An animal model for developing treatments of PTSD core features

描述(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，包括对行为疗法和药物疗法都具有抵抗力的退伍军人。目前的创伤后应激障碍动物模型是基于学习理论，在这些理论中，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大反应外，创伤后应激障碍的另一个核心特征是对应激事件本身的夸大行为和生理反应。我们已经证明，由于学习的结果，兔眼眨眼和心率等反射会变得非常夸张，当反射本身进行测试时，可以观察到这些变化。这种现象被称为条件性反射修正(CRM)，表现出类似于创伤后应激障碍症状的特征，即对应激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暗示可能构成了创伤后应激障碍的一种内在表型。我们的实验表明，通过以明显不成对的方式呈现线索和应激事件，条件性反应和应激反应都可以显著减少。然而，并不是所有的动物都会灭绝。我们认为，未能熄灭可能构成创伤后应激障碍的第二种内表型。当前提议所基于的假设是，与目前的治疗方法相比，逆转对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。目前的提案用两个特定的目标来检验这一假说，这两个目标将确定可能预测创伤后应激障碍的心理治疗方法的未配对的CRM消退的行为和生理特征(特定目标1)，以及定位和检查可能为PTSD的治疗开发药理靶点的CRM消退的神经底物(特定目标2)。这里研究的条件性反应和条件性反射的特定变化可能会提供比目前可用的更全面的创伤后应激障碍核心特征的动物模型，并有助于为这种疾病提供新的治疗策略。因此，这项研究与公共卫生有关，因为它可以为该国越来越多的学习和记忆应激相关障碍的人提供预防和治疗干预措施，特别是创伤后应激障碍，并提供对构成学习和记忆基础的生物过程的了解。公共卫生相关性：学习和记忆障碍对个人具有深远的后果，并导致社会的巨大代价。我们发现，一旦刺激和应激事件之间形成了强烈的联系，这种刺激的较弱版本就可以触发对原始应激源的全面甚至夸张的反应。这类似于创伤后应激障碍等障碍，在创伤后应激障碍中，强烈的痛苦是由于暴露在应激源或创伤以及与该事件相关的线索中而产生的。我们假设，通过一种明显不成对的消退程序，我们可以显着减少这两种反应，从而获得更好的创伤后应激障碍动物模型和更好的治疗策略。从目前的提案中获得的信息对于理解和制定治疗由于创伤经历导致对应激源的反应被夸大的障碍的策略将是重要的。

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.