Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury.
Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury.
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DOI：
10.3389/fneur.2014.00012
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发表时间：
2014
影响因子：
3.4
通讯作者：
Wyss-Coray T
中科院分区：
文献类型：
--
作者：
Luo J;Nguyen A;Villeda S;Zhang H;Ding Z;Lindsey D;Bieri G;Castellano JM;Beaupre GS;Wyss-Coray T
轻度创伤性脑损伤（mTBI，也称为脑震荡）占所有创伤性脑损伤的大多数。重复性mTBI的后果已经成为从事某些体育运动或军事行动的个人特别关注的问题。许多mTBI患者遭受长期的神经行为障碍。为了加快临床前研究和治疗开发，需要反映患者长期认知和病理特征的动物模型。在本研究中，我们开发了一种重复性mTBI的小鼠模型，并对其进行了表征，该模型通过电磁立体定位冲击装置在左额叶闭合头部上诱导。使用GFAP-荧光素酶生物发光报告小鼠，提供星形胶质细胞活化的读数，我们观察到生物发光相对于单次撞击后撞击器传递的力和重复mTBI的累积效应的增加。使用在报告小鼠中建立的损伤参数，我们在野生型C57 BL/6 J小鼠中诱导重复mTBI并表征长期结果。在损伤后2个月和6个月进行测试时，接受重复mTBI的动物显示出空间学习和记忆的显著损害。在死后病理学检查中观察到强烈的星形胶质细胞增生和增加的p-Tau免疫反应性。这些发现与人类mTBI相关的缺陷和病理学一致，并支持使用该模型来评估潜在的治疗方法。
Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all traumatic brain injuries. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity were observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches.