Project 2: Contribution of Traumatic Brain Injury to Fear Extinction and Avoidance

项目摘要/摘要 创伤性脑损伤每年影响约400万平民和士兵，其中许多是 被诊断为精神健康状况，如创伤后应激障碍(PTSD)。有几种常见的 创伤性脑损伤和创伤后应激障碍的神经生物学机制，这两种情况都会损害学习， 神经可塑性和情绪调节。对退伍军人的流行病学研究表明两者之间存在很强的相关性 在持续的创伤性脑损伤和发展的创伤后应激障碍之间。然而，动物研究显示了相互矛盾的结果。要确定 无论创伤性脑损伤和创伤后应激障碍之间是否存在联系，必须使用可靠的大脑建立生物联系 损伤模型和行为测试。临床上，有两大类脑损伤，其中研究模式 存在：局灶性(如挫伤)，由受控皮质撞击(CCI)产生，弥漫性(如脑震荡)， 由重量落在封闭式机头上产生。在CCI中，损伤程度和组织变形程度 与挫伤相关的生理参数相似。在脑震荡中，头部受到冲击，外加角度 加速会导致神经和认知功能障碍。此外，重复的脑震荡，如 运动和战斗会导致轴突损伤，扰乱大脑区域之间的沟通和活动， 潜在地损害情绪调节。一种可能被TBI改变的情绪调节形式是恐惧 消亡，一种减少恐惧表达的学习方式。消解是恐惧暴露疗法的基础 和焦虑症。除了消退受损外，创伤后应激障碍患者还会表现出过度的回避，这 减少目标和奖励的实现。值得注意的是，啮齿类动物和 人类需要灭绝和逃避。我们将使用CCI或重复闭合性脑损伤(rCHI；模型 重复脑震荡)，以测试脑损伤损害恐惧消退(导致高度恐惧)，并损害 取消避税(造成过度避税)。在脑外伤后，我们认为杏仁核功能障碍， 海马体和内侧前额叶皮质(MPFC)将是受损消退的基础，而功能障碍 杏仁核、mPFC和腹侧纹状体是过度回避的基础。这项工作将增加 关于脑损伤对物种灭绝和避免的影响的科学和公共卫生证据。主要技术 在这个项目中包括神经元束追踪和免疫组织化学方法来识别大脑的活动 区域。这些协议在很大程度上依赖于Cobre中可用的仪器和专业知识 神经成像和电生理学设施。的显微镜设备和图像分析支持 分子科学研究中心将为实现该项目的目标提供必要的工具。

Project Summary / Abstract Traumatic brain injury (TBI) affects about 4 million civilians and soldiers each year, many of whom are diagnosed with mental health conditions like post-traumatic stress disorder (PTSD). There are common mechanisms that contribute to the neurobiology of TBI and PTSD, and both conditions can impair learning, neuroplasticity, and emotional regulation. Epidemiological studies of veterans show a strong correlation between sustaining TBI and developing PTSD. However, animal studies show conflicting results. To determine whether a relationship exists between TBI and PTSD, a biological link must be established using reliable brain injury models and behavioral tests. Clinically, there are two broad classes of TBI in which research models exist: focal (e.g. contusion), produced by controlled cortical impact (CCI), and diffuse (e.g. concussion), produced by weight drop onto the closed head. With CCI, injury level and extent of tissue deformation resemble physiological parameters related to contusion. In concussion, impact to the head plus angular acceleration produces neurological and cognitive dysfunction. Furthermore, repeat concussions as seen in sports and combat, result in axonal damage that disrupts communication and activity between brain regions, potentially impairing emotional regulation. A form of emotional regulation that may be modified by TBI is fear extinction, a type of learning that reduces fear expression. Extinction is the basis of exposure therapy for fear and anxiety disorders. In addition to impaired extinction, PTSD patients display excess avoidance, which reduces the attainment of goals and rewards. Notably, there are homologous brain regions in rodents and humans needed for extinction and avoidance. We will use CCI or repeat closed head injury (rCHI; model of repeat concussion) to test the hypotheses that TBI impairs fear extinction (causing high fear), and impairs the extinction of avoidance (causing excess avoidance). After TBI, we propose that dysfunction in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) will underlie impaired extinction, whereas dysfunction in the amygdala, mPFC, and ventral striatum will underlie excess avoidance. This work will increase the base of scientific and public health evidence about the effects of TBI to extinction and avoidance. Principal techniques in this project include neuronal tract tracing and immunohistochemical approaches that identify activity in brain areas. These protocols rely heavily on the instrumentation and expertise available in the COBRE Neuroimaging and Electrophysiology Facility. The microscopy equipment and image analysis support at the Molecular Sciences Research Center will provide essential tools for achieving the objectives of this project.