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.

项目总结 这项研究计划的目的是评估应激诱导的多巴胺功能和 创伤后应激障碍的炎性反应与连接性和行为症状 (创伤后应激障碍)。我们小组和其他人对创伤后应激障碍的成像研究描述了激活和功能的改变 不同脑区之间的连接，包括内侧前额叶皮质(MPFC)，杏仁核和 海马体。尽管对创伤后应激障碍的电路功能障碍的了解越来越多，但功能神经成像研究 到目前为止还没有提供关于神经递质系统和神经生物学的足够信息 影响这类回路的通路维持创伤后应激障碍症状。创伤后应激障碍是一个重要的公共卫生问题 影响到总人口的7%至8%，性虐待受害者的发生率较高(10%)。 心理应激和创伤激活神经内分泌和免疫系统，提高血液循环 炎性标志物的浓度。激活免疫系统和释放炎性细胞因子 扰乱中皮质/边缘多巴胺系统，并与焦虑、重新体验、 性唤醒和回避在创伤后应激障碍中尤为突出。我们小组的发现显示钝化的释放 在细胞因子诱导的炎症动物模型中，用微透析法测定多巴胺。高架 炎症标志物(例如，血浆CRP和细胞因子)也与中边缘和 中脑皮质环路，包括腹侧纹状体和杏仁核到mPFC功能连接的减少，在 严重抑郁障碍患者焦虑症状的相关性，尤其是合并抑郁障碍患者的焦虑症状 创伤后应激障碍。到目前为止，脑功能成像研究已经概述了创伤后应激障碍的神经回路，但这些成像 测量方法仅提供大脑功能的一般测量(例如血液流动)，而不针对特定的 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患者应激诱导的前额叶和边缘DA神经传递是否减少？ 应激诱导的炎症生物标记物在创伤后应激障碍中是否更高，并与症状严重程度相关？和3)是 与创伤后应激障碍和症状相关的功能行为和连接性静息测量的中断 严重吗？我们建议的工作建立在我们实验室在创伤后应激障碍成像方面的经验基础上，包括演示 血流和血氧水平依赖的mPFC功能降低。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创伤后应激障碍的炎症反应的机制框架 确定可以预测创伤后应激障碍症状及其严重程度的机制，以改善未来的治疗 接近了。