# Mechanisms Governing the Estrogenic Modulation of Sleep

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $688,417

## Abstract

Quality sleep is imperative for the maintenance of good health. There is a growing recognition of sex
disparities in sleep and rhythm disorders. Complaints such as insufficient sleep and insomnia are ~40% more
prevalent in women than men. Yet, historically, women and female animals are underrepresented in studies of
sleep and its disorders. While gonadal steroids and gender are implicated as risk factors for sleep disruptions
and insomnia, the relationship between ovarian steroids and sleep is poorly understood. The broad, long-term
objective of the application is to understand the cellular mechanisms and functional consequences of estrogen-
mediated changes in vigilance states. Findings from the previous grant have established that estradiol (E2) acting
in the median preoptic nucleus (MnPO) is necessary and sufficient to reduce total sleep by ~50% of baseline in
females. However, our data present an intriguing paradox: E2 suppresses sleep while markedly increasing
extracellular adenosine, a potent inducer of sleep in the MnPO. Recent findings and preliminary data have begun
to shed light on this apparent contradiction. Our findings in the MnPO show that (1) E2 blocks the sleep inducing
actions of adenosine A2A receptor activation and activation of the adenosine A1 receptors or chemogenetic
activation of MnPO astrocytes mimic E2 suppression of sleep. Together, these findings have led us to our central
hypothesis that the E2-induced high levels of extracellular adenosine initiate a shift in adenosinergic balance from
an A2A excitatory tone that activates MnPO sleep neurons to an A1R inhibitory tone that inhibits the sleep-neurons
and E2 stimulation of MnPO astrocytes is responsible the increase in adenosine.
 We propose four independent, but related aims to address the following gaps in our knowledge that are
critical to understanding the mechanisms underlying estrogenic regulation of sleep: (1) Is the increase in MnPO
extracellular adenosine required for E2-induced suppression of sleep? (2) Is the activation of MnPO adenosine A1
receptors required for E2-induced suppression of sleep? (3) Is the suppression of MnPO adenosine A2A receptors
required for E2-induced suppression of sleep? and (4) Is E2 stimulation of MnPO astrocytes required for increases
in adenosine and sleep suppression? We approach these questions through a combination of modern
neuroscience techniques that include a GAD1-Cre transgenic rat line, fast scan cyclic voltammetry (FSCV) of
adenosine, fiber photometry and chemogenetics to investigate estrogenic regulation of sleep.
 There is heuristic value in comparing and contrasting cellular mechanisms between the sexes as this
approach has frequently reveal novel and previously unknown mechanisms of neural plasticity. Thus, we have
included a comparison of sex as a biological factor in addition to estrogenic influences on sleep mechanisms.
The significance of advancing our understanding of the mechanisms underlying E2 modulation of s...

## Key facts

- **NIH application ID:** 10466909
- **Project number:** 5R01HL129138-06
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jessica Aurora Mong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $688,417
- **Award type:** 5
- **Project period:** 2015-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466909

## Citation

> US National Institutes of Health, RePORTER application 10466909, Mechanisms Governing the Estrogenic Modulation of Sleep (5R01HL129138-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10466909. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*