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）：数十年来，抑郁症已经研究了“胁迫激素”皮质醇。但是，对于皮质醇在抑郁症的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（尤其是在学习和记忆形成中负偏见的神经底物）。但是，很少有研究直接检查了皮质醇对抑郁人学习神经回路的影响。此外，基础研究表明，皮质醇对男性和女性的学习神经底物的影响不同。女性的抑郁症损失尤其很高，女性的抑郁症的可能性大约是男性遭受抑郁症的可能性的两倍。因此，该项目的主要目标是研究皮质醇对抑郁妇女学习神经回路的影响。次要目标是研究早期生命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，早期逆境会导致终身偏见在与皮质醇升高有关的威胁性疾病中学习。此外，人类的新数据表明，传统上归因于抑郁症的皮质醇的改变可能部分源于早期逆境而不是抑郁本身。因此，这项研究将检查皮质醇对具有和没有早期逆境病史的抑郁和健康女性学习神经回路的影响。这项研究将在测量静止和中性刺激的记忆编码时使用皮质醇水平的药理学操纵（与安慰剂相比）。该研究还将衡量皮质醇加剧（或灌输）在抑郁症中经常看到的情绪记忆中的负偏见。在此过程中，该研究将研究皮质醇在与情绪学习相关的神经网络中的作用，这通常与抑郁症有关。靶向大脑皮质醇受体的药物可能对抑郁症的治疗有益。但是，这种知识尚未为临床实践提供依据，并且这些药物的作用机制尚不清楚。该项目之所以重要，是因为它提供了可用于制定更有效的有针对性干预策略的先决条件知识（并开发范式）。该项目具有创新性，因为它带来了皮质醇对学习抑郁症的影响的广泛文献。 “学习”广泛地是指获取相关知识以及适应性改变自己的行为以满足环境需求的能力。抑郁症的核心是很难适应并与一个人的环境环境互动，尤其是面对压力源。从抑郁症中恢复（无论是在医学上还是在行为上）需要神经变化，以支持适应对环境的适应。因此，该项目将信息从动物转化为人类研究，这表明从抑郁症中恢复需要改善与压力相关的研究中与压力相关的改变。