Psychological Modulation of the Human HPA Stress Axis

描述（由申请人提供）：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，介导对社会心理压力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各种疾病联系起来。阐明机制需要更精确地了解该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因素，如恐怖恐惧或惊恐发作，并不总是触发HPA激素（ACTH或皮质醇）的释放。动物数据表明，新奇、控制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。该项目的目标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疾病中HPA轴失调的相关性。特里尔社会压力测试（TSST）是一个研究ACTH和皮质醇对社会心理压力反应的“社会评估性威胁”实验室模型。第一项研究将检验控制感在形成激素反应方面比感知威胁水平更重要的假设——即，提供控制/应对反应的途径，即使控制没有被利用，主观上经历的焦虑没有减少，也会阻止通常由TSST的社会评价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，来检验控制感比恐惧本身对皮质醇释放的影响更显著的假设。第三项研究将把初步发现应用于一种精神疾病（恐慌症），其中下丘脑轴失调被认为是病因中心，并检验下丘脑轴异常可能是由对环境线索的过度敏感造成的假设，这表明下丘脑上是这种疾病中下丘脑轴失调的来源。这些实验将促进对正常下丘脑轴功能的理解，并展示如何利用这种理解来深入研究疑似下丘脑轴失调的精神疾病中中断电路的位置。使用这些范式的后续神经成像研究将追踪高级神经回路（杏仁核上和下丘脑上）调节低级自动情绪处理器的神经通路。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，并开发出改进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.