Goodfellow Molly J, Hrdlick Amanda L, Piskoun Boris, Proctor Julie L, Rangghran Parisa, Shaughness Michael C, Vesselinov Alexandra, Xu Su, Gullapalli Rao P, Leiste Ulrich H, Fourney William L, Miller Catriona H T, Cantu Jody C, Fiskum Gary
Department of Anesthesiology and the Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
J Neurosci Res. 2025 Sep;103(9):e70081. doi: 10.1002/jnr.70081.
Under-vehicle blast (UVB) generated from landmines is a unique traumatic brain injury (TBI) mechanism affecting warfighters. UVB hyperacceleration can result in injury independent of impact; however, a secondary impact injury can also occur. To date, translation of findings from rodent TBI models to improved patient outcomes has been unsuccessful, perhaps due to neuroanatomical differences between humans and rodents, including white-to-gray matter ratio and cortical gyrification. To address this modeling difference, a UVB model was developed in ferrets, the brains of which more closely resemble humans. Male ferrets underwent UVB-alone (Blast), controlled cortical impact (CCI)-alone, combined UVB + CCI (BCCI), or craniotomy (Sham) procedures. Neurobehavioral assays were optimized and used to assess mood, memory, and motor control. Blast and BCCI ferrets underwent neuroimaging at baseline and 7 days post-injury. All ferrets were euthanized by terminal perfusion with paraformaldehyde on day 7 for histologic analysis. Results indicate that UVB alters cortical metabolites and induces blood-brain barrier (BBB) disruption. CCI leads to BBB disruption and cortical diffuse axonal injury, but this is not exacerbated by combination with UVB. BCCI does result in several alterations in key cortical metabolites indicative of increased neuronal injury, oxidative stress, and glial activation as well as impaired neurotransmission and energy generation. Additionally, BCCI significantly increases hyperactivity and impairs spatial memory. Anxiety-like behavior, mood, and motor function approached statistical significance. Taken together, we provide a military-relevant model of UVB in a gyrencephalic animal, the ferret, that may be applied in future investigations into TBI pathophysiology and potential treatment.
地雷引发的车底爆炸（UVB）是一种影响作战人员的独特创伤性脑损伤（TBI）机制。UVB超加速可导致与撞击无关的损伤；然而，也可能发生二次撞击损伤。迄今为止，将啮齿动物TBI模型的研究结果转化为改善患者预后的尝试并不成功，这可能是由于人类和啮齿动物之间存在神经解剖学差异，包括白质与灰质比例以及皮质回旋。为了解决这种建模差异，在雪貂身上开发了一种UVB模型，雪貂的大脑与人类更为相似。雄性雪貂接受单独的UVB（爆炸）、单独的控制性皮质撞击（CCI）、联合UVB + CCI（BCCI）或开颅手术（假手术）。优化了神经行为学检测方法，并用于评估情绪、记忆和运动控制。对爆炸组和BCCI组雪貂在基线和损伤后7天进行神经影像学检查。所有雪貂在第7天通过用多聚甲醛进行终末灌注处死，用于组织学分析。结果表明，UVB会改变皮质代谢物并导致血脑屏障（BBB）破坏。CCI会导致BBB破坏和皮质弥漫性轴索损伤，但与UVB联合不会使其加重。BCCI确实会导致关键皮质代谢物发生一些改变，表明神经元损伤增加、氧化应激和胶质细胞激活，以及神经传递和能量生成受损。此外，BCCI显著增加多动并损害空间记忆。焦虑样行为、情绪和运动功能接近统计学显著性。综上所述，我们在脑回动物雪貂中提供了一种与军事相关的UVB模型，可应用于未来对TBI病理生理学和潜在治疗的研究。
