A Mouse Model for Emotional Disorder Caused by Mild Traumatic Brain Injury

描述(申请人提供)：通常由轻度创伤性脑损伤(TBI)引起的认知和情绪障碍是一个主要的公共心理健康问题。对于轻微的脑外伤如何改变大脑从而导致持久的认知和情绪症状，或者如何有效地治疗这些症状，目前只有有限的见解。轻度颅脑损伤在军事战斗、体育运动、娱乐活动和交通事故中极为常见。轻度颅脑损伤包括主要冲击波造成的闭合性头部损伤，或碰撞过程中头部加速-减速。由此造成的脑损伤似乎源于冲击波通过大脑传递的冲击波导致的快速脑组织变形，或者是由于头部快速加速-减速过程中大脑的压缩-扩张。快速交替的压迫和拉伸会导致特征尚不明确的神经元改变，以及未知的继发性变性事件，这些事件可能会导致持久的症状，对于慢性创伤性脑病(CTE)，甚至会加剧症状。虽然已经使用各种方法在动物身上建立了脑外伤的模型，但轻度脑损伤引起的焦虑、抑郁和记忆丧失通常只表现在短期(1天-2周)，很少出现在长期(1个月)。因此，脑震荡事件通过损害特定脑区的细胞和轴突而导致持续性症状或延迟效应的分子和细胞事件是不明确的。我们开发了一种闭合式初级冲击波轻度颅脑损伤的小鼠模型，该模型使用一种可控制的空气压力波传递到小的中颅区域。该模型模拟了冲击波引起的轻微脑外伤的时间和物理动力学。我们发现，在使用该系统进行50-60psi冲击后的第一个月内，我们可以在3月龄雄性C57BL/6小鼠中造成高度焦虑和抑郁，以及弥漫性轴突损伤。因此，我们的模型概括了这种侮辱，至少是通常与人类轻度脑震荡有关的短期结果。我们建议使用我们的轻度脑创伤BLAST模型来表征单次或多次爆炸后9个月内雄性C57BL/6小鼠的焦虑、恐惧、抑郁和记忆丧失。我们将进行组织学评估，将特定大脑区域的行为缺陷与病理联系起来，并对与导致继发性脑损伤的过程具有预测性和可能因果关系的生物标记物(例如，针对神经抗原的自身抗体)进行血清学评估。我们的研究将确定认知和情绪异常在单次或重复轻度脑损伤后发展、减弱或恶化的时间进程。我们的多重BLAST研究将为进行性多发性脑震荡障碍CTE建立小鼠模型。总体研究结果将为可靠地产生产生神经认知功能的轻度脑损伤提供参数。 本研究的目的是为了促进今后对轻度脑外伤患者情绪和认知障碍的神经生物学和神经遗传学基础的研究，并开发有效的治疗方法。

DESCRIPTION (provided by applicant): The cognitive and emotional disability that commonly results from mild traumatic brain injury (TBI) is a major public mental health problem. Only limited insight is available on how mild TBI alters brain to cause lasting cognitive and emotional symptoms, or how to effectively treat these symptoms. Mild TBI is an extremely common occurrence during military combat, sports, recreational activities, and vehicular accidents. Mild TBI involves closed-head injury from a primary blast shock wave, or head acceleration - deceleration during a collision. The resulting brain injury appears to stem from the rapid brain tissue deformation that results from the shock wave transmitted through brain by the blast, or from the brain compression - expansion during rapid head acceleration - deceleration. The rapidly alternating compression and stretching lead to neuronal alterations that are yet poorly characterized, and unknown secondary degenerative events that can cause lasting and, in the case of chronic traumatic encephalopathy (CTE), even intensifying symptoms. Although TBI has been modeled in animals using a variety of approaches, anxiety, depression, and memory loss caused by mild TBI have typically been characterized only over the short term (1 day - 2 weeks) and rarely over the long term (> 1 month). Accordingly, the molecular and cellular events by which a concussive event impairs cells and axons within specific brain regions to cause persistent symptoms or as a delayed effect are ill-defined. We have developed a mouse model of closed-head primary blast mild TBI using a controlled air pressure wave delivered to a small mid-cranial area. This model simulates the temporal and physical dynamics of the forces causing shock wave-mediated mild TBI. We have found that we can create hyper-anxiety and depression, and diffuse axonal injury, in 3-month old male C57BL/6 mice during the first month after 50-60 psi blast with this system. Our model thus recapitulates the insult and at least the short- term outcome commonly associated with mild concussions in humans. We propose to use our blast model of mild TBI to characterize anxiety, fear, depression and memory loss in male C57BL/6 mice over the 9-month period following single or multiple blasts. We will conduct histological assessments to relate behavioral deficits to pathology in specific brain regions, and serological assessments of biomarkers that are predictive and perhaps causally related (for example, autoantibodies against neural antigens) to the process causing secondary brain damage. Our studies will establish the time course over which cognitive and emotional abnormalities develop, wane, or worsen following single or repeat mild TBI. Our multiple blast studies will develop a mouse model for the progressive multi-concussive disorder CTE. The overall findings will provide parameters for reliably producing mild TBI that yields neurocognitive and emotional disorder, to facilitate future studies of the neurobiological and neurogenetic basis of the emotional and cognitive deficits of mild TBI, and for the development of effective treatments.