Neurobiological mechanisms underlying PTSD

 描述（由申请人提供）： 创伤后应激障碍（PTSD）正迅速成为伊拉克自由行动（OIF）/持久自由行动（OEF）/新黎明行动（OND）退伍军人面临的最普遍的心理健康问题。创伤后应激障碍是一种毁灭性的疾病，也会增加自杀，抑郁和物质使用障碍的风险。不幸的是，PTSD通常对目前的治疗干预有抵抗力，并且完全康复是罕见的。靶向治疗的发展是有效治疗创伤后应激障碍的一个有希望的途径，但要发展这些治疗方法，首先我们必须更好地了解潜在的神经生物学机制。该项目的目标是确定患有PTSD的退伍军人是否在由终纹床核（BNST）介导的焦虑神经回路中发生改变。在啮齿类动物中，BNST介导焦虑、过度警觉和压力的行为效应--类似于创伤后应激障碍的症状。在患有创伤后应激障碍的退伍军人中，这些症状在威胁不可预测的情况下会增加;也就是说，威胁事件可能发生也可能不发生。我们建议比较OEF/OIF/OND战斗暴露退伍军人与PTSD。我们已经开发了新的方法来检查BNST激活不可预测的威胁，使用功能性磁共振成像（fMRI）。这项研究将集中在三个具体目标：（1）确定与没有PTSD的退伍军人相比，患有PTSD的退伍军人是否具有更高的BNST激活;（2）确定患有PTSD的退伍军人中BNST与焦虑回路其他区域的连接改变;（3）判断应激反应是否（通过皮质醇和皮肤电导测量）介导BNST功能（激活和连接）和PTSD症状之间的关联。最终，我们的目标是阐明PTSD的神经生物学机制，以确定新的治疗脑靶点。

 DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is rapidly becoming the most prevalent mental health problem facing Veterans of Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF)/Operation New Dawn (OND). PTSD is a devastating disorder that also increases risk for suicide, depression, and substance use disorders. Unfortunately, PTSD is often resistant to current therapeutic interventions and a full recovery is uncommon. The development of targeted therapies is a promising avenue for the effective treatment of PTSD, but to develop these treatments, first we must better understand the underlying neurobiological mechanisms. The goal of the proposed project is to determine whether combat Veterans with PTSD have alterations in an anxiety neural circuit mediated by the bed nucleus of the stria terminalis (BNST). In rodents, the BNST mediates anxiety, hypervigilance, and behavioral effects of stress-similar to symptoms of PTSD. In combat Veterans with PTSD, these symptoms are increased in situations where a threat is unpredictable; that is, a threatening event may or may not occur. We propose to compare OEF/OIF/OND combat-exposed Veterans with and without PTSD. We have developed novel methods to examine BNST activation to unpredictable threats using functional magnetic resonance imaging (fMRI). The study will focus on three specific aims: (1) determine whether combat Veterans with PTSD have heightened BNST activation compared to combat Veterans without PTSD; (2) identify alterations in BNST connectivity with other regions of the anxiety circuit in Veterans with PTSD; (3) determine whether stress response (measured by cortisol and skin conductance) mediates the association between BNST function (activation and connectivity) and PTSD symptoms. Ultimately we aim to elucidate the neurobiological mechanisms underlying PTSD to identify novel brain targets for treatment.