An animal model for developing treatments of PTSD core features

描述（由申请人提供）：尽管基于行为的疗法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，特别是在特殊群体中，包括战斗退伍军人，他们对行为和药物治疗都有抵抗力。目前创伤后应激障碍的动物模型是基于学习理论的，其中与创伤压力相关的线索被认为会引发压力反应。然而，除了对创伤相关线索的夸张反应外，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可以作为学习的结果变得非常夸张，这些变化可以在单独测试反射时观察到。这种现象被称为条件特异性反射修正（CRM），其表现出的特征与PTSD症状类似，即对压力事件做出夸张的行为和生理反应。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创伤后应激障碍的一种内表型。我们的实验表明，通过以一种明确的不配对的方式呈现线索和压力事件，条件反应和客户关系管理都可以显著减少。然而，并不是所有的动物都会灭绝。我们认为，熄灭失败可能构成PTSD的第二种内表型。目前的建议所基于的假设是，与目前的治疗方法相比，逆转对创伤相关线索的反应以及对创伤本身的反应可能提供一种更好的方法来逆转创伤后应激障碍的两个核心特征。目前的提案以两个特定目标来验证这一假设，即确定未配对的CRM消失的行为和生理特征，这可能会预测PTSD的心理治疗方法（特定目标1），并定位和检查CRM消失的神经基质，从而可能开发PTSD治疗的药理学靶点（特定目标2）。本文研究的条件反应和反射中的条件特异性变化可能提供比现有的更全面的创伤后应激障碍核心特征的动物模型，并有助于提供新的治疗策略。因此，这项研究与公共卫生有关，因为它可以为这个国家越来越多的与压力有关的学习和记忆障碍，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，对社会造成巨大的代价。我们发现，一旦在刺激和压力事件之间形成强烈的联系，该刺激的较弱版本可以触发对原始压力源的全面反应，甚至是夸张的反应。这与创伤后应激障碍（PTSD）类似，后者是由于暴露于压力源或创伤以及与该事件相关的线索而产生强烈的痛苦。我们假设，我们可以显著减少这两种反应，通过明确的非配对灭绝程序，导致更好的创伤后应激障碍的动物模型和更好的治疗策略。从目前的建议中获得的信息对于理解和制定治疗因创伤经历而对压力源的反应被夸大的疾病的策略将是重要的。

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.