Learning, neural signaling of cortisol, and early adversity in depression

描述（由申请人提供）：“压力荷尔蒙”皮质醇已经在抑郁症中被研究了几十年。然而，相对而言，人们对皮质醇在抑郁症心理特征中的作用知之甚少。基础研究表明，皮质醇调节与抑郁症高度相关的大脑过程（特别是学习和记忆形成中的消极偏见的神经基质）。然而，很少有研究直接检查皮质醇对抑郁症患者学习神经回路的影响。此外，基础研究表明，皮质醇对学习神经基质的影响在男性和女性中是不同的。女性患抑郁症的人数尤其多，她们患抑郁症的可能性大约是男性的两倍。因此，该项目的主要目标是研究皮质醇对抑郁症女性学习神经回路的影响。第二个目标是研究早期生活中的逆境是否会调节皮质醇对学习神经回路的影响。动物数据表明，早期生活中的逆境会导致终生倾向于在与皮质醇升高相关的威胁条件下学习。此外，来自人类的新数据表明，传统上归因于抑郁症的皮质醇变化可能部分源于早期的逆境，而不是抑郁症本身。因此，本研究将研究皮质醇对有或没有早期生活逆境史的抑郁和健康女性学习神经回路的影响。这项研究将在测量休息时的大脑活动以及在情绪和中性刺激的记忆编码时，使用药物操纵皮质醇水平（与安慰剂相比）。这项研究还将测量皮质醇是否会加剧（或灌输）抑郁症中常见的情绪记忆中的负面偏见。在此过程中，该研究将检查皮质醇在与情绪学习相关的神经网络中的作用，而情绪学习通常与抑郁症有关。针对大脑中皮质醇受体的药物可能对治疗抑郁症有益。然而，这些知识尚未告知临床实践，这些药物的作用机制尚不清楚。该项目意义重大，因为它提供了可用于制定更有效的针对性干预策略的先决知识（并开发了一种范例）。这个项目是创新的，因为它将皮质醇对学习的影响的大量文献带到抑郁症的研究中。“学习”广义上指的是获取相关知识和自适应地改变自己的行为以满足环境要求的能力。抑郁症的核心是难以适应和参与一个人的环境背景，特别是在面对压力的时候。从抑郁症中恢复（无论是药物治疗还是行为治疗）需要神经变化来支持对环境的适应。因此，该项目将动物研究的信息转化为人类研究，表明从抑郁症中恢复需要改善与压力相关的神经过程中潜在的学习变化。

DESCRIPTION (provided by applicant): The "stress hormone" cortisol has been studied in depression for decades. However, relatively little is known about the role of cortisol in psychological features of depression. Basic research shows that cortisol modulates brain processes that are highly relevant to depression (especially the neural substrates of negative biases in learning and memory formation). However, very few studies have directly examined the effects of cortisol on neural circuitry of learning in depressed humans. In addition, basic research shows that the effects of cortisol on the neural substrates of learning differ for males and females. The toll of depression is especially high in women, who are roughly twice as likely as men to suffer from depression. Thus, the primary goal of this project is to investigate the effects of cortisol on the neural circuitry of learning in depressed women. A secondary goal is to investigate whether early life adversity moderates cortisol's effects on neural circuitry of learning. Animal data suggests that early life adversity causes life-long biases toward learning in threatening conditions associated with elevated cortisol. In addition, new data from humans suggests that alterations in cortisol traditionally ascribed to depression may stem in part from early adversity rather than depression per se. Thus, this study will examine effects of cortisol on neural circuitry of learning in depressed and healthy women with and without history of early life adversity. The study will use pharmacological manipulation of cortisol levels (compared to placebo) during measurement of brain activity at rest and during memory encoding of emotional and neutral stimuli. The study will also measure whether cortisol exacerbates (or instills) the negative biases in emotional memory often seen in depression. In doing so, the study will examine the role of cortisol in neural networks associated with emotional learning that are often implicated in depression. Medications that target cortisol receptors in the brain may be beneficial in the treatment of depression. However, this knowledge has yet to inform clinical practice, and mechanisms of action of these medications are not well understood. This project is significant because it provides the prerequisite knowledge (and develops a paradigm) that can be used in the development of more effective targeted intervention strategies. The project is innovative because it brings the vast literature of cortisol's effects on learning to research on depression. "Learning" broadly refers to acquisition of relevant knowledge and the capacity to adaptively alter one's behavior to meet demands of the environment. At the core of depression is difficulty adapting to and engaging with one's environmental context, especially in the face of stressors. Recovery from depression (whether treated medically or behaviorally) requires neural changes supporting adaptation to one's environment. Thus, the project translates information from animal to human research suggesting that recovery from depression entails amelioration of stress-related alterations in neural processes underlying learning.