Sexual dimorphisms in phrenic long-term facilitation following severe acute intermittent hypoxia

Abstract

Rigorous pre-clinical research in male rodents defined the cellular mechanisms of respiratory neuroplasticity following brief exposures to hypoxia (acute, intermittent hypoxia; AIH). AIH elicits phrenic long-term facilitation (pLTF), a progressive increase in phrenic nerve amplitude over time. Mechanisms to AIH-induced pLTF are complex and variable depending on the severity of hypoxemia during AIH. Moderate AIH (mAIH; PaO2 [~]35-45mmHg) triggers spinal serotonin receptor activation to induce pLTF expression. More severe AIH (sAIH; PaO2 [~]25-30mmHg) induces pLTF through an adenosine receptor-dependent pathway. Here we assessed: 1) if sAIH-induced pLTF is expressed in female rats, and whether sAIH-pLTF is impacted by the estrous cycle; 2) if the magnitude of sAIH-induced pLTF in female rats is similar to male rats; and 3) whether GDX alters the magnitude of sAIH-induced pLTF. We hypothesized that female rats would express sAIH-induced pLTF, and that circulating steroid hormone levels would have minimal impact on sAIH-induced pLTF in either sex. Our findings reveal that female rats express robust pLTF ([~]106% above baseline phrenic amplitudes) in response to sAIH, with minimal effects of estrous cycle stage. Female rats also showed a nearly 50% higher magnitude in sAIH-pLTF than males (p=0.006). Following GDX, pLTF magnitude was reduced in female rats (p=0.04), while males were unable to express pLTF. These findings predict unique cellular mechanisms to pLTF in female rats following sAIH, and sex-specific impacts of steroid hormone signaling on the expression of respiratory neuroplasticity.