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

项目摘要/摘要 青春期过渡(PT)是一个关键的发育窗口，其特征是明显的生殖 激素的变异性，额叶神经网络的广泛完善，以及显著增加的风险 女孩中的抑郁症。拒绝敏感性(RejSen)是抑郁症的强烈近端风险因素， 青春期女孩的发展相关心理结构。青春期女孩体验更强烈 对人际压力暴露的情绪和生理反应(IntStressExp)，可能有助于 他们患情感性疾病的风险不成比例。这种性别差异最初出现在青春期，并持续下去 在整个生殖寿命中，卵巢激素(如雌二醇、雌二醇)与易患 精神变态学。拟议的K01项目将采用多模式、多维的方法来研究 卵巢激素在调节额叶认知控制、皮质醇应激反应和 在PT和PT后的女孩中RejSen。一个次要的目标是定义使 PT是青春期女孩精神病理学的一个独特的脆弱性窗口.内源性雌二醇的特征 在PT过程中的变异性和E2通路到精神病理学的潜在介体代表着 未被充分研究和重要的研究领域，与NIMH的战略目标一致 精神疾病的轨迹。12 0名青春期女孩(60名11-14岁，≤月经初潮后1年，60名15-18岁； 月经初潮后数年)将提供为期1个月的每日唾液雌二醇测量和RejSen评级，以及 涉及皮质醇应激反应的实验室测试和认知控制的脑电测量来验证假设 初步数据显示(目标1)，在PT期间，E2的变异性可以预测RejSen，额叶认知控制 (目标2)和皮质醇应激反应(目标3)，特别是在IntStressExp较大的女孩中。导师被挑选出来 鉴于他们作为导师的有据可查的成功和经验，以及在以下领域的专业知识：生殖 和压力神经内分泌学(苏珊·格德勒博士，主要导师)，人际压力因素 导致女性青春期抑郁(米奇·普林斯坦，博士)，青春期内分泌学(阿里·卡里科格鲁， 和多水平统计分析，以研究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事业，专注于 研究卵巢激素流动在与女孩抑郁发生相关的病理生理学中的作用 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 向女童提供有针对性的干预战略，以便及早发现和预防抑郁症。职业生涯 发展：拟议的研究与我以前的研究经验和知识相辅相成 儿童内分泌学、青少年临床现象学方面的技术、专业和科学技能 抑郁和多水平统计建模，以开发独特的和具有竞争力的研究利基。

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.