The Molecular Circadian Clock of Phox2b-expressing Cells Drives Daily Variation of the Hypoxic but Not Hypercapnic Ventilatory Response in Mice

Authors

Aaron A. Jones, Marquette University
Gabriella M. Marino, Marquette University
Allison R. Spears, Marquette University
Deanna M. Arble, Marquette UniversityFollow

Document Type

Article

Publication Date

2023

Publisher

Oxford University Press

Source Publication

Function

Source ISSN

2633-8823

Original Item ID

DOI: 10.1093/function/zqad023

Abstract

While the suprachiasmatic nucleus (SCN) controls 24-h rhythms in breathing, including minute ventilation (V_E), the mechanisms by which the SCN drives these daily changes are not well understood. Moreover, the extent to which the circadian clock regulates hypercapnic and hypoxic ventilatory chemoreflexes is unknown. We hypothesized that the SCN regulates daily breathing and chemoreflex rhythms by synchronizing the molecular circadian clock of cells. We used whole-body plethysmography to assess ventilatory function in transgenic BMAL1 knockout (KO) mice to determine the role of the molecular clock in regulating daily rhythms in ventilation and chemoreflex. Unlike their wild-type littermates, BMAL1 KO mice exhibited a blunted daily rhythm in V_E and failed to demonstrate daily variation in the hypoxic ventilatory response (HVR) or hypercapnic ventilatory response (HCVR). To determine if the observed phenotype was mediated by the molecular clock of key respiratory cells, we then 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, similar to BMAL1 KO mice. However, unlike BMAL1 KO mice, BKOP mice exhibited circadian variations in V_E and HCVR comparable to controls. These data indicate that the SCN regulates daily rhythms in V_E, HVR, and HCVR, in part, through the synchronization of the molecular clock. Moreover, the molecular clock of Phox2b-expressing cells is specifically necessary for daily variation in the hypoxic chemoreflex. These findings suggest that disruption of circadian biology may undermine respiratory homeostasis, which, in turn, may have clinical implications for respiratory disease.

Comments

Published version. Function, Vol. 4, No. 4, 2023. DOI. © The Authors. Used with permission.

Published by Oxford University Press on behalf of American Physiological Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Recommended Citation

Jones, Aaron A.; Marino, Gabriella M.; Spears, Allison R.; and Arble, Deanna M., "The Molecular Circadian Clock of Phox2b-expressing Cells Drives Daily Variation of the Hypoxic but Not Hypercapnic Ventilatory Response in Mice" (2023). Biological Sciences Faculty Research and Publications. 944.
https://epublications.marquette.edu/bio_fac/944