Modeling Individual Differences in PTSD

描述(由申请人提供)： 这些临床前研究的长期目标是加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，以及几个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在战斗相关创伤后有患PTSD风险的个人。神经肽Y(NPY)已被认为是一种潜在的恢复力标志，NPY的应用具有缓解焦虑的作用。应激引起的外周NPY水平的升高被认为反映了交感神经的激活，因为它们与下丘脑-垂体-肾上腺(HPA)活动的测量以及其他交感神经激活的指标相关，包括去甲肾上腺素(NE)和肾上腺素(EPI)水平。尽管研究表明NPY反应的个体差异与行为结果有关，但创伤后应激障碍的复杂性表明，确定高危人群可能涉及识别生物标志物组合中的个体差异。因此，我们将检测在啮齿动物和人类群体中都容易检测到的多种指标，包括循环中的NPY水平、作为HPA活性衡量指标的皮质酮(Cort)、作为免疫功能标志的细胞因子以及交感神经激活指数包括NE、EPI、心率(HR)和血压(BP)。这一建议扩展了我们之前的工作，展示了焦虑相关反应的个体差异，以检验在捕食者气味/恐惧条件作用大鼠创伤模型中预测个体差异的标记。我们的研究还检查了外周变化如何反映在大脑(杏仁核)的变化中，以及NPY管理是否可以增强焦虑倾向个体的弹性。这些目标测试了我们的总体假设，即NPY、HPA、细胞因子和与创伤应激相关的交感反应的组合可以作为发展PTSD样表型的风险或弹性的生物标记物。在目标1中，我们使用我们的捕食者气味创伤应激模型，比较高焦虑、类似创伤后应激障碍的受试者和低焦虑、有弹性的大鼠，以确定他们是否表现出压力诱导的循环NPY、皮质醇、交感标志物和细胞因子水平的增加，以及更持久的恐惧条件作用水平以及增强的惊吓反应和风险评估行为。使用血管通路和我们的大鼠创伤后应激障碍模型，我们将检查循环NPY、皮质醇、NE、EPI、细胞因子、自主神经反应、消失期神经元激活和脑NPY水平的个体差异。目的2使用微透析来评估在恐惧条件反应消退期间杏仁核NPY、皮质醇和去甲肾上腺素反应的个体差异，而目的3将研究高焦虑动物是否可以通过杏仁核给予NPY而变得更有弹性。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，并将对评估可能的高危退伍军人的发展至关重要。 创伤后应激障碍，开发新的药物治疗目标，以及使用循证方法适当治疗退伍军人。OIF/OEF部署：这些研究考察了荷尔蒙和生理应激反应在使退伍军人在战斗创伤后易受PTSD表型表达方面的作用。创伤后应激障碍的结果可能反映了对环境应激源的反应性，而环境应激源是易受神经内分泌失调影响的遗传/表观遗传修饰的共同途径的一部分。这项基础研究为检验导致战斗创伤暴露后创伤后应激障碍结果的神经生物学因素提供了一个转换框架，并提供了一种潜在的干预措施，以提高士兵应对创伤后应激障碍的复原力。

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.