Date of Award
Summer 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biological Sciences
First Advisor
Arble, Deanna M.
Second Advisor
Blumenthal, Edward
Third Advisor
Manogaran, Anita
Abstract
Breathing, like many physiological functions, exhibits a daily rhythm in mammals that coincides with periods of wakefulness and increased metabolic activity. Dysregulation of daily breathing rhythms has been implicated in a variety of respiratory diseases with time-specific symptomatology including sleep apnea, asthma, chronic pulmonary disease, sudden unexpected death in epilepsy, and COVID-19. While the daily rhythm in breathing is regulated by the endogenous circadian clock in the brain, the underlying physiological and cellular mechanisms modulating daily breathing behavior remain largely unknown. Light is the most potent synchronizer of the circadian system in mammals and is likely the principal driver of respiratory behavior across the day. To determine the central role of light in modulating breathing, I present a series of experiments demonstrating that manipulation of the light environment and/or circadian timing/mechanisms reorganizes daily ventilatory rhythms. First, I demonstrate that changing the number of available light hours in the day (i.e., photoperiod), reorganizes the daily rhythm in minute ventilation and alters the relationship between breathing rhythms and metabolic rate. This finding establishes a fundamental role for environmental light in shaping breathing across the day. Then, using transgenic mouse models of circadian disruption, I demonstrate that the molecular circadian clock plays a pivotal role in regulating daily rhythms in ventilation and chemoreflex in a time- and cell-specific manner. This finding indicates for the first time that the circadian clock acts molecularly at the level of the neural respiratory network to organize breathing rhythms. Next, using a desynchronized feeding protocol, I provide additional evidence that the daily rhythm in minute ventilation is not solely dictated by circadian patterns of metabolic rate, but is simultaneously optimized by other clock-derived mechanisms such as clock gene expression in the neural respiratory network. Lastly, using a forced desynchrony protocol and additional transgenic mouse lines, I reveal that light can organize daily ventilation rhythms independent of retinal input to the master circadian clock by activating a unique Opn4-expressing retinal ganglion cell that additionally expresses the transcription factor Brn3b. Collectively, this work identifies several novel neural mechanisms that environmental light modulates to ensure that breathing is properly optimized across the day. These findings provide new mechanistic insights into the photic and circadian modulation of breathing which may have clinical implications for respiratory diseases with time-specific symptomatology.