Teasell Elizabeth M, Potts Emilie, Geremia Nicole, Lu Lihong, Xu Xiaoyun, Mao Haojie, Brown Arthur
Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
Neuroscience program, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
Neurotrauma Rep. 2025 Feb 17;6(1):184-190. doi: 10.1089/neur.2024.0165. eCollection 2025.
Clinically relevant models of concussion are critical in understanding the pathophysiology of concussion and its long-term outcomes. To bridge the gap between preclinical and clinical research, animal models of concussion should be produced by mild traumatic brain injuries (mTBIs) that possess the same physical and biomechanical properties found in the mTBIs that cause concussion in humans. Specifically, to have good construct validity the mTBIs used in animal models of concussion should feature closed-head impacts with unrestrained head and body motion, resulting in peak angular velocities that approximate the human experience. We describe a mouse model of concussion using a cortical impactor to deliver closed-head mTBIs. Mice are placed on a break-away platform that allows free head and body movement during and after impact resulting in rapid head rotation. We assessed this model of concussion in over 100 mice carrying humanized versions of the genes encoding the amyloid precursor protein and tau. We found that this method consistently produced injuries with peak angular velocities in mice that, when scaled, approximated the average peak angular velocities reported in concussive football impacts. Face validity of this model of concussion was evaluated by histopathology and revealed that three impacts delivered 24 hours apart led to diffuse axonal injury, astrogliosis, and microglial activation one week after injury, particularly in white matter tracts aligned orthogonally to the axis of rotation. Persistent axonal degeneration was observed up to 6 months postinjury. This mouse model of concussion captures key biomechanical and pathological features of human concussions.
临床上相关的脑震荡模型对于理解脑震荡的病理生理学及其长期后果至关重要。为弥合临床前研究与临床研究之间的差距，脑震荡的动物模型应由轻度创伤性脑损伤（mTBI）产生，这些损伤应具有在导致人类脑震荡的mTBI中发现的相同物理和生物力学特性。具体而言，为了具有良好的构建效度，用于脑震荡动物模型的mTBI应具有闭合性头部撞击，头部和身体运动不受限制，从而产生接近人类体验的峰值角速度。我们描述了一种使用皮质撞击器进行闭合性头部mTBI的小鼠脑震荡模型。将小鼠放置在一个可分离的平台上，该平台允许在撞击期间和撞击后头部和身体自由移动，从而导致头部快速旋转。我们在100多只携带编码淀粉样前体蛋白和tau基因的人源化版本的小鼠中评估了这种脑震荡模型。我们发现，这种方法在小鼠中始终产生具有峰值角速度的损伤，按比例缩放后，接近在脑震荡性足球撞击中报告的平均峰值角速度。通过组织病理学评估了该脑震荡模型的表面效度，结果显示，间隔24小时进行三次撞击会在损伤后一周导致弥漫性轴索损伤、星形胶质细胞增生和小胶质细胞激活，特别是在与旋转轴正交排列的白质束中。在损伤后6个月仍观察到持续性轴索变性。这种小鼠脑震荡模型捕捉到了人类脑震荡的关键生物力学和病理学特征。
