An animal model for developing treatments of PTSD core features

描述（由申请人提供）：尽管基于行为的治疗在治疗创伤后应激障碍（PTSD）方面取得了一定的成功，但仍有相当大的改进空间，特别是在对行为和药物治疗都有抵抗力的特殊群体中，包括退伍军人。目前的创伤后应激障碍动物模型是基于学习理论，其中与创伤应激相关的线索被认为会引发应激反应。然而，除了对与创伤相关的线索的夸张反应之外，PTSD的另一个核心特征是对压力事件本身的夸张行为和生理反应。我们已经证明，像兔子眨眼和心率这样的反射会因为学习而变得非常夸张，当反射本身被测试时，这些变化可以被观察到。这种现象被称为条件反射修正（CRM），表现出与对压力事件的夸张行为和生理反应的PTSD症状相当的特征。我们认为，对压力的过度反应和与压力相关的线索可能构成PTSD的内表型。我们的实验表明，条件反应，以及CRM都可以显着减少提出的线索和压力事件在一个明确的不成对的方式。然而，并非所有的动物都会灭绝。我们认为，未能扑灭可能构成了第二个内表型的创伤后应激障碍。目前的建议所基于的假设是，逆转与创伤相关的线索的反应以及对创伤本身的反应可能提供比当前疗法更好的逆转PTSD的两个核心特征的方法。目前的建议测试这一假设有两个具体的目标，将确定未配对CRM灭绝的行为和生理特征，可以预测PTSD的心理治疗方法（具体目标1），并定位和检查CRM灭绝的神经基质，可能开发治疗PTSD的药理学靶点（具体目标2）。无论是条件反射和条件反射的具体变化，在这里研究可能提供一个更全面的动物模型的核心功能的创伤后应激障碍比目前可用的，并有助于提供新的治疗策略的障碍。因此，这项研究与公共卫生有关，因为它可以为该国越来越多的学习和记忆中与压力有关的障碍，特别是创伤后应激障碍的人提供预防和治疗干预措施，并提供对学习和记忆基础的生物过程的理解。公共卫生相关性：学习和记忆障碍对个人有深远的影响，并导致社会付出巨大代价。我们发现，一旦刺激和压力事件之间形成强烈的联系，较弱的刺激可以引发对原始压力源的全面甚至夸张的反应。这类似于创伤后应激障碍，其中强烈的痛苦是由于暴露于压力源或创伤以及与该事件相关的线索。我们假设，我们可以显着减少这两个反应与明确的非配对灭绝程序，导致更好的动物模型的创伤后应激障碍和更好的治疗策略的障碍。从目前的建议中获得的信息将是重要的理解和发展战略，以治疗疾病的反应，压力被夸大的创伤经历的结果。

DESCRIPTION (provided by applicant): Despite modest success of behavior-based therapy in treating Post Traumatic Disorder Stress (PTSD), there is still considerable room for improvement especially among special groups including combat veterans that have been resistant to both behavioral and pharmacological therapy. Current animal models of PTSD are based on learning theories where cues associated with traumatic stress are thought to elicit stress reactions. However, in addition to exaggerated reactions to the cues associated with trauma, another core feature of PTSD is exaggerated behavioral and physiological responding to stressful events themselves. We have shown that reflexes such as the rabbit eyeblink and heart rate can become quite exaggerated as a result of learning and these changes can be observed when the reflex is tested by itself. This phenomenon is called conditioning-specific reflex modification (CRM) and demonstrates traits that are comparable to the PTSD symptoms of exaggerated behavioral and physiological responding to stressful events. We propose that exaggerated responding to stress and the cues associated with stress may constitute an endophenotype of PTSD. Our experiments show that conditioned responses as well as CRM can both be dramatically reduced by presenting the cues and the stressful event in an explicitly unpaired manner. However, no all animals extinguish. We propose that a failure to extinguish may constitute a second endophenotype of PTSD. The hypothesis on which the current proposal is based is that reversing the responses to cues associated with trauma as well as the reactions to trauma itself may provide a better means of reversing two core features of PTSD than current therapies. The current proposal tests this hypothesis with two specific aims that will determine the behavioral and physiological characteristics of unpaired CRM extinction that may predict psychotherapeutic approaches to PTSD (Specific Aim 1) and locate and examine neural substrates for CRM extinction that may develop pharmacological targets for the treatment of PTSD (Specific Aim 2). Both the conditioned responses and the conditioning-specific changes in the reflex studied here may provide a more comprehensive animal model of core features of PTSD than those currently available and help provide new treatment strategies for the disorder. The research is therefore relevant to public health because it may provide preventive and therapeutic interventions for the growing numbers of persons in this country with stress-related disorders in learning and memory, particularly PTSD, as well as provide an understanding of the biological processes that underlie learning and memory. PUBLIC HEALTH RELEVANCE: Disorders of learning and memory have profound consequences for the individual and result in an enormous cost to society. We have found that once a strong association is formed between a stimulus and a stressful event, weaker versions of that stimulus can trigger the reaction to the original stressor in its full-blown or even exaggerated form. This is similar to disorders such as PTSD where intense distress results from exposure to a stressor or trauma and the cues associated with that event. We hypothesize that we can significantly reduce both these reactions with an explicitly unpaired extinction procedure leading to a better animal model of PTSD and better treatment strategies for the disorder. The information obtained from the current proposal will be important for understanding and developing strategies to treat disorders where reactions to stressors are exaggerated as a result of traumatic experience.