# Mechanisms of Estrogenic Modulation of Adenosinergic Sleep Pressure

> **NIH NIH F30** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $37,370

## Abstract

Project Summary:
Primary sleep disorders are among the most common medical conditions, and clinical data show women are far
more likely to experience sleep disorders over their lifespan. This increased risk emerges at puberty and has
been associated with fluctuations in ovarian steroids, particularly estrogens, suggesting that gonadal steroids
and biological sex are significant risk factors for sleep disruptions. Despite a growing understanding of sleep
regulatory mechanisms, how estrogens influence the sleep circuitry is poorly understood. Historically, male
rodents have served as the cornerstone for elucidating the neural circuitries governing sleep. Unfortunately, this
has resulted in a significant gap in our understanding of how estrogens modulate these circuits in females. The
female rodent offers the opportunity to probe the sleep circuitry to elucidate the mechanisms by which ovarian
steroids modulate sleep, as sleep patterns in the female rat are exquisitely sensitive to natural fluctuations in
ovarian steroids such as estradiol (E2). Using adult female Sprague-Dawley rats, our group has made inroads
into understanding estrogenic influences over normal wake and sleep patterns. Our studies consistently
demonstrate that sleep time is significantly reduced when endogenous ovarian steroids or exogenous E2 are
elevated in females but not males. This effect is mediated through the inhibition of sleep-active neurons in the
median preoptic nucleus (MnPN). Moreover, we have demonstrated that E2 is capable of marked suppression
of sleep under sleep deprivation, when homeostatic sleep need, also known as sleep pressure, is increased.
Taken together with our previous findings, this observation suggests that E2 may dissipate the homeostatic need
for sleep. Furthermore, preliminary data suggest that E2 attenuates the action of adenosine signaling at the
sleep-promoting A2A receptor, resulting in reduced sleep duration. This finding is significant because adenosine
is a known mediator of sleep pressure, with established actions at the MnPN and a closely related (but non-E2
sensitive) nucleus, the ventral lateral preoptic (VLPO). These data suggest that there is an interplay between E2
and adenosine which modulates the ability of adenosine to generate sleep pressure. However, the specific
mechanism for this interplay remains undetermined. This project will test the hypothesis that estrogenic
modulation of sleep pressure requires the attenuation of adenosine signaling efficacy. We will test this
hypothesis by (1) determining if estradiol reduces the homeostatic need for sleep through both behavioral
experiments and molecular assays of adenosine content, synthesis, and clearance, and (2) determining if
estradiol attenuates neuronal activity of sleep active MnPN neurons, through inhibiting the cellular action of
adenosine in the sleep circuitry, through experiments in both receptor pharmacology and neuronal activity.
Understanding interactions of E2 and ade...

## Key facts

- **NIH application ID:** 9913990
- **Project number:** 5F30HL145901-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Philip Carver Smith
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,370
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913990

## Citation

> US National Institutes of Health, RePORTER application 9913990, Mechanisms of Estrogenic Modulation of Adenosinergic Sleep Pressure (5F30HL145901-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9913990. Licensed CC0.

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