Phrenic long-term facilitation following severe acute intermittent hypoxia is preserved in geriatric male rats

Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Although AIH comprised of moderate versus severe hypoxic episodes both elicit pLTF, they do so via completely distinct cellular mechanisms. In young adult male rats, moderate AIH (mAIH) elicits pLTF via a serotonin-driven, adenosine-constrained mechanism. In aged rats, mAIH-induced pLTF is diminished due to increased basal spinal adenosine levels that further constrain serotonin-driven pLTF. In contrast, in young male rats, severe AIH (sAIH) elicits pLTF via an adenosine-dominant, serotonin-constrained mechanism. Since basal spinal adenosine levels are elevated in aged male rats, we tested the hypothesis that adenosine-dependent, sAIH-induced pLTF is enhanced in aged versus young male rats. Young (∼3 mo) and aged (∼20 mo) male Sprague-Dawley rats were urethane-anesthetized, ventilated, vagotomized, paralyzed, and exposed to sAIH (3, 5-min episodes, arterial Po₂ = 25-30 mmHg; 5-min intervals). Integrated phrenic nerve activity was measured before (baseline), during each hypoxic episode, and for 60 min post sAIH. Neither baseline phrenic burst amplitude, the short-term hypoxic phrenic response, nor pLTF (% change from baseline in phrenic burst amplitude) were different in aged versus young male rats (132 ± 19% vs. 99 ± 17%, respectively). Thus, although sAIH-induced pLTF is not significantly elevated in aged versus young male rats as predicted, the capacity for adenosine-driven plasticity is preserved, in contrast with serotonin-dependent, mAIH-induced pLTF.<b>NEW & NOTEWORTHY</b> We report new findings that advance our understanding of how cellular mechanisms underlying respiratory motor plasticity shift with age. Age-related shifts in the magnitude or mechanism driving plasticity have major clinical relevance as we work to translate AIH for therapeutic benefit in conditions such as chronic spinal cord injury or ALS, where subjects in ongoing clinical trials are often males of advanced age.