Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Department of Neurology, Alfred Health, Melbourne, Victoria, Australia.
J Neurotrauma. 2023 Oct;40(19-20):2174-2192. doi: 10.1089/neu.2022.0463. Epub 2023 Jul 18.
Traumatic brain injury (TBI) often causes seizures associated with a neuroinflammatory response and neurodegeneration. TBI responses may be influenced by differences between individuals at a genetic level, yet this concept remains understudied. Here, we asked whether inherent differences in one's vulnerability to acquired epilepsy would determine acute physiological and neuroinflammatory responses acutely after experimental TBI, by comparing selectively bred "seizure-prone" (FAST) rats with "seizure-resistant" (SLOW) rats, as well as control parental strains (Long Evans and Wistar rats). Eleven-week-old male rats received a moderate-to-severe lateral fluid percussion injury (LFPI) or sham surgery. Rats were assessed for acute injury indicators and neuromotor performance, and blood was serially collected. At 7 days post-injury, brains were collected for quantification of tissue atrophy by cresyl violet (CV) histology, and immunofluorescent staining of activated inflammatory cells. FAST rats showed an exacerbated physiological response acutely post-injury, with a 100% seizure rate and mortality within 24 h. Conversely, SLOW rats showed no acute seizures and a more rapid neuromotor recovery compared with controls. Brains from SLOW rats also showed only modest immunoreactivity for microglia/macrophages and astrocytes in the injured hemisphere compared with controls. Further, group differences were apparent between the control strains, with greater neuromotor deficits observed in Long Evans rats compared with Wistars post-TBI. Brain-injured Long Evans rats also showed the most pronounced inflammatory response to TBI across multiple brain regions, whereas Wistar rats showed the greatest extent of regional brain atrophy. These findings indicate that differential genetic predisposition to develop acquired epilepsy (i.e., FAST vs. SLOW rat strains) determines acute responses after experimental TBI. Differences in the neuropathological response to TBI between commonly used control rat strains is also a novel finding, and an important consideration for future study design. Our results support further investigation into whether genetic predisposition to acute seizures predicts the chronic outcomes after TBI, including the development of post-traumatic epilepsy.
创伤性脑损伤（TBI）常引起与神经炎症反应和神经退行性变相关的癫痫发作。TBI 反应可能受个体遗传水平差异的影响，但这一概念仍未得到充分研究。在这里，我们通过比较选择性繁殖的“易发性癫痫”（FAST）大鼠与“抗发性癫痫”（SLOW）大鼠以及对照亲代品系（Long Evans 和 Wistar 大鼠），来研究个体对获得性癫痫的易感性差异是否会决定 TBI 后急性生理和神经炎症反应。11 周龄雄性大鼠接受中度至重度外侧液动冲击伤（LFPI）或假手术。评估大鼠的急性损伤指标和神经运动表现，并连续采集血液。在损伤后 7 天，收集大脑进行 Cresyl Violet（CV）组织学定量组织萎缩，以及激活的炎症细胞免疫荧光染色。FAST 大鼠在损伤后急性表现出更严重的生理反应，24 小时内癫痫发作率和死亡率达到 100%。相反，SLOW 大鼠与对照组相比，无急性癫痫发作，且神经运动恢复更快。与对照组相比，SLOW 大鼠损伤半球中小胶质细胞/巨噬细胞和星形胶质细胞的免疫反应也仅适度。此外，在对照组之间也存在明显的组间差异，与 Wistar 大鼠相比，Long Evans 大鼠在 TBI 后表现出更严重的神经运动缺陷。脑损伤的 Long Evans 大鼠在多个脑区对 TBI 也表现出最明显的炎症反应，而 Wistar 大鼠则表现出最大程度的区域性脑萎缩。这些发现表明，获得性癫痫的遗传易感性差异（即 FAST 与 SLOW 大鼠品系）决定了实验性 TBI 后的急性反应。常用对照大鼠品系对 TBI 的神经病理学反应的差异也是一个新发现，也是未来研究设计的一个重要考虑因素。我们的研究结果支持进一步研究急性癫痫发作的遗传易感性是否预测 TBI 后的慢性结局，包括创伤后癫痫的发生。
