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

项目总结/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 激素变异性，额叶神经网络的广泛完善，以及 女孩的抑郁症拒绝敏感性（RejSen）是抑郁症的一个强近端危险因素， 青春期女孩的发展相关心理结构。青春期的女孩 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过高。这种性别差异首先出现在青春期， 在整个生殖寿命中，涉及卵巢激素（例如，雌二醇（E2）在 精神病理学拟议的K 01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 在PT和PT后女孩RejSen。第二个目标是确定神经生理机制， PT是青春期女孩心理病理学脆弱性的一个独特窗口。表征内源性E2 PT期间的变异性和E2通路的潜在介质代表了精神病理学的一个重要特征。 研究不足和重要的研究领域，并符合NIMH的战略目标， 精神疾病的发展轨迹120名青春期女孩（60名11-14岁，初潮后≤1年，60名15-18岁，>2岁） 月经初潮后30年）将提供1个月的每日唾液E2测量和RejSen评级，以及 实验室测试包括皮质醇应激反应和认知控制的EEG测量，以验证假设 如初步数据所示，PT期间的E2变异性预测了RejSen（目标1），额叶认知控制 (Aim 2），和皮质醇应激反应（目的3），特别是在女孩更大的IntStressExp。导师被选中 鉴于她们作为导师的成功记录和经验，以及在以下领域的专门知识： 和应激神经内分泌学（Susan Girdler，Ph.D.，初级导师），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（AliCalikoglu， 医学博士），和多层次的统计分析，以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事业，重点是 调查卵巢激素流量在病理生理学相关的出现抑郁症的女孩， 的PT。我的长期目标是建立一个综合的抑郁症易感性模型， 向女孩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：拟议的研究补充了我以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 抑郁症和多层次的统计建模，以发展一个独特的和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.