The cellular circadian clock of Phox2b-expressing cells drives daily variation of the hypoxic but not hypercapnic ventilatory response in mice

Abstract

While the suprachiasmatic nucleus (SCN) controls 24-hour rhythms in breathing including minute ventilation (VE), the mechanisms by which the SCN drives these daily changes are not well-understood. Moreover, the extent to which the circadian clock regulates the ventilatory responses to hypercapnia and hypoxia (i.e., the ventilatory chemoreflex), is unknown. We hypothesized that the SCN regulates daily breathing and chemoreflex rhythms by synchronizing the molecular circadian clock within cells. Here, we used whole-body plethysmography to assess ventilatory function in transgenic BMAL1 knockout (KO) mice to determine the role of the cellular clock in regulating daily rhythms in ventilation and chemoreflex. We observed that, unlike their wildtype littermates, BMAL1 KO mice exhibited a blunted daily rhythm in VE and failed to demonstrate daily variation in the hypoxic ventilatory response (HVR). The absence of a functional cellular clock in BMAL1 KO mice also resulted in an overall decrease in the hypercapnic ventilatory response (HCVR) and a sex-specific absence of circadian variation of HCVR. Next, to determine the extent to which these effects on minute ventilation and ventilatory chemoreflex were mediated by the cellular clock within the neural respiratory network, we assessed ventilatory rhythms in BMAL1fl/fl;Phox2bCre/+ mice which lack BMAL1 in all Phox2b-expressing chemoreceptor cells (hereafter called BKOP). BKOP mice lacked daily variation in HVR consistent with our observations in the BMAL1 KO mice. However, unlike BMAL1 KO mice, BKOP continued to exhibit daily variations in VE and HCVR similar to wildtype littermates. These data indicate that the cellular clock contributes to the daily rhythms in VE, HVR, and HCVR. Moreover, the cellular clock of Phox2b-expressing cells specifically is necessary for day-night variations in HVR. Taken together, these data suggest that the SCN regulates daily ventilatory rhythms in part through the synchronization of cellular clocks within respiratory cell populations. These findings open the possibility that circadian disruption or circadian misalignment may affect respiratory homeostasis which, in turn, may have clinical implications for shift workers and respiratory diseases with time-of-day-specific symptomology. American Heart Association (Arble, 20IPA35320195) This is the full abstract presented at the American Physiology Summit 2023 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.