BACKGROUND Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial activation after TBI may play a role in hippocampal circuit and/or synaptic remodeling; however, the potential effects of chronic microglial changes are currently unknown. The objective of the current study was to assess neuropathological and neuroinflammatory changes in subregions of the dentate gyrus at acute to chronic time points following mild TBI using an established model of closed-head rotational acceleration induced TBI in pigs. METHODS This study utilized archival tissue of pigs which were subjected to sham conditions or rapid head rotation in the coronal plane to generate mild TBI. A quantitative assessment of neuropathological changes in the hippocampus was performed via immunohistochemical labeling of whole coronal tissue sections at 3 days post-injury (DPI), 7 DPI, 30 DPI, and 1 year post-injury (YPI), with a focus on mossy cell atrophy and synaptic reorganization, in context with microglial alterations (e.g., density, proximity to mossy cells) in the dentate gyrus. RESULTS There were no changes in mossy cell density between sham and injured animals, indicating no frank loss of mossy cells at the mild injury level evaluated. However, we found significant mossy cell hypertrophy at 7 DPI and 30 DPI in anterior (> 16% increase in mean cell area at each time; p = <  0.001 each) and 30 DPI in posterior (8.3% increase; p = <  0.0001) hippocampus. We also found dramatic increases in synapsin staining around mossy cells at 7 DPI in both anterior (74.7% increase in synapsin labeling; p = <  0.0001) and posterior (82.7% increase; p = <  0.0001) hippocampus. Interestingly, these morphological and synaptic alterations correlated with a significant change in microglia in proximity to mossy cells at 7 DPI in anterior and at 30 DPI in the posterior hippocampus. For broader context, while we found that there were significant increases in microglia density in the granule cell layer at 30 DPI (anterior and posterior) and 1 YPI (posterior only) and in the molecular layer at 1 YPI (anterior only), we found no significant changes in overall microglial density in the hilus at any of the time points evaluated post-injury. CONCLUSIONS The alterations of mossy cell size and synaptic inputs paired with changes in microglia density around the cells demonstrate the susceptibility of hilar mossy cells after even mild TBI. This subtle hilar mossy cell pathology may play a role in aberrant hippocampal function post-TBI, although additional studies are needed to characterize potential physiological and cognitive alterations.

中文翻译：

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猪轻度弥漫性创伤性脑损伤后门部苔藓细胞肥大和突触变化。

背景 在美国，每年有超过 240 万人经历轻度创伤性脑损伤 (TBI)，这会导致长期的神经功能缺损。海马齿状回在 TBI 后特别容易受到损伤，因为肺门苔藓细胞的变化尤其可能导致 TBI 后功能障碍。此外，TBI 后小胶质细胞的激活可能在海马回路和/或突触重塑中发挥作用；然而，慢性小胶质细胞变化的潜在影响目前尚不清楚。本研究的目的是评估轻度 TBI 后齿状回亚区域在急性到慢性时间点的神经病理学和神经炎症变化，使用已建立的猪闭头旋转加速诱导 TBI 模型。方法 本研究利用猪的档案组织，这些组织在假条件下或在冠状面上快速旋转头部以产生轻度 TBI。通过在伤后 3 天 (DPI)、7 DPI、30 DPI 和伤后 1 年 (YPI) 对整个冠状组织切片进行免疫组织化学标记，对海马神经病理学变化进行定量评估，重点是苔藓细胞萎缩和突触重组，与齿状回中的小胶质细胞改变（例如，密度，接近苔藓细胞）有关。结果 假动物和受伤动物之间的苔藓细胞密度没有变化，表明在评估的轻度损伤水平上没有明显的苔藓细胞损失。然而，我们发现前部在 7 DPI 和 30 DPI 时有明显的苔藓细胞肥大（每次平均细胞面积增加 > 16%；p = < 0.001）和后部 30 DPI（增加 8.3%；p = < 0.0001）海马体。我们还发现在 7 DPI 时，海马前部（突触标记增加 74.7%；p = < 0.0001）和后部（增加 82.7%；p = < 0.0001）海马体中苔藓细胞周围的突触蛋白染色显着增加。有趣的是，这些形态学和突触改变与靠近苔藓细胞的小胶质细胞在前海马体 7 DPI 和后海马体 30 DPI 时发生显着变化相关。对于更广泛的背景，虽然我们发现在 30 DPI（前部和后部）和 1 YPI（仅后部）和 1 YPI（仅前部）的分子层中，颗粒细胞层的小胶质细胞密度显着增加，我们发现在受伤后评估的任何时间点，肺门的整体小胶质细胞密度没有显着变化。结论 苔藓细胞大小和突触输入的改变与细胞周围小胶质细胞密度的变化相结合，证明了即使是轻度 TBI 后肺门苔藓细胞的易感性。这种微妙的肺门苔藓细胞病理学可能在 TBI 后异常的海马功能中发挥作用，尽管需要更多的研究来表征潜在的生理和认知改变。