Modeling Individual Differences in PTSD

创伤后应激障碍（PTSD）个体差异建模

• 批准号: 8678695
• 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/8678695
• 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 (PTSD) 神经生物学基础的个体差异的理解，以及几种容易获得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有风险的个体。战斗相关创伤后出现创伤后应激障碍 (PTSD)。神经肽 Y (NPY) 被认为是弹性的潜在标志，并且 NPY 给药具有抗焦虑作用。压力引起的外周 NPY 水平增加被认为反映了交感神经激活，因为它们与下丘脑-垂体-肾上腺 (HPA) 活性和其他交感神经激活指标（包括去甲肾上腺素 (NE) 和肾上腺素 (EPI) 水平）相关。尽管研究表明 NPY 反应的个体差异与行为结果相关，但 PTSD 的复杂性表明，确定高危人群可能涉及识别生物标志物组合的个体差异。因此，我们将检查可在啮齿动物和人类群体中轻松检测的多种标记物，包括 NPY 的循环水平、作为 HPA 活性指标的皮质酮 (CORT)、作为免疫功能标记物的细胞因子以及包括 NE 在内的交感神经激活指数、EPI、心率 (HR) 和血压 (BP)。该提案扩展了我们之前显示焦虑相关反应个体差异的工作，以检查预测大鼠创伤捕食者气味/恐惧调节模型中个体差异的标记。我们的研究还研究了外周变化如何反映在大脑（杏仁核）变化中，以及 NPY 给药是否可以增强易焦虑个体的弹性。这些目标测试了我们的总体假设，即与创伤应激相关的 NPY、HPA、细胞因子和交感神经反应的组合可以作为形成 PTSD 样表型的风险或恢复能力的生物标志物。在目标 1 中，我们使用捕食者气味创伤应激模型，并将对恐惧消退有抵抗力的高焦虑、类似 PTSD 的受试者组与低焦虑、有弹性的大鼠进行比较，以确定它们是否表现出应激诱导的循环 NPY、CORT 水平增强、交感神经标记物和细胞因子，加上更持久的恐惧调节水平以及增强的惊吓反应和风险评估行为。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、自主反应、消退期间神经元激活和大脑 NPY 水平的个体差异。目标 2 使用微透析来评估恐惧条件反应消退过程中 NPY、CORT 和 NE 杏仁核反应的个体差异，而目标 3 将检查杏仁核给予 NPY 是否可以使高度焦虑的动物变得更有“弹性”。我们的研究结果将提高我们对创伤事件反应的个体差异的理解，并且对于评估可能处于危险中的退伍军人的发展至关重要 创伤后应激障碍（PTSD），开发新的药物治疗目标，并使用基于证据的方法适当治疗退伍军人。 OIF/OEF 部署：这些研究探讨了激素和生理应激反应在退伍军人遭受战斗创伤后易出现 PTSD 表型表达方面的作用。 PTSD 结果可能反映了对环境压力源的反应，环境压力源是易受神经内分泌失调影响的遗传/表观遗传修饰的常见途径的一部分。这项基础研究提供了一个转化框架，用于检查在战斗创伤暴露后导致 PTSD 结果的神经生物学因素，以及提高士兵对抗 PTSD 的弹性的潜在干预措施。