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

学习、皮质醇的神经信号传导和抑郁症的早期逆境

• 批准号: 8825533
• 负责人: HEATHER C ABERCROMBIE
• 金额: $ 43.5万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-29 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825533
• 关键词: Accounting; Action Potentials; Acute; Address; Adrenal Glands; Affect; Amygdaloid structure; Animals; Award; Basic Science; Behavior; Biological Neural Networks; Brain; Cognitive; Corticosteroid Receptors; Corticotropin; Data; Depressed mood; Depressive disorder; Development; Disease; Emotional; Environment; Equilibrium; Family; Feedback; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hippocampus (Brain); Hormones; Human; Hydrocortisone; Hypothalamic structure; Impairment; Individual; Intervention; Knowledge; Learning; Life; Ligands; Literature; Measurement; Measures; Mediator of activation protein; Memory; Mental Depression; National Institute of Mental Health; Neurocognitive; Peripheral; Pharmaceutical Preparations; Pituitary Gland; Placebos; Plasma; Prefrontal Cortex; Process; Public Health; Recording of previous events; Recovery; Regulation; Research; Rest; Rodent; Role; Saline; Signal Transduction; Stimulus; Stress; Structure; Testing; Translating; Treatment Efficacy; Woman; Work; animal data; base; clinical practice; cognitive process; cost; depressive symptoms; design; early experience; hormone regulation; human data; hydrocortisone receptor; hypothalamic-pituitary-adrenal axis; innovation; interest; intravenous administration; male; meetings; memory encoding; men; neural circuit; neurophysiology; neurotransmission; novel; psychologic; relating to nervous system; response; stem; stressor

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.

描述（由申请人提供）：“应激激素”皮质醇在抑郁症中的研究已有数十年历史。然而，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，皮质醇调节与抑郁高度相关的大脑过程（尤其是学习和记忆形成中负面偏见的神经基质）。然而，很少有研究直接检验皮质醇对抑郁人群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对于男性和女性来说是不同的。女性患抑郁症的人数尤其高，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女性学习神经回路的影响。第二个目标是研究早年的逆境是否会减轻皮质醇对学习神经回路的影响。动物数据表明，早年的逆境会导致终生对在与皮质醇升高相关的威胁条件下学习产生偏见。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，这项研究将研究皮质醇对有或没有早年逆境史的抑郁和健康女性学习神经回路的影响。该研究将在测量休息时的大脑活动以及情绪和中性刺激的记忆编码期间使用皮质醇水平的药理学操作（与安慰剂相比）。该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。针对大脑皮质醇受体的药物可能有助于治疗抑郁症。然而，这些知识尚未应用于临床实践，并且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有针对性的干预策略的先决知识（并开发了范式）。该项目具有创新性，因为它将大量有关皮质醇对学习影响的文献引入抑郁症的研究中。 “学习”广义上是指获取相关知识以及适应性地改变自己的行为以满足环境需求的能力。抑郁症的核心是难以适应和融入环境，尤其是面对压力源时。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适应环境。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学习神经过程中与压力相关的变化。