Development of ventilatory long-term facilitation is dependent on estrous cycle stage in adult female rats

Abstract

Ventilatory long-term facilitation (vLTF) is a form of respiratory plasticity characterized by a progressive and sustained increase in minute ventilation over time following acute, intermittent hypoxia (AIH). Though vLTF has been repeatedly demonstrated in adult males (rats and humans), few studies have assessed vLTF in adult females and no studies have explored differential expression of vLTF across the normal female estrous cycle. We recently reported that AIH-induced plasticity of phrenic motor output (phrenic long-term facilitation, pLTF), a phenotypically similar form of respiratory plasticity presenting as a sustained increase in phrenic nerve amplitude, develops in adult female rats only during the proestrus stage of the estrous cycle, notable for high levels of serum estrogen. Here, we tested the hypothesis that AIH-induced vLTF would also be estrous-stage dependent; developing in female rats during proestrus, but not estrus. Barometric plethysmography in adult (4-5 months), normally cycling female rats revealed a progressive increase in minute ventilation for 60 min following AIH (5 × 5 min episodes; 10% O₂) during proestrus indicative of vLTF, while estrus rats showed no changes in minute ventilation over the same time period. The development of vLTF in proestrus rats was driven by changes in tidal volume production versus respiratory frequency consistent with prior studies. These data are the first to investigate differential vLTF expression across the estrous cycle in adult female rats and highlight the importance of female estrous cycle stage as a critical physiological variable to consider in studies of AIH-induced plasticity.

Keywords: Intermittent hypoxia; Long-term facilitation; Plasticity; Ventilation.