Dopamine function, inflammation and connectivity in PTSD

PTSD 中的多巴胺功能、炎症和连接

• 批准号: 10405521
• 负责人: James Douglas Bremner
• 金额: $ 71.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405521
• 关键词: Acute-Phase Proteins; Address; Affect; American; Amygdaloid structure; Anhedonia; Animal Model; Arousal; Behavior; Behavioral; Behavioral Symptoms; Biological Markers; Blood; Blood flow; Blood specimen; Brain; Brain imaging; Brain region; C-reactive protein; Clinical; Coronary Arteriosclerosis; Corpus striatum structure; DSM-IV; Dopamine; Early-life trauma; Enrollment; Extinction (Psychology); Fright; Functional disorder; Future; General Population; Goals; Health; Hippocampus (Brain); Image; Immune system; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Knowledge; Laboratories; Lateral; Lead; Learning; Macaca mulatta; Major Depressive Disorder; Measures; Medial; Mental disorders; Meta-Analysis; Microdialysis; Modeling; Motivation; Negative Valence; Neurobiology; Neurosecretory Systems; Neurotransmitters; Pathway interactions; Patients; Performance; Peripheral; Plasma; Positive Valence; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Protocols documentation; Psychological reinforcement; Psychosocial Stress; Public Health; Reporting; Research; Research Proposals; Resolution; Rest; Rewards; Role; Severities; Sexual abuse; Short-Term Memory; Signal Transduction; Stress; Symptoms; System; Therapeutic; Trauma; Traumatic Stress Disorders; Ventral Striatum; Visit; Woman; Work; acute stress; anxiety symptoms; base; behavior measurement; biological adaptation to stress; blood oxygen level dependent; cognitive performance; cohort; combat; comorbidity; cytokine; depression model; dopamine system; effective therapy; experience; imaging study; immune activation; improved; inflammatory marker; laboratory experience; men; neural circuit; neurochemistry; neuroimaging; neuropsychiatric disorder; neurotransmission; pre-clinical; psychiatric symptom; response; reward circuitry; sex; stress symptom; stressor; symptom cluster; transmission process; trauma exposure; vehicular accident

PROJECT SUMMARY The objective of this research proposal is to assess changes in stress-induced dopamine function and inflammatory response with connectivity and behavioral symptoms in posttraumatic stress disorder (PTSD). Imaging studies of PTSD from our group and others have described altered activation and functional connectivity between a variety of brain regions including the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Despite increasing knowledge of circuit dysfunction in PTSD, functional neuroimaging studies performed to date have not provided adequate information about neurotransmitter systems and neurobiological pathways that affect such circuits to maintain PTSD symptoms. PTSD is an important public health problem that affects 7 to 8 % of the general population with higher rates of occurrence in victims of sexual abuse (10%). Psychosocial stress and trauma activate neuroendocrine and immune systems and elevate circulating concentrations of inflammatory markers. Activation of the immune system and release of inflammatory cytokines disrupts the mesocortical/limbic dopamine system and are associated with symptoms of anxiety, re-experiencing, arousal and avoidance that are prominent in PTSD. Findings from our group demonstrate blunted release of dopamine, as measured by microdialysis, in a cytokine-induced inflammatory animal models. Elevated inflammatory markers (e.g. plasma CRP and cytokines) were also associated with disrupted mesolimbic and mesocortical circuits, including decreased ventral striatum and amygdala to mPFC functional connectivity, in association with symptoms of anxiety in major depressive disorder, and particularly in patients with comorbid PTSD. Functional brain imaging studies to date have outlined a neural circuitry of PTSD but these imaging measures provide only general measures of brain function (e.g. blood flow) and do not address specific neurochemical pathways. The proposed research will address this knowledge gap by examining the following questions 1) Is stress-induced prefrontal and limbic DA neurotransmission reduced in patients with PTSD?, 2) Are stress-induced inflammatory biomarkers higher in PTSD and associated with symptom severity? and 3) Are disruptions in resting measures of functional behavior and connectivity associated with PTSD and symptom severity? Our proposed work builds on our laboratory’s experience in imaging PTSD including demonstration of blood flow and blood oxygen level-dependent reductions in mPFC function. Our long-term goal is to improve our mechanistic framework of stress-induced dopaminergic function and the inflammatory response in PTSD, and to identify mechanisms that can predict PTSD symptoms and their severity that may improve future treatment approaches.

项目摘要 该研究建议的目的是评估压力引起的多巴胺功能的变化和 创伤后应激障碍的连通性和行为症状的炎症反应 （PTSD）。来自我们小组和其他人的PTSD的成像研究描述了激活和功能的改变 各种大脑区域之间的连通性，包括介质前额叶皮层（MPFC），杏仁核和 海马。尽管对PTSD中电路功能障碍的了解越来越多，但功能性神经影像学研究 迄今为止执行的尚未提供有关神经递质系统和神经生物学的足够信息 影响此类电路以保持PTSD症状的途径。 PTSD是一个重要的公共卫生问题 影响7％至8％的普通人群，违反性虐待的发生率较高（10％）。 社会心理压力和创伤激活神经内分泌和免疫系统，并提升循环 炎症标记的浓度。免疫系统的激活和炎症细胞因子的释放 破坏中皮层/边缘多巴胺系统，与动画，重新体验，体验症状有关 PTSD中突出的唤醒和回避。我们小组的发现表明发行的钝器 通过微透析测量的多巴胺在细胞因子诱导的炎性动物模型中。高架 炎症标记（例如等离子体CRP和细胞因子）也与中断中断和中断有关 中皮层圆，包括腹侧纹状体和杏仁核的减少到MPFC功能连接性 与主要抑郁症的动画症状相关，尤其是合并症患者 PTSD。迄今为止的功能性脑成像研究概述了PTSD的神经回路，但这些成像 措施仅提供一般的脑功能措施（例如血流），并且不解决特定的问题 神经化学途径。拟议的研究将通过检查以下内容来解决这一知识差距 问题1）PTSD患者的压力诱导的前额叶和边缘DA神经传递是否减少了？ 压力引起的炎症生物标志物在PTSD中是否较高并且与症状严重程度相关？和3）是 与PTSD和症状相关的功能行为和连通性的休息措施中断 严重程度？我们提出的工作以实验室在成像PTSD方面的经验为基础 MPFC功能中的血流和血氧水平依赖性降低。我们的长期目标是改善我们的 应激诱导的多巴胺能功能和PTSD中的炎症反应的机理框架， 确定可以预测PTSD症状及其严重程度的机制，以改善未来的治疗 方法。