Mapping neuroendocrine risk for depression across adolescence - PROJECT ABSTRACT Neuroendocrine transitions, such as puberty, pregnancy, and menopause, are increasingly recognized as vulnerable windows for depression risk. Menarche (the onset of menstruation) is a universal milestone during the first postnatal neuroendocrine transition, puberty. Menarche marks the activation of the hypothalamic- pituitary-ovarian axis and a shift toward cyclical ovarian hormone surges which can shape the development of brain networks. Of particular relevance is the salience network, which is enriched for ovarian hormone receptors and implicated in depression. Following menarche, the subsequent menstrual cycle stabilization period can last several years, creating a prolonged window during which irregular hormone patterns may influence neural development and affective risk. This proposal investigates menarche and menstrual cycle stabilization as two components of a neuroendocrine transition underlying adolescent vulnerability to depression. The overarching goal is to understand how the pronounced changes in hormonal fluctuations that accompany this transition shape salience network development and mental health risk. Aim 1 will characterize how menarche functions as a developmental inflection point for depression risk and salience network organization. Using currently available data from the ABCD Study (v6.0, ages 9–16; n=5,676 females), we will quantify how menarche onset influences changes in depressive symptoms and salience network topography. We will extend these analyses to the complete ABCD dataset (v10.0, ages 9–20) to examine how age at menarche moderates cumulative risk and salience network topography. Aim 2 will investigate menstrual cycle stabilization as a second window of vulnerability in adolescence using a multi-cohort approach. We will leverage a retrospective ultra-high-field 7T dataset (n=45, ages 16–20, ~3–11 years post-menarche) alongside a newly collected dense prospective dataset (n=45, ages 13–15, ~2 years post-menarche). This design allows us to examine both short-term neuroendocrine dynamics in the early post-menarcheal years and longer-term patterns of salience network organization and depression risk. Together, these aims will identify how early neuroendocrine transitions and the process of menstrual cycle stabilization relate to depression risk, highlighting the role of developmental changes in salience network organization that are influenced by ovarian hormone dynamics. The support of this K99/R00 Pathway to Independence award will provide the applicant with the training necessary to achieve these aims, including training in developmental neuroscience, neuroendocrinology, and psychiatry, big data neuroinformatics, network neuroscience, and precision functional mapping. These training objectives will be accomplished with the support of an outstanding mentorship team, Drs. Larsen, Jacobs, Beltz, Cullen, Fair, and Nelson, and the world class technical and intellectual resources of the University of Minnesota. Together, the proposed scientific aims and training objectives will establish the foundation for an independent research program aimed at elucidating the neurodevelopmental pathways linking neuroendocrine transitions to adolescent depression.
