BNST neurocircuitry in PTSD

PTSD 中的 BNST 神经回路

• 批准号: 9269675
• 负责人: JENNIFER URBANO BLACKFORD
• 金额: $ 19.75万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-28 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269675
• 关键词: Acute; Address; Adult; Afghanistan; Amygdaloid structure; Animal Model; Anxiety; Behavior; Brain; Brain region; Complex; Data; Depression and Suicide; Development; Disease; Disease remission; Exhibits; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Galvanic Skin Response; General Population; Hippocampus (Brain); Home environment; Human; Hydrocortisone; Hypothalamic structure; Imaging technology; Individual; Individual Differences; Intervention; Iraq; Knowledge; Lead; Left; Maps; Measures; Mediating; Mental Health; Methods; Negative Valence; Neurobiology; Nucleic Acid Regulatory Sequences; Patient Self-Report; Pattern; Physiological; Physiology; Post-Traumatic Stress Disorders; Prefrontal Cortex; Public Health; Recovery; Research; Research Domain Criteria; Resistance; Rodent; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Stress; Structure of terminal stria nuclei of preoptic region; Substance Use Disorder; Symptoms; System; Testing; Therapeutic Intervention; Time; Trauma; Uncertainty; Veterans; Work; base; biological adaptation to stress; combat; common symptom; effective therapy; in vivo; learning extinction; neural circuit; neurobiological mechanism; neuroimaging; novel; prevent; public health relevance; response; success; suicidal risk; targeted treatment; therapy development

 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.

 描述（由申请人提供）：创伤后应激障碍（PTSD）是一种致残和流行的疾病，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，次要影响包括自杀，抑郁和物质使用障碍的风险增加。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。针对潜在病理生理学的治疗方法的发展是有效治疗PTSD的一个有希望的途径，但要开发这些治疗方法，首先我们必须更好地了解潜在的神经生物学机制。迄今为止，大多数关于PTSD神经生物学机制的研究都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还介导了对压力的过度警觉和反应，这可能解释了PTSD的关键特征。因此，我们认为患有PTSD的退伍军人在BNST介导的焦虑回路中发生了改变。我们最近的特点BNST神经回路在人类和开发了新的方法来检查BNST功能。我们的初步数据表明，BNST是专门从事的情况下，威胁是不可预测的，和PTSD的个人表现出显着提高BNST反应不可预测的威胁相对于可预测的威胁。该研究将集中在三个特定的目标：（1）调查BSNT功能在PTSD个体，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PTSD相关的功能障碍模式。电路级方法对于识别电路中区域之间的相互作用至关重要。(3)在RDoC负效价系统/对潜在伤害的反应中检测分析单位之间的关系。一个维度的方法，是符合NIMH的RDoC目标是在这个项目中，通过检查一个新的神经生物学机制的PTSD跨多个单元的分析，从神经回路的行为。该项目还将阐明负价系统的两个结构中的脑生理症状关系：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PTSD的神经生物学机制，以确定新的治疗脑靶点。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提供新的治疗靶点。