Defining the Neuropathophysiological Mechanisms Linking Ovarian Hormone Variability with Depression Risk in Peripubertal Girls

定义青春期前后女孩卵巢激素变异与抑郁风险之间联系的神经病理生理学机制

• 批准号: 10685576
• 负责人: Elizabeth Helen Andersen
• 金额: $ 15.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685576
• 关键词: Acute; Adolescence; Adolescent; Affective; Affective Symptoms; Age; Area; Award; Childhood; Clinical; Cognitive; Complement; Data; Development; Dimensions; Disease susceptibility; Doctor of Medicine; Doctor of Philosophy; Early Diagnosis; Early identification; Electroencephalography; Emotional; Endocrine; Endocrinology; Enrollment; Estradiol; Estrogens; Event; Female; Female Adolescents; Functional disorder; Funding; Future; Goals; Gonadal Steroid Hormones; Hormonal; Hormones; Hydrocortisone; Impairment; Intervention; Knowledge; Laboratories; Link; Longevity; Measurement; Measures; Mediator; Menarche; Mental Depression; Mental disorders; Mentors; Moods; National Institute of Mental Health; Neuroendocrinology; Neuroregulator; Ovarian hormone; Participant; Pathway interactions; Perimenopause; Physiological; Positioning Attribute; Predisposition; Psychopathology; Psychophysiology; Psychosocial Stress; Puberty; Reproductive Endocrinology; Research; Research Training; Risk; Risk Factors; Role; Salivary; Sampling; Statistical Data Interpretation; Statistical Models; Stress; Stressful Event; Symptoms; Testing; Time; Training; Trier Social Stress Test; Woman; biobehavior; boys; brain circuitry; brain morphology; career; career development; child depression; cognitive control; depression model; depression prevention; depressive symptoms; experience; experimental study; frontal lobe; girls; insight; male; multilevel analysis; multimodality; neural network; neurophysiology; novel; phenomenological models; psychologic; puberty transition; reproductive; reproductive hormone; response; sex; sex disparity; skills; stress reactivity; success

PROJECT SUMMARY/ABSTRACT The pubertal transition (PT) is a critical developmental window characterized by pronounced reproductive hormone variability, extensive refinement of frontal neural networks, and substantially increased risk for depression in girls. Rejection sensitivity (RejSen) is a strong proximal risk factor for depression and a developmentally relevant psychological construct in adolescent girls. Adolescent girls experience stronger emotional and physiological reactivity to interpersonal stress exposure (IntStressExp), possibly contributing to their disproportionate risk for affective illness. This sex disparity, first emerging at puberty and continuing throughout the reproductive lifespan, implicates ovarian hormones (e.g., estradiol, E2) in the vulnerability to psychopathology. The proposed K01 project will employ a multimodal, dimensional approach to investigating the pathophysiological role of ovarian hormones in regulating frontal cognitive control, cortisol stress reactivity and RejSen in PT and post-PT girls. A secondary objective is to define the neurophysiological mechanisms that make the PT a unique window of vulnerability for psychopathology in adolescent girls. Characterizing endogenous E2 variability during the PT and potential mediators of the E2 pathway to psychopathology represents an understudied and significant area of research, and is consistent with NIMH’s strategic objective of defining the trajectory of mental illness. 120 adolescent girls (60 ages 11-14, ≤1 year post-menarche and 60 ages 15-18, >2 years post-menarche) will provide daily salivary E2 measurements and RejSen ratings for 1 month, and laboratory testing involving cortisol stress reactivity and EEG measures of cognitive control to test the hypothesis that E2 variability during the PT predicts RejSen as preliminary data has shown (Aim 1), frontal cognitive control (Aim 2), and cortisol stress reactivity (Aim 3), especially in girls with greater IntStressExp. Mentors were selected given their documented success and experience as mentors, and expertise in the following areas: reproductive and stress neuroendocrinology (Susan Girdler, Ph.D., primary mentor), interpersonal stress factors contributing to female adolescent depression (Mitch Prinstein, Ph.D.), endocrinology of puberty (Ali Calikoglu, M.D.), and multilevel statistical analyses to investigate state changes in hormones and affective symptoms (Daniel Bauer, Ph.D.). Career Goal: I am committed to an independently funded research career focused on investigating ovarian hormone flux in the pathophysiology relevant to the emergence of depression in girls during the PT. My long-term objective is to construct a comprehensive model of depression susceptibility in peripubertal girls to inform targeted intervention strategies for the early detection and prevention of depression. Career Development: The proposed study complements my previous research experience and knowledge with new technical, professional, and scientific skills in pediatric endocrinology, clinical phenomenology of adolescent depression and multilevel statistical modeling to develop a unique and competitive research niche.

项目概要/摘要 青春期过渡（PT）是一个关键的发育窗口，其特征是明显的生殖能力 激素变异性、额叶神经网络的广泛细化以及显着增加的风险 女孩的抑郁症。拒绝敏感性 (RejSen) 是抑郁症的一个重要近端危险因素，也是 青春期女孩发育相关的心理构造。青春期女孩经历更坚强 对人际压力暴露的情绪和生理反应（IntStressExp），可能有助于 他们患情感疾病的风险不成比例。这种性别差异首先出现在青春期并持续存在 在整个生殖寿命期间，表明卵巢激素（例如雌二醇、E2）与易受感染的风险有关 精神病理学。拟议的 K01 项目将采用多模式、多维度的方法来调查 卵巢激素在调节额叶认知控制、皮质醇应激反应和 RejSen 在 PT 和 PT 后女孩中。第二个目标是定义神经生理学机制 PT 是青春期女孩心理病理学脆弱性的独特窗口。表征内源性 E2 PT 期间的变异性和 E2 通路的潜在中介因素代表了一种 未充分研究的重要研究领域，并且与 NIMH 定义 精神疾病的轨迹。 120 名青春期女孩（60 名 11-14 岁，月经初潮后 ≤1 年，60 名 15-18 岁，>2 月经初潮后数年）将提供 1 个月的每日唾液 E2 测量和 RejSen 评级，以及 实验室测试涉及皮质醇应激反应和认知控制的脑电图测量，以检验假设 PT 期间的 E2 变化可预测 RejSen，如初步数据所示（目标 1），额叶认知控制 （目标 2）和皮质醇应激反应性（目标 3），尤其是 IntStressExp 较高的女孩。导师已选拔 鉴于他们作为导师的成功经验和经验，以及以下领域的专业知识：生殖 和压力神经内分泌学（Susan Girdler，博士，主要导师），人际压力因素 导致女性青春期抑郁症（Mitch Prinstein，博士），青春期内分泌学（Ali Calikoglu， M.D.），以及多层次统计分析来调查激素和情感症状的状态变化 （丹尼尔·鲍尔博士）。职业目标：我致力于独立资助的研究生涯，重点关注 研究与女孩抑郁症出现相关的病理生理学中的卵巢激素通量 PT。我的长期目标是构建一个青春期前后抑郁易感性的综合模型 向女孩提供有针对性的干预策略，以便及早发现和预防抑郁症。职业 发展：拟议的研究补充了我之前的研究经验和知识 儿科内分泌学、青少年临床现象学的技术、专业和科学技能 抑郁症和多层次统计模型，以开发独特且有竞争力的研究领域。