Can Blocking the Orexin System Enhance Sleep’s Benefits to Therapeutic Exposure for PTSD?

项目摘要/摘要 认知行为疗法(CBT)是治疗创伤后应激障碍(PTSD)的一线疗法，它有 局限性，尤其是在治疗过度觉醒症状方面。因此，当务之急是确定战略以 提高创伤后应激障碍的治疗效果。睡眠障碍在创伤后应激障碍中很常见。睡眠已被牵连 在学习过程中，这是创伤记忆适应性处理的关键。我们的初步调查结果 对创伤后应激障碍患者的研究表明，睡眠特征表明夜间唤醒增加 书面叙述暴露(WNE)干预的折衷治疗效果(写自己的创伤 经验)。食欲素是一种神经肽，与调节睡眠/清醒和压力有关。 反应和情绪行为。一种双重增食欲素受体拮抗剂Suvorexant被发现可以 增强与人类情绪适应相关的睡眠特征。一种食欲素的用药 受体-1拮抗剂促进条件恐惧的消退，这是一种从创伤后应激障碍中恢复的动物模型 和焦虑症。候选人研究计划的长期目标是阐明 睡眠对恢复力和创伤后应激障碍的潜在神经生理机制 恢复并应用这些知识来改进创伤后应激障碍的预防和治疗。要实现这些目标 目标，将追求以下具体目标：1)检查药物阻断的效果 WNE后的食欲素系统对睡眠、创伤后应激障碍症状和间歇期习服的影响；以及2)使用动物 模型阐明抑制食欲素系统对睡眠和睡眠影响的神经机制 恐惧消退后的记忆巩固。在拟议的临床项目中，患有创伤后应激障碍的成年参与者 将在晚上和早上通过干预睡眠完成WNE，或者是Suvorexant(FDA批准的 用于治疗失眠)或安慰剂将在晚上WNE后上床睡觉前服用。 这项拟议的研究是第一次调查食欲素系统在治疗高血压病中的作用。 以暴露为基础的睡眠治疗创伤后应激障碍。在动物研究中，下丘脑中的食欲素神经元 在恐惧消退训练后，使用光遗传方法将被抑制。为了职业发展 计划，候选人将参加神经科学和高级课程的教学和实验室培训活动 临床研究和动物研究的研究方法。将在K01期间获得的新技能集 这段时间将补充候选人目前的专业知识，并使她能够发展一种独立的 翻译研究计划，战略性地利用临床和动物研究方法阐明 睡眠对恢复力和创伤后应激障碍恢复的潜在作用机制。

PROJECT SUMMARY/ABSTRACT Cognitive behavioral therapies (CBT), a first line treatment for posttraumatic stress disorder (PTSD), have limitations particularly in treating hyperarousal symptoms. It is, therefore, imperative to identify strategies to improve effectiveness of treatments for PTSD. Disturbed sleep is common in PTSD. Sleep has been implicated in learning processes that are a key to adaptive processing of trauma memories. Findings of our preliminary study of people with PTSD suggest that sleep characteristics indicating increased nocturnal arousal compromise therapeutic effects of written narrative exposure (WNE) intervention (writing about one’s traumatic experience). Orexins (hypocretins) are neuropeptides implicated in regulating both sleep/wake and stress responses and emotional behaviors. A dual orexin receptor antagonist, suvorexant, has been found to enhance sleep characteristics associated with emotional adaptation in humans. Administration of an orexin receptor-1 antagonist to mice facilitated extinction of conditioned fear, an animal model of recovery from PTSD and anxiety disorders. The long-term objectives of the candidate’s research program are to elucidate neurophysiological mechanisms underlying the potential for sleep to contribute to resilience and PTSD recovery and apply this knowledge to improve PTSD prevention and treatment. To accomplish these objectives, the following specific aims will be pursued: 1) to examine effects of pharmacologically blocking the orexin system after WNE on sleep, PTSD symptoms, and intersession habituation; and 2) to use an animal model to elucidate neural mechanisms underlying the effects of inhibiting the orexin system on sleep and memory consolidation following fear extinction. In the proposed clinical project, adult participants with PTSD will complete WNE in the evening and morning with intervening sleep, and either suvorexant (FDA-approved for treatment of insomnia) or placebo will be administered prior to going to bed following the evening WNE. This proposed study is the first to investigate the contribution of the orexin system to therapeutic effects of exposure-based treatment for PTSD through sleep. In the animal study, orexin neurons in the hypothalamus will be inhibited using optogenetic methods following a fear extinction training. For the career development plan, the candidate will participate in didactic and in-lab training activities in neuroscience and advanced research methodologies of both clinical and animal studies. The new skill set to be acquired during the K01 period will complement the candidate’s current expertise and enable her to develop an independent translational research program that strategically utilizes clinical and animal study methods to elucidate mechanisms underlying sleep’s contribution to resilience and PTSD recovery.