The training activities, research strategy, and career development activities outlined in this proposal are designed to enable the PI to meet the immediate career goal of gaining experience in epigenetic mechanisms of stress-induced neural reprogramming and neuroendocrinology, and to attain the skills, technical expertise, and career development necessary to succeed in the ultimate career goal of becoming an independent Principle Investigator. This research will help to build a foundation of knowledge for future success in developing translational animal models of stress susceptibility and attain the primary career objective of becoming a successful, independent Principal Investigator, focused on understanding neurobiology and behavior in complex systems that aim to more accurately represent a translationally relevant life experience. The PI is proposing a strategy consisting of coursework, professional development activities, and laboratory research under the guidance of the primary mentor, Dr. Tracy Bale and with guidance from the Advisory Committee. The skills and knowledge gained in the fields of epigenetics and neuroendocrinology are a critical foundation for the proposed work. All of the training will occur at the University of Pennsylvania, a world-renowned research institution with an incredible breadth of state of the art research facilities at my disposal. The proposed research will take place over the course of 5 years, while the training portion will largely take place during Years 1 and 2. Both clinical and animal studies have suggested that females may be more susceptible to stress during puberty. However, the mechanisms underlying these findings are very poorly understood. We have developed a novel peripubertal stress model that enables the examination of both the consequences of peripubertal stress and how that experience interacts with later times of hormonal change, such as pregnancy. In this model, peripubertal stress produces a disruption of the hypothalamic-pituitary-adrenal (HPA) axis response to acute stress only during pregnancy. Exciting preliminary data implicate long-term epigenetic changes to the PVN that interact with the unique neuroendocrine milieu of pregnancy to elicit stress dysregulation. Based on these data, we hypothesize that stress dysregulation during pregnancy results from an interaction of pubertal stress reprogramming of the PVN with pregnancy-related increases in allopregnanolone, and that this dysregulation represents an underlying factor that increases disease risk.
Three Specific Aims will address this hypothesis by determining the mechanism by which peripuberty stress-induced alterations in the PVN GABA system are due to stable chromatin modifications (Aim 1), how allopregnanolone within the PVN facilitates the blunted HPA axis response in peripubertally stressed females (Aim 2), and the long-term consequences of a subsequent ?second hit? stressor experienced during pregnancy (Aim 3).
Adversity experienced in the years surrounding puberty onset is one of the greatest predictors of affective disorder onset in women. We have developed a novel mouse model of peripubertal stress, and find that peripubertal stress programs a blunted corticosterone response to acute stress that is evident only during pregnancy. As disruption of stress responsiveness is a key endophenotype of affective disorders, this mouse model provides an avenue for investigating the mechanisms of this long-term reprogramming and how this phenotype may put individuals at further risk for additional life adversity to provoke disease risk or resilience. This model provides the opportunity to gain mechanistic insight into how neuropsychiatric disease risk is compounded throughout the life of a woman, a process that is complex and not well understood.
