# New Tools to Study Neurosteroid Estrogens

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $750,162

## Abstract

PROJECT SUMMARY
This proposal seeks to map and study the function of a likely widespread and potentially powerful modulatory
system in the brain that is currently `under the radar' of both basic and clinical neuroscience: the neurosteroid
estrogen system. Although estrogens have been studied for decades as reproductive hormones that act
through nuclear receptors to regulate gene expression, compelling evidence has accumulated for an
additional, distinct system of estrogen action in the brain. In this system, estrogens are produced directly
within the brain, of both sexes, where they act through extranuclear receptors to regulate neurophysiology and
behavior on a time scale of minutes. Although relatively little is known about the neurosteroid estrogen
system, especially in vivo, what is known indicates tremendous potential for neurosteroid estrogens to
influence brain functions broadly, from cognition to neuropsychiatric disorders to seizures in epilepsy. Despite
this potential, however, current research aimed at understanding where and how neurosteroid estrogens
operate in the brain is severely limited by a lack of reliable research tools. We propose to address this problem
using a two-pronged approach. First, in a collaborative project, we will generate multiple lines of gene-targeted
mice to visualize and map the distribution of key components of the neurosteroid estrogen system: P450
aromatase (estrogen synthase) and three estrogen receptors (ERs), ERβ, ERα, and G protein-coupled ER-1
(GPER1), in both males and females. Second, we will adapt approaches for in vivo microdialysis to directly
measure steroid levels in specific regions of the male and female brain to identify sites and circumstances of
neurosteroid estrogen synthesis. Microdialysis will be followed by targeted manipulation of aromatase activity
to investigate the functional consequences of neurosteroid estrogen synthesis. Together, these studies will
address five key questions about the neurosteroid estrogen system: (1) Where in the brain are neurosteroid
estrogens synthesized? (2) Under what circumstances are they synthesized in vivo? (3) Through what
receptors, located where, do neurosteroid estrogens signal? (4) What are the downstream physiological and
behavioral consequences of neurosteroid estrogen signaling? (5) How is the neurosteroid estrogen system the
same or different in males and females? At the completion of this project, we expect to have generated the
first comprehensive maps of the neurosteroid estrogen system in both the male and female brain and to have
identified specific behaviors/functions that are influenced by neurosteroid estrogens. Moreover, we expect that
this work will transform the field by providing powerful new tools to overcome limitations of current approaches
and permit reliable investigation of the neurosteroid estrogen system for the first time.

## Key facts

- **NIH application ID:** 9917830
- **Project number:** 5R01MH113189-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** CATHERINE S WOOLLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $750,162
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917830

## Citation

> US National Institutes of Health, RePORTER application 9917830, New Tools to Study Neurosteroid Estrogens (5R01MH113189-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9917830. Licensed CC0.

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