In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.

中文翻译：

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轻度闭合性颅脑损伤对啮齿动物tauopathy和认知缺陷的影响：野生型和rTg4510小鼠的主要结果，并进行系统的综述。

在人类中，大多数持续性创伤性脑损伤（TBI）被归类为“轻度”，最常见的原因是闭合性颅脑损伤（CHI）。非穿透性CHI的影响不是良性的，可能会导致慢性病理和行为障碍，反复头部受伤可能会加重病情。临床神经病理学相关研究提供了证据，证明tau转化为异常磷酸化的蛋白毒性中间体（p-tau）可能是单个TBI触发并通过重复TBI增强病理生理的一部分。然而，啮齿动物中p-tau和CHI之间的联系仍然存在争议。为了实验性地解决这个问题，我们向WT或rTg4510小鼠诱导了一个CHI或两个CHI。我们发现2 x CHI增加WT小鼠和rTg4510小鼠的tau磷酸化。WT小鼠的行为特征发现2x CHI小鼠的arm臂水迷宫存在慢性缺陷，而在1x CHI小鼠中已部分缓解。此外，使用具有R1映射的锰增强磁共振成像（一种新颖的功能性神经成像技术），我们发现2T CHI后的rTg4510小鼠与1X CHI相比存在更大的缺陷。为了将我们的发现与该领域的先前工作相结合，我们对啮齿类动物轻度重复性CHI研究进行了系统综述。根据Prisma准则，我们确定了25篇经过同行评审的原始论文。我们的实验结果以及我们的系统评价提供了令人信服的证据，表明通过温和的TBI研究可修饰tau磷酸化；然而，尚未普遍报道p-tau含量的变化。一起，