI 后 90 天，NRF-2 染色在损伤侧海马和皮质的齿状回明显减少，但在未损伤侧与假手术相比无显著差异。CD68 阳性小胶质细胞在损伤动物的同侧胼胝体、皮质和内囊明显增加。通过增加 GFAP 染色确定的反应性星形胶质细胞也在损伤侧的胼胝体、皮质、内囊和丘脑明显可见。有趣的是，与假手术动物相比，损伤动物的中线胼胝体厚度减少，并有明显的脱髓鞘。尽管存在这些发现，但在最后一次损伤后 90 天的神经学评估中没有显著差异。在 MWM 测试中，在训练阶段、在触壁回避区花费的时间或在探测试验中的目标象限中没有显著差异。然而，在探测试验中，假手术和损伤动物之间在平台区穿越方面存在显著差异。这些结果表明，重复性头部创伤可能导致脑结构的持久、长期病理改变，这些改变可能难以通过标准的认知和神经学评估来检测。
