Stemper Brian D, Shah Alok, Chiariello Rachel, McCarthy Cassandra, Jessen Kristin, Sarka Bailey, Seifert Jack, Budde Matthew D, Wang Kevin, Olsen Christopher M, McCrea Michael
Joint Department of Biomedical Engineering, Medical College of Wisconsin, Marquette University, Milwaukee, WI, United States.
Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Behav Neurosci. 2022 Mar 9;16:805124. doi: 10.3389/fnbeh.2022.805124. eCollection 2022.
Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human.
在一个赛季的过程中，一些未受过脑震荡的接触性运动运动员反复遭受亚脑震荡性头部撞击，这与临床和磁共振成像（MRI）变化有关。然而，由于脑震荡、头部撞击暴露史、遗传因素和其他个人因素，分析人类对反复头部撞击的耐受性变得复杂。因此，本研究的目的是建立一种用于反复亚脑震荡性头部撞击暴露的啮齿动物模型，以了解人类的损伤机制和耐受性。本研究采用威斯康星医学院旋转损伤模型，在4周的时间内，每天让大鼠暴露于多次低水平头部加速度。头部加速度的峰值幅度是根据我们之前对接触性运动运动员的人体研究进行缩放的，每天的暴露次数基于整个人类样本中每天暴露次数的中位数（中度暴露）和第95百分位数（高度暴露）。按照暴露方案，对大鼠进行认知缺陷、情绪变化、轴突损伤生物标志物的血清水平以及损伤的组织病理学证据评估。与假手术组相比，高度暴露组的大鼠表现出认知缺陷和类似焦虑行为的证据。中度暴露组的大鼠未表现出上述任何一种行为。同样，高度暴露组的大鼠在基底外侧杏仁核和其他区域有组织病理学证据显示胶质增生（即与假手术组相比，离子钙结合衔接分子1（Iba1）强度升高和胶质纤维酸性蛋白（GFAP）体积增加）。神经丝轻链（NFL）的血清水平显示出与低水平头部加速度暴露次数增加的剂量反应关系，与中度暴露组相比，高度暴露组的NFL每周增加率更高。这些发现证明了反复低水平头部加速度的累积效应，并提供了一个模型，可用于未来的研究，以更好地理解反复低水平头部加速度导致脑损伤的机制和耐受性，大鼠和人类之间具有可扩展的生物力学。
