Sex Differences In The Phenotype Of Sleep-Disordered Breathing In C57BL/6J Mice

Abstract

Sex differences in sleep-disordered breathing (SDB) are widely recognized. SDB is more prevalent in men, but women appear to exhibit more symptoms at lower levels of SDB severity, including insomnia symptoms. Mechanisms underlying sex differences in SDB are unknown. In this study, we compared the sleep architecture and breathing patterns during sleep between male and female mice and examined the effects of ovariectomy on SDB. We hypothesized that female and male mice differed in sleep and SDB, which are related to differences in carbon dioxide (CO2) chemosensitivity between sexes. Adult male (n=9) and female (n=10) C57BL/6J mice underwent full-polysomnography inside a whole-body plethysmography chamber. Arousals from sleep and apneas were manually scored. Breathing variability was assessed with Poincaré plots of minute ventilation. Hypercapnic ventilatory response (HCVR) was assessed during wakefulness and NREM sleep by acute administration of 8% CO2. In female mice, we performed bilateral ovariectomy and repeated sleep studies after 14 days. We found that arousal index was 55% increased in females compared to males, but sleep fragmentation was mainly attributed to spontaneous arousals in both groups. Surprisingly, apnea severity was significantly increased in female mice compared to males (32.4±6.7 vs 11.8±4.5, P=0.001). Breathing instability was also increased in females. HCVR was positively correlated with apnea index (r=0.55, P=0.05) and was significantly augmented in females compared to males. Ovariectomy did not affect sleep fragmentation, but attenuated CO2 sensitivity and improved breathing stability during sleep. Our results have suggested different SDB phenotypes between male and female C57BL/6J mice. SDB in female mice is associated with a hyperarousal state and increased HCVR compared to males. An exacerbated CO2 responsiveness related to ovarian hormones in females is an important determinant of differences in SDB severity and respiratory patterns between male and female sex. American Heart Association Postdoctoral Fellowship Award 828142 (to L.J.K.), NHLBI grant 2R01 HL133100-05, NIH R01 HL128970, and R01 HL13892 (to V.Y.P.), 1K23HL155730 and American Academy of Sleep Medicine Foundation 238-BS-20 (to L.V.P.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.