Nongenomic actions of 17-β estradiol restore respiratory neuroplasticity in young ovariectomized female rats

Brendan J. Dougherty, Elizabeth S. Kopp, Jyoti J. Watters

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Gonadal steroids modulate CNS plasticity, including phrenic long-term facilitation (pLTF), a form of spinal respiratory neuroplasticity resulting in increased phrenic nerve motor output following exposure to acute intermittent hypoxia (aIH; three 5 min episodes, 10.5% O2). Despite the importance of respiratory system neuroplasticity, and its dependence on estrogen in males, little is known about pLTF expression or mechanisms of estrogen signaling in females. Here, we tested the hypotheses that (1) pLTF expression in young, gonadally intact female rats would be expressed during estrous cycle stages in which 17β-estradiol (E2) is naturally high (e.g., proestrus vs estrus), (2) pLTF would be absent in ovariectomized (OVX) rats and in physiological conditions in which serum progesterone, but not E2, is elevated (e.g., lactating rats, 3–10 d postpartum), and (3) acute E2 administration would be sufficient to restore pLTF in OVX rats. Recordings of phrenic nerve activity in female Sprague Dawley rats (3–4 months) revealed a direct correlation between serum E2 levels and pLTF expression in cycling female rats. pLTF was abolished with OVX, but was re-established by acute E2 replacement (3 h, intraperitoneal). To identify underlying E2 signaling mechanisms, we intrathecally applied BSA-conjugated E2 over the spinal phrenic motor nucleus and found that pLTF expression was restored within 15 min, suggesting nongenomic E2 effects at membrane estrogen receptors. These data are the first to investigate the role of ovarian E2 in young cycling females, and to identify a role for nongenomic estrogen signaling in any form of respiratory system neuroplasticity.

Original languageEnglish (US)
Pages (from-to)6648-6660
Number of pages13
JournalJournal of Neuroscience
Issue number28
StatePublished - 2017

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute of Health (R01 HL111598 and R01 NS085226;


  • Estradiol
  • Long-term facilitation
  • Phrenic
  • Plasticity

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