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

项目总结/摘要 创伤性脑损伤（TBI）每年影响约400万平民和士兵，其中许多人是 被诊断出患有创伤后应激障碍（PTSD）等心理健康状况。有共同 导致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显示， 创伤性脑损伤和创伤后应激障碍的区别然而，动物研究显示了相互矛盾的结果。以确定 无论创伤性脑损伤和创伤后应激障碍之间是否存在关系，都必须使用可靠的大脑来建立生物学联系。 损伤模型和行为测试。临床上，有两大类TBI，其中研究模型 存在：局灶性（例如挫伤），由受控皮质撞击（CCI）产生，和弥漫性（例如脑震荡）， 通过重力落在封闭的头部上而产生。对于CCI，损伤水平和组织变形程度 与挫伤相关的生理参数相似。在脑震荡中，头部的撞击加上角度 加速会产生神经和认知功能障碍。此外，重复脑震荡，如在 运动和战斗，导致轴突损伤，破坏大脑区域之间的交流和活动， 可能会影响情绪调节一种可能被TBI改变的情绪调节形式是恐惧 灭绝，一种减少恐惧表达的学习方式。灭绝是恐惧暴露疗法的基础 和焦虑症除了消退受损，PTSD患者还表现出过度回避， 减少目标和奖励的实现。值得注意的是，在啮齿动物中有同源的脑区， 人类需要灭绝和避免。我们将使用CCI或重复闭合性脑损伤（rCHI; 重复脑震荡），以测试假设，TBI损害恐惧灭绝（引起高度恐惧）， 避免的消失（导致过度避免）。脑外伤后，我们认为杏仁核功能障碍， 海马和内侧前额叶皮质（mPFC）的功能障碍将导致消退受损，而 杏仁核、mPFC和腹侧纹状体将成为过度回避的基础。这项工作将增加基础 关于TBI对灭绝和避免的影响的科学和公共卫生证据。种主要技术 包括神经束追踪和免疫组织化学方法， 地区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 神经成像和电生理设施。显微镜设备和图像分析支持在 分子科学研究中心将为实现本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.