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

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2021 · $579,910

## Abstract

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.

## Key facts

- **NIH application ID:** 10198244
- **Project number:** 1P50MH122379-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jamie Lynn Maguire
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $579,910
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198244

## Citation

> US National Institutes of Health, RePORTER application 10198244, Elucidating the Mechanisms Mediating the Impact of Neuroactive Steroids on Network and Behavioral States (1P50MH122379-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10198244. Licensed CC0.

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