Developing Treatments for Hyperarousal in a Model System

描述（由申请人提供）：创伤后应激障碍是军人和平民的主要健康问题，治疗已被证明效果不佳。有许多遭受创伤的人会遭受闪回、噩梦、麻木、恐惧、焦虑、失眠、高度警惕、过度觉醒和无法应对的痛苦。目前的行为和药物治疗策略是基于恐惧条件反射，并且只能治疗PTSD的一些症状，因为恐惧的消除并不能处理PTSD患者所经历的各种形式的过度觉醒。无法治疗创伤后应激障碍的更多症状是该领域的一个主要问题。为了解决这个问题，研究人员开发了创伤后应激障碍的动物模型，但许多模型都有一些局限性。首先，他们专注于消除与创伤相关的恐惧，而没有评估或治疗创伤引起的过度觉醒。其次，他们依赖于群体数据，很明显，并不是每个遭受创伤的人都会患上创伤后应激障碍。我们已经开发了一种创伤后应激障碍的动物模型，在这种模型中，条件反射和过度唤醒可以被消除。该模型是基于观察到，随着音调和电击的配对，起跳膜反应变得夸张。这种夸张的反应发生在单独测试电击时（没有音调），是一种被称为条件反射修饰（CRM）的过度唤醒形式。通过比较经典条件反射之前和之后他们对一系列美国强度的反应来检测CRM。我们现在有强有力的证据表明，我们可以“治疗”CRM，也可以消除cr，这使我们能够独特地解决PTSD的两个核心特征，并研究它们之间的关系。重要的是，高水平的CRM只出现在15- 25%暴露于音调-电击配对的兔子中，这与创伤后应激障碍的发病率一致。当前的更新将使用我们的创伤后应激障碍模型来测试三个具体目标，这些目标将在实验台上和床边之间移动，以：(1)通过发现更好的消除CRM的方法，确定CRM治疗的特征，预测创伤后应激障碍症状的治疗；(2)通过失活执行反应的关键区域和使用治疗PTSD的药物来更好地理解CRM治疗的机制；(3)定位和表征CRM治疗的神经底物，开发PTSD症状治疗的靶点。这些目标旨在满足我们提供治疗PTSD的临床方法的目标。

DESCRIPTION (provided by applicant): PTSD is a major health problem for military and civilian populations and treatment has proven to be less than effective. There are many people exposed to trauma who suffer flashbacks, bad dreams, numbing, fear, anxiety, sleeplessness, hyper-vigilance, hyperarousal, and an inability to cope. Current behavioral and drug treatment strategies are based on fear conditioning and are capable of treating only some of the symptoms of PTSD because the extinction of fear does not deal with the various forms of hyperarousal experienced by people with PTSD. The inability to treat more of the symptoms of PTSD is a major problem for the field. To help address this problem, researchers have developed animal models of PTSD but many of these models suffer from several limitations. First, they focus on extinguishing the fear associated with trauma without assessing or treating the hyperarousal caused by trauma. Second, they rely on group data, and it is clear that not everyone exposed to trauma develops PTSD. We have developed an animal model of PTSD in which conditioning and hyperarousal can be extinguished. The model is based on observations that the nictitating membrane response becomes exaggerated as a function of pairing a tone and shock. This exaggerated response occurs when the shock is tested by itself (without the tone) and is a form of hyperarousal termed conditioning-specific reflex modification (CRM). CRM is detected by comparing responses to a range of US intensities by themselves before and after classical conditioning. We now have strong evidence we can "treat" CRM as well as extinguish CRs which uniquely positions us to address two core features of PTSD and examine the relationship between them. Importantly, high levels of CRM only occur in 15-25 percent of rabbits exposed to tone-shock pairings - levels consistent with the incidence of PTSD. The current renewal will use our model of PTSD to test three specific aims that will move between the bench and the bedside to: (1) Determine the characteristics of CRM treatment that predict PTSD symptom treatment by uncovering better ways to extinguish CRM; (2) Understand the mechanisms underlying CRM treatment by inactivating areas key to executing responses and using drugs that treat PTSD to better understand CRM; and (3) Locate and characterize neural substrates of CRM treatment to develop targets for PTSD symptom treatment. These aims are designed to meet our goal of providing clinical approaches to treating PTSD.