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）：PTSD是军事和平民人口的主要健康问题，事实证明，治疗效果不佳。有很多人遭受创伤，他们遭受了倒叙，噩梦，麻木，恐惧，焦虑，失眠，过度保存，过度疗程，并且无法应付。当前的行为和药物治疗策略是基于恐惧调节的，并且能够仅治疗PTSD的某些症状，因为恐惧的灭绝并不涉及PTSD患者所经历的各种形式的超阳光。无法治疗PTSD的更多症状是该领域的主要问题。为了帮助解决这个问题，研究人员开发了PTSD的动物模型，但其中许多模型都受到了一些局限性。首先，他们专注于消除与创伤相关的恐惧，而无需评估或治疗受创伤引起的高伴。其次，他们依靠小组数据，很明显，并非每个人都会受到创伤的每个人都会发展PTSD。我们已经开发了一种动物模型的PTSD模型，其中可以熄灭调理和高音。该模型是基于观察到的，即作为配对音调和冲击的函数，刺激性膜响应被夸大了。当电击本身测试（没有音调）时，就会发生这种夸大的响应，并且是一种高响应的条件特异性反射修饰（CRM）的形式。通过在经典条件之前和之后，通过比较对美国强度范围的响应来检测到CRM。现在，我们有强有力的证据我们可以“治疗” CRM以及熄灭CRS，这些CRS唯一地定位了我们解决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仅发生在15-25％的兔子中暴露于音调震动配对的兔子中 - 与PTSD的发生率一致。当前的续订将使用我们的PTSD模型来测试三个特定目标，这些特定目标将在板凳和床边移动到：（1）确定CRM治疗的特征，这些特征通过发现更好的方法来熄灭CRM，以预测PTSD症状治疗；（2）通过使CRM治疗的机制通过灭活区域来理解执行反应和使用治疗PTSD的药物以更好地了解CRM的药物的关键；（3）定位和表征CRM治疗的神经底物，以开发用于PTSD症状治疗的靶标。这些目标旨在满足我们提供治疗PTSD的临床方法的目标。