Modeling Individual Differences in PTSD

创伤后应激障碍（PTSD）个体差异建模

• 批准号: 8542633
• 负责人: Marlene A. Wilson
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542633
• 关键词: Adrenal Glands; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Basic Science; Behavior; Behavioral; Behavioral Symptoms; Biological Assay; Biological Markers; Blood Pressure; Blood Vessels; Brain; Brain region; Cardiovascular system; Catecholamines; Comorbidity; Corticosterone; Development; Disease model; Endocrine; Epigenetic Process; Epinephrine; Event; Exhibits; Exposure to; Extinction (Psychology); Fright; Genetic; Goals; Heart Rate; Hormonal; Hormones; Human; Hydrocortisone; Hypothalamic structure; Individual; Individual Differences; Inflammatory; Intervention; Literature; Measures; Medical; Microdialysis; Modeling; Modification; Neurobiology; Neurologic; Neurons; Neurosecretory Systems; Norepinephrine; Odors; Outcome; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Pituitary Gland; Plasma; Population; Populations at Risk; Post-Traumatic Stress Disorders; Prevention; Rattus; Research; Resistance; Risk; Risk Assessment; Rodent; Rodent Model; Role; Soldier; Stress; Suggestion; Symptoms; Testing; Training; Translating; Trauma; Variant; Veterans; Woman; Work; base; biological adaptation to stress; combat; conditioned fear; cytokine; disability; environmental stressor; evidence base; experience; immune function; improved; in vivo; indexing; innovative technologies; insight; member; men; neuropeptide Y; new therapeutic target; novel therapeutic intervention; preclinical study; predictive modeling; prevent; programs; protective effect; psychologic; public health relevance; resilience; response; therapeutic target

DESCRIPTION (provided by applicant): The long-term goals of these preclinical studies are to enhance our understanding of individual differences in the neurobiological underpinnings of post-traumatic stress disorder (PTSD), and the potential synergy between several easily accessible biomarkers that might predict individuals that are at-risk for developing PTSD after combat-related trauma. Neuropeptide Y (NPY) has been suggested as a potential marker of resiliency, and NPY administration is anxiolytic. Stress-induced increases in peripheral NPY levels are thought to reflect sympathetic activation, since they correlated with measures of hypothalamic-pituitary- adrenal (HPA) activity and other indices of sympathetic activation including norepinephrine (NE) and epinephrine (EPI) levels. Although studies suggest that individual differences in NPY responses are associated with behavioral outcomes, the complexity of PTSD suggests that determining at risk populations may involve identifying individual differences in a combination of biomarkers. Therefore, we will examine multiple markers that can be easily assayed in both rodent and human populations, including circulating levels of NPY, corticosterone (CORT) as a measure of HPA activity, cytokines as markers of immune function, and indices of sympathetic activation including NE, EPI, heart rate (HR) and blood pressure (BP). This proposal expands our previous work showing individual differences in anxiety-related responses, to examine markers that predict individual differences in a predator odor/fear-conditioning model of rat trauma. Our studies also examine how peripheral changes are reflected in brain (amygdalar) changes and if NPY administration can enhance resiliency in anxiety-prone individuals. The Aims test our overarching hypothesis that a combination of NPY, HPA, cytokine, and sympathetic responses associated with traumatic stress can serve as biomarkers for risk or resilience for developing a PTSD-like phenotype. In Aim 1 we use our predator odor traumatic stress model and compare groups of high-anxiety, PTSD-like subjects that are resistant to fear extinction with low anxiety, resilient rats to determine if they exhibit enhanced stress-induced levels of circulating NPY, CORT, sympathetic markers, and cytokines, plus more persistent levels of fear conditioning and enhanced startle responses and risk-assessment behaviors. Using vascular ports and our rat PTSD model we will examine individual differences in circulating NPY, CORT, NE, EPI, cytokines, autonomic responses, neuronal activation during extinction, and brain NPY levels. Aim 2 uses microdialysis to assess individual differences in amygdalar responses in NPY, CORT and NE during extinction of fear-conditioned responses, while Aim 3 will examine if high anxiety animals can be made more "resilient" by amygdalar administration of NPY. The results of our studies will improve our understanding of the individual differences in response to a traumatic event, and will be critical in assessing possible at-risk Veterans for the development of PTSD, developing new pharmacologic treatment targets, and in appropriately treating Veterans using evidence-based approaches. OIF/OEF DEPLOYMENT: These studies examine the role of hormonal and physiological stress responses in predisposing Veterans to phenotypic expression of PTSD after exposure to combat trauma. PTSD outcomes may reflect reactivity to environmental stressors that are part of a common pathway of genetic/epigenetic modification for vulnerability to neuroendocrine dysregulation. This basic research provides a translational framework for examining neurobiological factors contributing to PTSD outcomes after combat trauma exposure, and a potential intervention to improve resiliency against developing PTSD in soldiers.

