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: 10231246
• 负责人: Elizabeth Helen Andersen
• 金额: $ 15.77万
• 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/10231246
• 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; 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; Life; Link; Longevity; Measurement; Measures; Mediator of activation protein; Menarche; Menopause; 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; 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.

项目摘要/摘要 青春期过渡（PT）是一个关键的发育窗口，其特征是显着的生殖 马烯的变异性，额叶神经元网络的广泛改进，并大大增加了风险的风险 女孩的抑郁症。拒绝敏感性（REJSEN）是抑郁症和A的强大替代风险因素 青春期女孩中与发展相关的心理结构。青春期女孩体验更强大 对人际压力暴露（IntStressExp）的情绪和身体反应性，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，首先出现在青春期和继续 在整个生殖寿命中，在脆弱性中实现卵巢激素（例如雌二醇，E2） 心理病理学。拟议的K01项目将采用多模式的维度方法来调查 卵巢骑马在控制额叶认知控制，皮质醇应激反应性和的病理生理作用 PT和PT后女孩的Rejsen。次要目标是定义使神经生理机制的定义 PT是青春期女孩心理病理学脆弱性的独特窗口。表征内源E2 PT期间的可变性以及E2途径的潜在介体的心理病理学途径代表 研究且重要的研究领域，与NIMH的战略目标是一致的 精神疾病的轨迹。 120名青少年女孩（60岁11-14岁，梅纳尔后≤1年，60年代15-18岁，> 2 MENARCARE后的年）将提供每日唾液E2测量和Rejsen评级1个月，并且 涉及皮质醇应激反应性和认知控制的脑电图测量的实验室测试以检验假设 PT期间的E2变异性预测了Rejsen，因为初步数据显示（AIM 1），正面认知控制 （AIM 2）和皮质醇应力反应性（AIM 3），尤其是在具有更大intstressExp的女孩中。选择导师 鉴于他们作为导师的成功和经验，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），人际应激因素 促进女性青少年抑郁症（Mitch Prinstein，Ph.D.），青春期内分泌学（Ali Calikoglu， M.D.）和多级统计分析，以研究激素和情感症状的状态变化 （丹尼尔·鲍尔（Daniel Bauer）博士）。职业目标：我致力于专注于独立资助的研究职业 研究与女孩在病理生理学中的卵巢骑马通量有关 Pt。我的长期目标是在周围构建抑郁易感性的综合模型 女孩为有针对性的干预策略告知早期发现和预防抑郁症的策略。职业 发展：拟议的研究完成了我以前的研究经验和知识 小儿内分泌学的技术，专业和科学技能，青少年的临床现象学 抑郁症和多层次统计建模，以开发独特且竞争性的研究利基市场。