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

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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.