Spinal Conversion of Testosterone to Estradiol for the Expression of Phrenic Long‐term Facilitation in Adult Male Rats

Abstract

Estrogen modulates the expression of neuroplasticity, including phrenic long‐term facilitation (pLTF), a persistent increase in phrenic nerve activity observed after acute exposure to intermittent hypoxia (AIH; three 5 min episodes of 10.5% O2, delivered at 5‐minute intervals). Though robustly expressed in adult males, adult female rats express pLTF only in the presence of adequate circulating estradiol (E2); removal of the ovaries, the primary source of circulating E2, abolishes pLTF. Acute, spinal application of membrane‐impermeable E2 (E2‐BSA) restores plasticity in ovariectomized female rats through a fast‐acting cellular mechanism involving membrane‐associated estrogen receptors, suggesting spinal E2 signaling may be important for pLTF expression in females. Previous studies indicate that E2 may play an important role in the expression of AIH‐induced pLTF in adult male rats as well. Specifically, gonadectomy blunts pLTF expression by reducing circulating testosterone, and systemic testosterone replacement restores pLTF. However, this testosterone‐induced restoration of pLTF is only effective in the presence of aromatase, an enzyme that converts testosterone to E2. Here we tested the hypothesis that the relevant conversion of testosterone to E2 necessary for expression of pLTF in male rats occurs in the spinal cord near phrenic motor neurons. We recorded phrenic nerve activity and pLTF expression in anesthetized, paralyzed and ventilated male Sprague‐Dawley rats (3–4 mos) in the presence or absence of intrathecally delivered Letrozole, an aromatase inhibitor, over the cervical spinal cord. We combined these data with immunohistochemical characterization of aromatase expression in the ventral cervical spinal cord. Collectively, these data provide important information regarding the necessity for spinal E2 signaling in the expression of AIH‐induced pLTF in male rats, and underscore the utility of this model to dissect the role of E2 signaling in expression of spinal neuroplasticity.Support or Funding InformationFunding: This work was supported by the University of Minnesota Division of Physical Therapy with a generous contribution from the University of Minnesota Department of Rehabilitation Medicine.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.