Developing Treatments for Hyperarousal in a Model System

在模型系统中开发过度觉醒的治疗方法

基本信息

批准号：
9223738
负责人：
BERNARD G. SCHREURS
金额：
$ 37万
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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223738
关键词：
Address Adrenergic Agents Affect Agonist Amygdaloid structure Animal Model Anterior Anxiety Area Behavior Therapy Behavioral Behavioral Paradigm Biological Models Blinking Cerebellar Nuclei Characteristics Clinical Cues Data Dreams Drug usage Extinction (Psychology)Fright Glutamates Goals Health Incidence Infusion procedures Light Literature Medial Military Personnel Modeling Modification Muscimol National Institute of Mental Health Nictitating Membrane Numbness Oryctolagus cuniculus Paper Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Physiological Population Positioning Attribute Post-Traumatic Stress Disorders Predisposition Prefrontal Cortex Red nucleus structure Reflex action Research Personnel Role Shock Sleeplessness Stimulus Structure Symptoms System Testing Time Trauma base bench to bedside cingulate cortex classical conditioning clinically relevant conditioned fear conditioning design experience experimental study improved indexing insight novel public health relevance relating to nervous system resilience response stressor symptom treatment treatment strategy vigilance

项目摘要

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.

描述（由申请人提供）：创伤后应激障碍（PTSD）是军人和平民的主要健康问题，且治疗已被证明效果不佳。许多遭受创伤的人会出现闪回、噩梦、麻木、恐惧、焦虑、失眠、高度警惕、过度警觉和无法应对等症状。目前的行为和药物治疗策略基于恐惧条件反射，只能治疗 PTSD 的部分症状，因为恐惧的消除并不能解决 PTSD 患者经历的各种形式的过度兴奋。无法治疗更多 PTSD 症状是该领域的一个主要问题。为了帮助解决这个问题，研究人员开发了 PTSD 动物模型，但其中许多模型都存在一些局限性。首先，他们专注于消除与创伤相关的恐惧，而不评估或治疗创伤引起的过度警觉。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（PTSD）。我们开发了一种创伤后应激障碍（PTSD）动物模型，其中条件反射和过度兴奋可以被消除。该模型基于这样的观察：瞬膜响应随着音调和电击的配对而变得夸大。当电击本身（没有音调）进行测试时，就会出现这种夸张的反应，这是一种过度唤醒的形式，称为条件反射修正（CRM）。 CRM 是通过比较经典条件反射前后对一系列美国强度的反应来检测的。我们现在拥有强有力的证据，可以“治疗”CRM 并消除 CR，这使我们能够独特地解决 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 只出现在 15%-25% 暴露于音调电击配对的兔子身上，这一水平与 PTSD 的发生率一致。当前的更新将使用我们的 PTSD 模型来测试三个具体目标，这些目标将在实验室和临床之间移动：（1）通过发现消除 CRM 的更好方法来确定预测 PTSD 症状治疗的 CRM 治疗的特征； (2) 通过灭活执行反应的关键区域并使用治疗 PTSD 的药物来了解 CRM 治疗的潜在机制，以更好地了解 CRM； (3) 定位并表征 CRM 治疗的神经基质，以制定 PTSD 症状治疗的目标。这些目标旨在实现我们提供治疗 PTSD 临床方法的目标。