Aging Impairs Respiratory Motor Plasticity in Rest Phase <i>APOE4</i> Knock-In Rats

Moderate acute intermittent hypoxia (mAIH) elicits respiratory motor plasticity and is emerging as a promising strategy to improve breathing and non-respiratory movements in clinical disorders that typically end life due to respiratory insufficiency ( e.g., spinal cord injury &amp; ALS). AIH-induced phrenic long-term facilitation (pLTF) is a form of respiratory motor plasticity expressed as a persistent increase in phrenic nerve activity lasting hours post-mAIH. We reported previously that pLTF decreases in geriatric male and female rats. Further, an apolipoprotein E4 ( APOE 4), but not E3 ( APOE 3) genotype undermines mAIH-induced pLTF in the diurnal active phase of young adult, male humanized APOE knock-in Sprague Dawley rats. Although pLTF exhibits a powerful diurnal rhythm, effects of aging and APOE genotype on mAIH-induced pLTF have not been studied across the daily rest/active cycle. We tested the hypotheses that APOE4 undermines mAIH-induced pLTF differentially in the rest vs active phase and in young vs middle-aged male rats. Young (3-4 months) and middle-aged Sprague Dawley rats (13-15 months) expressing humanized APOE3 (neuro-neutral) and APOE4 (neuro-degenerative) were compared in the mid-rest vs mid-active phases. Rats were anesthetized, vagotomized, paralyzed and ventilated and, after establishing baseline phrenic nerve activity, were exposed to isocapnic mAIH (15,1 min episodes; arterial PO 2 = 40-50mmHg) at zeitgeber times 6 (mid-rest) and 18 hrs (mid-active). In mid-active rats, pLTF was significantly greater in APOE3 (young: 33±11%; aged: 24±12%) vs h APOE4 rats (young: -26±7%; aged: -39±5%; n=3-6 per group), regardless of age (all p&lt;0.001). Whereas rest phase pLTF was similar in young h APOE3 and h APOE4 rats (121±12% and 122±5%, respectively; n=7 per group) and middle-aged h APOE3 rats (108±11%; n=4), middle-aged h APOE4 rats exhibited significantly reduced pLTF in the rest phase (34±11%; n=4; all p&lt;0.002). Thus, APOE genotype impacts mAIH-induced pLTF in an age and time-of-day dependent manner. Since AIH has emerged as a promising neurotherapeutic with variable inter-individual effects, understanding how genetic factors (such as APOE genotype), age and time-of-day affect AIH-induced motor plasticity will help identify individuals most/least likely to respond to treatment and enable precision interventions of AIH. NIH K99HL175029 (ABM), Parker B. Francis Foundation (ABM), NIH R01HL149800 (GSM) and NIH R01HL148030 (GSM) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.