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。有许多人暴露在创伤中，他们遭受闪回，噩梦，麻木，恐惧，焦虑，失眠，过度警惕，过度觉醒和无法科普。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，因为恐惧的消失不能处理PTSD患者经历的各种形式的过度觉醒。无法治疗更多的PTSD症状是该领域的一个主要问题。为了帮助解决这个问题，研究人员已经开发了PTSD的动物模型，但这些模型中的许多都受到一些限制。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，并不是每个暴露于创伤的人都会患上创伤后应激障碍。我们已经建立了一个创伤后应激障碍的动物模型，在这个模型中，条件反射和过度觉醒可以被消除。该模型是基于瞬膜反应成为一个函数的配对音调和冲击夸大的观察。当电击本身被测试时（没有音调），这种夸张的反应就会发生，这是一种被称为条件反射修正（CRM）的过度觉醒形式。通过比较经典条件反射前后对一系列US强度的反应来检测CRM。我们现在有强有力的证据，我们可以“治疗”CRM以及消除CR，这使我们能够解决PTSD的两个核心特征，并检查它们之间的关系。重要的是，高水平的CRM只发生在15- 25%的兔子暴露于色调休克配对-水平与创伤后应激障碍的发病率一致。目前的更新将使用我们的PTSD模型来测试三个具体的目标，这些目标将在实验室和床边之间移动：（1）通过发现更好的消除CRM的方法来确定CRM治疗的特征，从而预测PTSD症状的治疗;（2）通过灭活执行响应的关键区域和使用治疗PTSD的药物来更好地理解CRM，从而了解CRM治疗的机制;以及（3）定位和表征CRM治疗的神经基质以开发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.