School of Health, Medical and Applied Sciences, Central Queensland University, Rockhampton, Queensland, Australia.
Mackay Institute of Research and Innovation, Mackay Hospital and Health Service, Mackay, Queensland, Australia.
PLoS One. 2021 May 7;16(5):e0251315. doi: 10.1371/journal.pone.0251315. eCollection 2021.
The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TARDBP, TNF, and NEFL, with expression changes observed based on location and follow-up duration. The cortex and hippocampus showed vulnerability to insult, displaying upregulation of key excitotoxicity and inflammation genes. Serum samples showed no difference between groups for proteins phosphorylated tau and GFAP. These data suggest that the cumulative effect of the impacts was sufficient to induce mTBI pathophysiology and clinical features. The genes investigated in this study provide opportunity for further investigation of mTBI-related neuropathology and may provide targets in the development of therapies that help mitigate the effects of mTBI.
轻度创伤性脑损伤 (mTBI) 的累积效应可导致慢性神经损伤，但支持这种损害的分子机制仍需进一步研究。使用一种闭合性颅脑打击模型，该模型可复制人类 mTBI 的生物力学和头部加速度力，以探索单次和重复打击后的急性和慢性后果。成年雄性 C57BL/6J 小鼠被随机分为四组冲击组（对照组；一次、五次和十五次冲击），在 23 天内完成。在最后一次 mTBI 后 48 小时和 3 个月评估结果。海马空间学习和记忆评估显示，在急性阶段，15 次冲击组的表现较对照组受损，在慢性测量时仍持续存在。使用定量 RT-PCR 对皮质和海马组织样本进行脑内基因表达分析。评估了 8 个基因，即 MAPT、GFAP、AIF1、GRIA1、CCL11、TARDBP、TNF 和 NEFL，根据位置和随访时间观察到表达变化。皮质和海马显示出易受损伤的迹象，显示关键的兴奋性毒性和炎症基因上调。各组血清样本中磷酸化 tau 和 GFAP 蛋白无差异。这些数据表明，打击的累积效应足以诱导 mTBI 病理生理学和临床特征。本研究中研究的基因为进一步研究 mTBI 相关神经病理学提供了机会，并可能为开发有助于减轻 mTBI 影响的治疗方法提供靶点。
