Project Summary Many psychiatric illnesses are characterized by episodes of behavioral disruption. The current project attempts to understand the mechanisms mediating transitions between healthy and unhealthy brain and behavioral states. Stress is a major risk factor for psychiatric illnesses and is routinely employed to alter behavioral states in preclinical models. This application will utilize chronic and postpartum stress to facilitate the transition to the unhealthy network and behavioral state and investigate the mechanisms mediating these transitions. Neuroactive steroids (NAS) exert robust anxiolytic and antidepressant effects and a NAS-based treatment, brexanolone/Zulresso®, recently received FDA approval as the first antidepressant treatment for postpartum depression. This project will utilize these clinically effective NAS to investigate the impact on network and behavioral states. Our preliminary data demonstrates that chronic unpredictable stress and inappropriate postpartum stress can corrupt network activity in the basolateral amygdala (BLA) and that NAS can restore healthy network and behavioral states. Further, we demonstrate the ability of NAS to alter network activity across species, including in humans (Conte Center Overview preliminary data), highlighting the translational relevance of this approach. Despite these provocative preliminary findings, we still lack an understanding of the mechanisms mediating transitions between network and, therefore, behavioral states. The prolonged antidepressant effects of allopregnanolone are not easily explained by the known mechanism of action as positive allosteric modulators (PAMs) at GABAA receptors. In collaboration with our Conte Center collaborators and the Chemistry Core, we will investigate which of the diverse properties of NAS are capable of restoring healthy network and behavioral states with the goal of gaining a better understanding of their therapeutic properties.