描述（由申请人提供）： 这些临床前研究的长期目标是增强我们对创伤后应激障碍神经生物学基础（PTSD）神经生物学基础（PTSD）的理解，以及几种易于访问的生物标志物之间的潜在协同作用，这些生物标志物可能预测可能预测与战斗相关的创伤后在患有PTSD的处于危险中的个人。神经肽Y（NPY）被认为是弹性的潜在标志，而NPY给药是抗焦虑。人们认为应激诱导的周围NPY水平的增加反映了交感神经激活，因为它们与下丘脑 - 垂体 - 肾上腺（HPA）活性的度量以及包括去甲肾上腺素（NE）（NE）和肾上腺素（Epiphrine（EPI））的其他交感神经激活指数相关。尽管研究表明，NPY反应的个体差异与行为结果有关，但PTSD的复杂性表明，确定在风险种群中可能涉及确定生物标志物组合中的个体差异。因此，我们将检查可以在啮齿动物和人类种群中易于测定的多个标记，包括循环水平的NPY水平，皮质酮（CORT）作为HPA活性，细胞因子作为免疫功能的标记的量度，以及包括NE，EPI，心率（HR）和血压（BP）在内的交感激活指数。该提案扩大了我们以前的工作，显示了与焦虑相关反应的个体差异，以检查预测大鼠创伤的捕食者气味/恐惧调节模型中个体差异的标记。我们的研究还研究了周围变化如何反映在大脑（杏仁核）变化中，以及NPY给药是否可以提高容易发生焦虑的个体的弹性。目的测试了我们的总体假设，即NPY，HPA，细胞因子和与创伤性压力相关的同情反应的组合可以作为生物标志物，以实现生物标志物的风险或弹性，以开发PTSD样表型。在AIM 1中，我们使用捕食者气味创伤性压力模型，并比较一组高焦虑，类似于PTSD的受试者，这些受试者抵抗恐惧灭绝的恐惧，焦虑症低，弹性大鼠，以确定它们是否表现出增强的压力诱导的NPY循环NPY，CORT，CORT，交感神经标记，交感神经，以及恐惧的效果和持久性和增强的危险和增强的危险和增强的危险。使用血管端口和我们的大鼠PTSD模型，我们将检查循环NPY，CORT，NE，EPI，细胞因子，自主神经反应，灭绝期间的神经元激活和脑NPY水平的个体差异。 AIM 2使用微透析来评估在恐惧条件的反应灭绝期间，NPY，Cort和NE中杏仁核反应的个体差异，而AIM 3将检查NPY的杏仁核给药是否可以使高焦虑动物更加“弹性”。我们的研究结果将提高我们对响应创伤事件的个体差异的理解，并且对于评估可能的处于危险的退伍军人而言至关重要 PTSD，开发新的药物治疗靶标，并使用基于证据的方法适当治疗退伍军人。 OIF/OEF部署：这些研究检查了暴露于战斗创伤后，激素和生理压力反应在诱发退伍军人对PTSD表型表达的易感性表达中的作用。 PTSD结局可能反映了对环境压力源的反应性，这是遗传/表观遗传学修饰对神经内分泌失调的脆弱性的共同途径的一部分。这项基础研究提供了一个转化框架，用于检查作战创伤暴露后导致PTSD结果的神经生物学因素，以及一种潜在的干预措施，以提高士兵发展PTSD的弹性。