BNST neurocircuitry in PTSD

 描述(申请人提供)：创伤后应激障碍(PTSD)是一种致残和流行的障碍，正迅速成为从伊拉克和阿富汗回国的退伍军人面临的最常见的心理健康问题。除了创伤后应激障碍的破坏性影响外，次要影响还包括增加自杀、抑郁和物质使用障碍的风险。不幸的是，创伤后应激障碍往往对当前的治疗干预措施具有抵抗力，完全康复的情况并不常见。针对创伤后应激障碍的潜在病理生理机制的治疗方法的发展是有效治疗创伤后应激障碍的有效途径，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。到目前为止，关于创伤后应激障碍的神经生物学机制的研究大多集中在杏仁核介导的恐惧回路上。令人信服的动物模型表明，由终纹床核(BNST)介导的不同神经回路对焦虑至关重要。BNST还调节对压力的高度警惕和反应，这可能解释了创伤后应激障碍的关键特征。因此，我们认为患有创伤后应激障碍的战斗退伍军人在BNST介导的焦虑回路中存在变化。我们最近已经确定了人类BNST神经回路的特征，并开发了新的方法来检测BNST功能。我们的初步数据表明，BNST特别适用于威胁不可预测的情况，患有创伤后应激障碍的人对不可预测威胁的BNST反应明显高于可预测威胁。这项研究将集中于三个特定的目标：(1)调查PTSD患者的BSNT功能，以确定PTSD是否与BNST对不可预测的威胁的反应增强有关(2)确定BNST介导的焦虑回路中与PTSD相关的功能障碍的模式。电路级方法对于识别电路中各区域之间的相互作用至关重要。(3)测试RDOC负价系统中的分析单位之间的关系/对潜在危害的响应。在这个项目中，采用了一种与NIMH的RDoC目标一致的维度方法，通过从神经回路到行为的多个分析单元来研究创伤后应激障碍的新的神经生物学机制。这个项目还将阐明负价系统两个结构中的大脑-生理-症状关系：对潜在伤害的反应(不可预测的威胁，BNST)和对急性威胁的反应(可预测的威胁，杏仁核)。最终，我们的目标是阐明创伤后应激障碍背后的神经生物学机制，以确定用于治疗的新的大脑靶点。重要的是，BNST和杏仁核对药物的反应不同；因此，如果我们发现PTSD中BNST改变的证据，BNST和对不可预测的威胁的反应将为治疗提供新的靶点。

 DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a disabling and prevalent disorder that is rapidly becoming the most common mental health problem facing Veterans returning home from Iraq and Afghanistan. In addition to the devastating effects of PTSD, secondary effects include increased 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 therapies targeted at the underlying pathophysiology is a promising avenue for the effective treatment of PTSD, but to develop these treatments, first we must better understand the underlying neurobiological mechanisms. To date, most research on the neurobiological mechanisms of PTSD has focused on an amygdala-mediated fear circuit. Compelling animal models show that a different neural circuit, mediated by the bed nucleus of the stria terminalis (BNST), is critical for anxiety. The BNST also mediates hypervigilance and responses to stress, which may explain the critical features of PTSD. Thus, we propose that combat Veterans with PTSD have alterations in a BNST-mediated anxiety circuit. We have recently characterized the BNST neural circuitry in humans and have developed novel methods to examine BNST function. Our preliminary data demonstrates that the BNST is specifically engaged in situations where a threat is unpredictable, and that individuals with PTSD show significantly heightened BNST responses to unpredictable threat relative to predictable threat. The study will focus on three specific aims: (1) Investigate BSNT function in individuals with PTSD to determine if PTSD is associated with heightened BNST responses to unpredictable threat (2) Identify patterns of PTSD-related functional dysconnectivity in the BNST-mediated anxiety circuit. A circuit-level approach is critical for identifying interactions between regions in the circuit. (3) Test for relationships between units o analysis in the RDoC Negative Valence System/Response to Potential Harm. A dimensional approach that is consistent with NIMH's RDoC objectives is employed in this project by examining a novel neurobiological mechanism of PTSD across multiple units of analysis, from neural circuit to behavior. This project will also elucidate the brain-physiology-symptom relationships within two constructs of the Negative Valence system: Response to Potential Harm (unpredictable threat, BNST) and Response to Acute Threat (predictable threat, amygdala). Ultimately we aim to elucidate the neurobiological mechanisms underlying PTSD to identify novel brain targets for treatment. Importantly, the BNST and amygdala respond differently to pharmacological agents; therefore, if we find evidence for BNST alteration in PTSD, the BNST and responses to unpredictable threat will provide novel targets for treatment.