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（由适用提供）：创伤后应激障碍（PTSD）是一种残疾和普遍的疾病，它正迅速成为退伍军人从伊拉克和阿富汗回家的老兵面临的最常见的心理健康问题。除了PTSD的毁灭性影响外，次要影响还包括增加自杀，抑郁和药物使用障碍的风险。不幸的是，PTSD通常对当前的治疗干预措施有抵抗力，并且完全恢复并不常见。针对潜在病理生理学的疗法的发展是有效治疗PTSD的途径，但是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，关于PTSD神经生物学机制的大多数研究都集中在杏仁核介导的恐惧回路上。引人注目的动物模型表明，由脊柱末端（BNST）介导的不同神经生理学对焦虑至关重要。 BNST还介导了过度维护和对压力的反应，这可能解释了PTSD的关键特征。这就是我们建议，与PTSD的战斗退伍军人在BNST介导的动画电路中具有改变。我们最近表征了人类的BNST神经回路，并开发了研究BNST功能的新方法。我们的初步数据表明，BNST是研究PTSD个体的BSNT功能，以确定PTSD是否与BNST对不可预测的威胁的增强响应有关（2）识别PTSD与PTSD相关的功能性功能障碍性模式在BNST介导的动画电路中。电路级方法对于确定电路中区域之间的相互作用至关重要。 （3）测试单位之间的关系o分析在RDOC负面价系统/对潜在危害的响应中。该项目中与NIMH的RDOC目标一致的维度方法是通过在多个分析中检查PTSD的新型神经生物学机制，从神经元电路到行为。该项目还将阐明负价系统的两个结构内的脑生理 - 症状关系：对潜在伤害（不可预测的威胁，BNST）的响应和对急性威胁（可预测的威胁，杏仁核）的反应。最终，我们旨在阐明PTSD基础的神经生物学机制，以鉴定新的大脑靶标。重要的是，BNST和Amygdala对药物的反应不同。因此，如果我们找到了PTSD中BNST改变的证据，那么BNST和对不可预测的威胁的反应将为治疗提供新的目标。