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

Rigorous preclinical 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; [Formula: see text] ∼35-45 mmHg) triggers spinal serotonin receptor activation to induce pLTF expression. More severe AIH (sAIH; [Formula: see text] ∼25-30 mmHg) induces pLTF through an adenosine receptor-dependent pathway. Here we assessed: 1) whether sAIH-induced pLTF is expressed in female rats, and whether sAIH-pLTF is impacted by the estrous cycle; 2) whether the magnitude of sAIH-induced pLTF in female rats is similar to male rats; and 3) whether gonadectomy (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 100% higher magnitude in sAIH-pLTF than males (P = 0.006). Following GDX, pLTF magnitude was reduced in female rats (P = 0.04), whereas 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.NEW & NOTEWORTHY Our findings indicate sexual dimorphisms in the magnitude of phrenic long-term facilitation (pLTF) following severe, acute intermittent hypoxia (sAIH), and sex-specific impacts of gonadectomy. Female rats express sAIH-induced pLTF of larger magnitude than age-matched male rats. Gonadectomy abolishes sAIH pLTF in male rats, but only reduces the magnitude of pLTF in females by ∼50%. These data suggest unique, sex-specific mechanisms to AIH-induced respiratory neuroplasticity.