The impact of natural aging and ovariectomy on neuroplasticity in female rats: Is all estrogen loss the same?

Abstract

In adult female rats, circulating sex hormone levels fluctuate significantly across the normal estrus cycle. The most abundant and neuroactive of these sex hormones is 17β‐estradiol (a form of estrogen). We previously demonstrated that 17β‐estradiol is necessary to permit development of respiratory neuroplasticity induced by acute intermittent hypoxia (AIH), called phrenic long‐term facilitation (pLTF). Female rats only develop pLTF during proestrus when circulating estrogen levels are high, and do not express plasticity during periods of low circulating 17β‐estradiol. Additionally, ovariectomy (OVX) abolishes neuroplasticity, but it can be restored with estrogen supplementation. As part of the natural aging process in female rats, estrous‐cycle related fluctuations in circulating 17β‐estradiol levels gradually cease. Rats settle into a state of persistent diestrus, with low levels of circulating estrogen, similar to human menopause. Accordingly, we hypothesized that a reduction in circulating estrogen, either through ovariectomy (OVX) or with natural aging, would eliminate the expression of pLTF. Four experimental groups of female rats were used to test this hypothesis: (1) aged (>22 months old), ovary‐intact, in persistent diestrus (min of 2, 5‐day cycles), (2) young (3 months old), ovary‐intact, in proestrus, (3) young, OVX (2wk post‐surgery), and (4) time controls (both young and aged). Phrenic neurophysiology was used to assess pLTF in anesthetized, ventilated, and vagotomized rats. Circulating estrogen levels were quantified using an ELISA assay for all groups. Contrary to our hypothesis, preliminary results indicate that aged female rats in persistent diestrus produce robust AIH‐induced pLTF (>250% increase in integrated phrenic amplitude 60min post‐AIH). Full results and mechanistic discussion will be presented.