An animal model for developing treatments of PTSD core features

用于开发 PTSD 核心特征治疗方法的动物模型

基本信息

批准号：
7770864
负责人：
BERNARD G. SCHREURS
金额：
$ 20.8万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-16 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7770864
关键词：
Acceleration Aftercare Amygdaloid structure Animal Model Animals Anterior Area Behavior Behavioral Biological Biological Process Blinking Brain Categories Cessation of life Characteristics Clinical Complex Conditioned Reflex Conditioned Stimulus Country Cues Data Deceleration Diagnosis Diagnostic Disease Distress Employee Strikes Event Exhibits Exposure to Extinction (Psychology)Face Failure Fluoxetine Fright General Population Heart Rate Human Image Individual Infusion procedures Intervention Lead Learning Learning Disorders Literature Measures Memory Modality Modeling Modification Muscimol Nature Nictitating Membrane Oryctolagus cuniculus Persons Phase Phenotype Physiological Play Post-Traumatic Stress Disorders Preparation Preventive Procedures Public Health Reaction Recovery Reflex action Research Resistance Risk Role Selective Serotonin Reuptake Inhibitor Signal Transduction Societies Stimulus Stress Stressful Event Structure Symptoms Syndrome Testing Therapeutic Intervention Trauma Treatment Failure Unconscious State Ursidae Family Veterans Work base biological adaptation to stress cingulate cortex classical conditioning combat conditioned fear conditioning cost design disease characteristic effective therapy endophenotype expectation experience improved innovation insight interest named group public health relevance relating to nervous system research study response stress related disorder stressor success theories trait treatment strategy

项目摘要

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.

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，特别是在包括对行为和药物治疗都具有抗药性的退伍军人在内的特殊群体中。目前的创伤后应激障碍动物模型基于学习理论，其中与创伤性应激相关的线索被认为会引发应激反应。然而，除了对创伤相关线索的夸大反应之外，创伤后应激障碍的另一个核心特征是对压力事件本身的夸大行为和生理反应。我们已经证明，诸如兔子眨眼和心率之类的反射可能会因学习而变得相当夸张，并且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反射修正（CRM），它表现出与创伤后应激障碍（PTSD）症状类似的特征，即对压力事件的过度行为和生理反应。我们认为，对压力的过度反应以及与压力相关的线索可能构成 PTSD 的内表型。我们的实验表明，通过以明确不成对的方式呈现线索和压力事件，可以显着降低条件反应和 CRM。然而，并不是所有的动物都会灭绝。我们认为未能消除可能构成 PTSD 的第二种内表型。当前提议所基于的假设是，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比当前疗法更好的逆转 PTSD 两个核心特征的方法。目前的提案通过两个具体目标测试这一假设，这两个目标将确定不成对的 CRM 消退的行为和生理特征，这些特征可以预测 PTSD 的心理治疗方法（具体目标 1），并定位和检查 CRM 消退的神经基质，这可以为 CRM 消退开发药理学靶点。治疗 PTSD（具体目标 2）。这里研究的条件反射和条件反射的特定变化可能会提供比目前可用的更全面的 PTSD 核心特征动物模型，并有助于为该疾病提供新的治疗策略。因此，这项研究与公共卫生相关，因为它可以为这个国家越来越多的患有与压力相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，并提供对背后的生物过程的理解。学习和记忆。公共卫生相关性：学习和记忆障碍对个人产生深远的影响，并给社会带来巨大的成本。我们发现，一旦刺激和压力事件之间形成强烈的关联，该刺激的较弱版本就可以引发对原始压力源的全面甚至夸大的反应。这类似于创伤后应激障碍（PTSD）等疾病，其中由于暴露于压力源或创伤以及与该事件相关的线索而导致强烈的痛苦。我们假设我们可以通过明确不配对的消退程序显着减少这两种反应，从而产生更好的 PTSD 动物模型和更好的治疗策略。从当前提案中获得的信息对于理解和制定治疗因创伤经历而夸大对压力源的反应的疾病的策略非常重要。