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

阐明神经活性类固醇对网络和行为状态影响的调节机制

基本信息

批准号：
10662441
负责人：
Jamie Lynn Maguire
金额：
$ 94.92万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662441
关键词：
Acute Affective Allopregnanolone Amygdaloid structure Animal Model Anti-Anxiety Agents Antidepressive Agents Behavioral Brain Brain region CRISPR/Cas technology Chemistry Chronic Clinical Clinical Trials Collaborations Communication Data Drug Utilization Formulation Generations Goals Hippocampus Human Interneurons Knock-out Knowledge Link Medial Mediating Mental disorders Modeling Mood Disorders Nature Neurons Parvalbumins Patients Play Postpartum Depression Postpartum Period Pre-Clinical Model Prefrontal Cortex Property Psychiatric therapeutic procedure Research Support Risk Factors Role Site Stress Techniques Testing Therapeutic antidepressant effect behavior influence brain cell cell type delta receptors in vivo insight intraperitoneal intravenous administration member neurosteroids new technology novel positive allosteric modulator receptor

项目摘要

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.

项目概要许多精神疾病的特点是行为紊乱。当前的项目尝试。了解介导健康和不健康大脑和行为之间转变的机制状态。压力是精神疾病的主要危险因素，通常用来改变行为状态。在临床前模型中，该应用程序将利用慢性和产后压力来促进过渡。不健康的网络和行为状态并研究介导这些转变的机制。神经活性类固醇 (NAS) 具有强大的抗焦虑和抗抑郁作用以及基于 NAS 的治疗， brexanolone/Zulresso®，最近获得 FDA 批准，成为第一个产后抗抑郁治疗药物该项目将利用这些临床上有效的 NAS 来研究对网络和抑郁症的影响。我们的初步数据表明，长期的不可预测的压力和不适当的行为状态。产后压力会破坏基底外侧杏仁核 (BLA) 的网络活动，而 NAS 可以恢复该网络活动此外，我们还展示了 NAS 改变网络活动的能力。跨物种，包括人类（Conte Center Overview 初步数据），强调了转化尽管有这些令人兴奋的初步发现，我们仍然缺乏对这种方法的理解。介导网络和行为状态之间转换的机制。四氢孕酮的抗抑郁作用不容易用已知的作用机制来解释： GABAA 受体的正变构调节剂 (PAM) 与我们的 Conte 中心合作者合作。和化学核心，我们将研究 NAS 的哪些不同属性能够恢复健康的网络和行为状态，目的是更好地了解其治疗方法特性。