Elucidating the Mechanisms Mediating the Impact of Neuroactive Steroids on Network and Behavioral States

项目摘要 许多精神疾病的特征是行为紊乱的发作。当前项目尝试 了解健康和不健康大脑和行为之间转换的调节机制 各州。压力是精神疾病的主要风险因素，通常被用来改变行为状态 在临床前模型中。这项应用将利用慢性和产后应激来促进过渡到 不健康的网络和行为状态，并调查这些转变的中介机制。 神经活性类固醇(NAS)具有强大的抗焦虑和抗抑郁作用，并以NAS为基础进行治疗， Brexanolone/Zulresso®，最近获得FDA批准，作为产后的第一种抗抑郁药物 抑郁症。该项目将利用这些临床有效的NAS来调查对网络和 行为状态。我们的初步数据表明，慢性不可预测的压力和不适当的 产后应激可以破坏杏仁基底外侧核(BLA)的网络活动，NAS可以恢复这种活动 健康的网络和行为状态。此外，我们还演示了NAS改变网络活动的能力 跨物种，包括人类(Conte Center概述初步数据)，突出了翻译 这一方法的相关性。尽管有这些挑衅性的初步发现，但我们仍然缺乏对 调节网络和行为状态之间转换的机制。经久不衰 别孕酮的抗抑郁作用不容易用已知的作用机制来解释，如 GABAA受体的正变构调节剂(PAM)。与我们的Conte Center合作者合作 和化学核心，我们将调查NAS的不同属性中的哪些能够恢复 健康的网络和行为状态，目标是更好地了解其治疗方法 属性。

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.