A novel closed-head model of mild traumatic brain injury caused by primary overpressure blast to the cranium produces sustained emotional deficits in mice.
A novel closed-head model of mild traumatic brain injury caused by primary overpressure blast to the cranium produces sustained emotional deficits in mice.
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DOI：
10.3389/fneur.2014.00002
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发表时间：
2014
影响因子：
3.4
通讯作者：
Reiner A
中科院分区：
文献类型：
--
作者：
Heldt SA;Elberger AJ;Deng Y;Guley NH;Del Mar N;Rogers J;Choi GW;Ferrell J;Rex TS;Honig MG;Reiner A
情绪障碍是人类轻度创伤性脑损伤（TBI）的常见结果，但其病理生理基础尚不清楚。我们已经开发了一个封闭头部爆炸损伤的小鼠模型，使用空气压力波传递到颅骨一侧的小区域，以产生轻度TBI。我们发现，在3个月大的C57BL/6雄性小鼠中，20 psi的爆炸没有产生明显的脑损伤行为或组织学证据，而25-40 psi的爆炸在露天竞技场中产生短暂的焦虑，但几乎没有脑损伤的组织学证据。相比之下，50-60 psi的爆炸会在露天场地导致类似焦虑的行为，随着爆炸时间的推移，这种行为变得更加明显。在爆炸后2-8周进行的额外行为测试中，50-60 psi的小鼠也表现出增加的声惊吓，习得性恐惧的坚持，增强的情境恐惧，以及抑郁样行为和减少的脉冲前抑制。我们没有发现明显的脑病理，但在爆炸后3-8周，在50 ~ 60 psi小鼠的脑切片中观察到分散的轴突变性。因此，单次50-60 psi爆炸引起的小鼠TBI表现出最小的神经元损失，并伴有人类轻度TBI特征的“弥漫性”轴突损伤。然而，观察到基底外侧杏仁核中富含Thy1的兴奋性投射神经元亚群的丰度减少。据报道，这些神经元群与恐惧抑制的联系表明，轻度脑外伤对它们的损害可能导致我们的小鼠爆炸后观察到的高度焦虑和恐惧。我们的小鼠脑震荡超压空气爆炸模型将有助于进一步研究轻度脑外伤后各种情绪缺陷的机制。
Emotional disorders are a common outcome from mild traumatic brain injury (TBI) in humans, but their pathophysiological basis is poorly understood. We have developed a mouse model of closed-head blast injury using an air pressure wave delivered to a small area on one side of the cranium, to create mild TBI. We found that 20-psi blasts in 3-month-old C57BL/6 male mice yielded no obvious behavioral or histological evidence of brain injury, while 25–40 psi blasts produced transient anxiety in an open field arena but little histological evidence of brain damage. By contrast, 50–60 psi blasts resulted in anxiety-like behavior in an open field arena that became more evident with time after blast. In additional behavioral tests conducted 2–8 weeks after blast, 50–60 psi mice also demonstrated increased acoustic startle, perseverance of learned fear, and enhanced contextual fear, as well as depression-like behavior and diminished prepulse inhibition. We found no evident cerebral pathology, but did observe scattered axonal degeneration in brain sections from 50 to 60 psi mice 3–8 weeks after blast. Thus, the TBI caused by single 50–60 psi blasts in mice exhibits the minimal neuronal loss coupled to “diffuse” axonal injury characteristic of human mild TBI. A reduction in the abundance of a subpopulation of excitatory projection neurons in basolateral amygdala enriched in Thy1 was, however, observed. The reported link of this neuronal population to fear suppression suggests their damage by mild TBI may contribute to the heightened anxiety and fearfulness observed after blast in our mice. Our overpressure air blast model of concussion in mice will enable further studies of the mechanisms underlying the diverse emotional deficits seen after mild TBI.
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