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战斗相关创伤后有发展PTSD风险的个体。神经肽Y（NPY）已被认为是一个潜在的标志物的弹性，和NPY管理是抗焦虑。应激诱导的外周NPY水平的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）活性的测量和交感神经激活的其他指数（包括去甲肾上腺素（NE）和肾上腺素（EPI）水平）相关。虽然研究表明，NPY反应的个体差异与行为结果相关，但PTSD的复杂性表明，确定风险人群可能涉及识别生物标志物组合中的个体差异。因此，我们将研究多种标记物，可以很容易地在啮齿动物和人类群体，包括循环水平的神经肽Y，皮质酮（CORT）作为HPA活性的测量，细胞因子作为免疫功能的标记物，和指数的交感神经激活，包括NE，EPI，心率（HR）和血压（BP）。这个建议扩展了我们以前的工作，显示焦虑相关反应的个体差异，检查标记物，预测个体差异的捕食者气味/恐惧调节模型的大鼠创伤。我们的研究还研究了外周变化如何反映在大脑（杏仁核）的变化，以及NPY管理是否可以提高焦虑倾向个体的弹性。目的测试我们的总体假设，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发展PTSD样表型的风险或弹性的生物标志物。在目标1中，我们使用我们的捕食者气味创伤应激模型，并比较了高焦虑，PTSD样的主题，抵抗恐惧消退与低焦虑，弹性大鼠，以确定他们是否表现出增强的循环NPY，CORT，交感神经标记物和细胞因子的应激诱导水平，加上更持久的恐惧条件反射水平和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，我们将研究循环NPY，CORT，NE，EPI，细胞因子，自主反应，神经元激活过程中的灭绝，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NPY，CORT和NE的杏仁核反应的个体差异，而目的3将检查是否可以通过杏仁核施用NPY使高度焦虑动物更具“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，并将在评估可能处于危险中的退伍军人的发展中发挥关键作用。 创伤后应激障碍，开发新的药物治疗目标，并在适当治疗退伍军人使用循证方法。伊解/持久自由行动部署：这些研究检查了激素和生理应激反应在退伍军人暴露于战斗创伤后易患PTSD表型表达中的作用。PTSD的结果可能反映了对环境应激源的反应，这些应激源是神经内分泌失调脆弱性的遗传/表观遗传修饰的共同途径的一部分。这项基础研究提供了一个翻译框架，用于检查战斗创伤暴露后导致PTSD结果的神经生物学因素，以及一种潜在的干预措施，以提高士兵对PTSD发展的弹性。

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.