An Allopregnanolone-Mediated Model of Early Life Adversity and HPA Axis Dysregulation

Abstract

Early life adversity (ELA) is a major risk factor for the development of psychiatric disorders, including major depressive disorder (MDD), as it often leads to persistent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. However, the mechanisms linking ELA to HPA axis dysregulation are not entirely understood. This thesis proposes a model in which ELA induces long-term HPA axis dysregulation primarily through reductions of the neurosteroid allopregnanolone (ALLO) in the ventral hippocampus. Decreased ALLO weakens GABAergic inhibition of corticotropin-releasing hormone (CRH) neurons, promoting increased CRH release from the hypothalamic paraventricular nucleus (PVN) and, subsequently, increased glucocorticoid secretion from the adrenal glands. This leads to increases in the intensity, density, and C4S sulfation of perineuronal nets (PNNs) surrounding parvalbumin-containing (PV+) interneurons in the ventral hippocampus, stabilizing these neurons and altering their firing patterns. This further disrupts the inhibition of CRH neurons, reinforcing HPA axis hyperactivity, which is characteristic of MDD and postpartum depression (PPD) in adulthood. This thesis presents a series of experiments designed to test each step of the proposed pathway using a rodent model of ELA. This thesis also emphasizes the importance of understanding the mechanisms underlying ELA-induced psychiatric disorders in adulthood by drawing a comparison to PPD, a condition for which recent advances in mechanistic understanding have allowed for the development of effective treatment. This comparison suggests ELA-induced depression may represent a mechanistically distinct subtype of MDD, and thus requires a comprehensive understanding to best treat those affected. Ultimately, this work proposes a novel mechanistic model linking ELA to adult psychiatric disorders and emphasizes the importance of understanding unique neural pathways to effectively treat individuals.