Psychological Modulation of the Human HPA Stress Axis

描述(申请人提供)：下丘脑-垂体肾上腺(HPA)轴是一个中央控制的神经内分泌系统，调节对心理社会应激的适应性生物行为反应。它还通过不清楚的机制将压力与抑郁症和艾滋病等不同疾病联系在一起。阐明机制需要更准确地了解这一系统的特定激活剂和调节剂。令人惊讶的是，产生高度痛苦的预期激活剂，如恐惧症恐惧或恐慌症发作，并不总是触发HPA激素(ACTH或皮质醇)的释放。动物数据显示，新鲜感、控制力和社会环境可以调节HPA的激活，但这些因素在人类身上的研究很少。这个项目的目的是通过三个互补的实验，探索环境因素(例如，新颖性、控制性)在正常人类HPA轴活动中的作用，以及它们与更全面地理解精神障碍中HPA轴失调的相关性。Trier社会压力测试(TSST)是一个研究ACTH和皮质醇对心理社会压力反应的“社会评估威胁”实验室模型。第一项研究将检验这一假设，即在塑造荷尔蒙反应时，控制感比感知到的威胁水平更重要--即提供获得控制/应对反应的途径，即使没有利用控制，主观体验的焦虑也没有减少，这将阻止通常由TSST的社会评估威胁产生的皮质醇反应。第二项研究将使用对非社会威胁(恐惧症)的恐惧敏感性模型，来检验这样一个假设，即控制感比恐惧本身更容易释放皮质醇。第三项研究将把最初的发现应用于一种精神障碍(恐慌症)，其中HPA轴调节失调被认为是病因学上的中心，并检验HPA轴异常可以由对上下文线索的高敏感性造成的假设，表明这种疾病中HPA轴调节失调的来源是下丘脑上。这些实验将促进对正常HPA轴功能的理解，并展示如何利用这种理解来磨练疑似HPA轴失调的精神疾病中被破坏的电路的位置。使用这些范例的后续神经成像研究将追踪高级神经回路(杏仁体上和下丘脑上)调节低级、自动情绪处理器的神经路径。最终，这些努力将帮助我们更好地理解压力在疾病中的作用，并开发出更好的方法来调节其负面影响。

DESCRIPTION (provided by applicant): The hypothalamic-pituitary adrenal (HPA) axis is a centrally controlled neuroendocrine system that mediates adaptive, biobehavioral responses to psychosocial stress. It also links stress to diseases as divergent as depression and AIDS, through unclear mechanisms. Clarifying mechanisms requires more precise understanding of specific activators and modulators of this system. Surprisingly, expected activators that generate high distress, like phobic fear or a panic attack, do not always trigger release of HPA hormones (ACTH or cortisol). Animal data show that novelty, control, and social milieu can modulate HPA activation, but these factors are little studied in humans. The goal of this project is to explore the role of contextual factors (e.g., novelty, control) in normal human HPA axis activity and their relevance to a more complete understanding of HPA axis dysregulation in psychiatric disorders, through three complementary experiments. The Trier Social Stress Test (TSST) is a "social evaluative threat" laboratory model for studying ACTH and cortisol responses to psychosocial stress. The first study will test the hypothesis that sense of control is more important than level of perceived threat in shaping hormonal responses - i.e., providing access to control/coping responses, even when control is not utilized and subjectively experienced anxiety is not reduced, will block the cortisol response usually produced by the social evaluative threat of the TSST. The second study will use a model of fear sensitivity to non-social threats (phobias), to test the hypothesis that sense of control is more salient to cortisol release than fear itself. The third study will apply initial findings to a psychiatric disorder (panic disorder) in which HPA axis dysregulation has been considered to be etiologically central and test the hypothesis that HPA axis abnormalities can be created by hypersensitivity to contextual cues, suggesting a supra-hypothalamic source for HPA axis dysregulation in this disorder. These experiments will advance understanding of normal HPA axis functioning and demonstrate how this understanding can be used to hone in on the location of disrupted circuitry in a psychiatric disorder with suspected HPA axis dysregulation. Follow-up neuroimaging studies using these paradigms will trace the neural pathways through which higher neural circuits (supra-amygdaloid and supra-hypothalamic) modulate lower, automatic emotional processors. Ultimately, these efforts will help us better understand the role of stress in disease and develop improved methods for modulating its negative effects.