Daily and circadian regulation of respiratory plasticity in freely behaving rats

Plasticity is a hallmark feature of the neural system controlling breathing. As one example, acute intermittent hypoxia (AIH) elicits plasticity in multiple respiratory motor systems including phrenic, intercostal, hypoglossal and laryngeal (Mitchell and Baker, 2022). Recent work from our lab demonstrates that interactions between time of day and hypoxic episode duration have important implications, regulating the magnitude and dominant mechanism driving phrenic long-term facilitation (LTF), a well-studied model of AIH-induced respiratory plasticity in anesthetized rats. Given the potential impact of anesthesia and invasive physiological manipulations in prior studies, it is crucial to understand how the daily rest/active cycle influences AIH-induced respiratory motor plasticity in unanesthetized, freely-behaving rats with intact physiology. One major hypothesis guiding this proposal is that the daily rest/active cycle determines the magnitude and mechanism of diaphragm and ventilatory LTF, both forms of AIH-induced respiratory motor plasticity studied in unanesthetized rats. The importance of these findings is reinforced by the fact that AIH is being used in ongoing clinical trials to improve breathing (and non-respiratory) function in individuals with spinal cord injury and ALS. Given the reverse diurnal rhythm of rodents and humans, our ability to harness AIH as a therapeutic modality will be enhanced through greater understanding of circadian effects on respiratory outcomes. Since the endogenous circadian clock is the predominant organizer of daily behavioral and physiological rhythms in mammals, including natural 24-hr rest/active cycles, a second major goal of this proposal is to test the hypothesis that a local circadian clock within phrenic motor neurons regulates mechanisms giving rise to AIH-induced respiratory motor plasticity. Currently, there is no information available concerning how the endogenous circadian clock influences any form of respiratory plasticity, presenting a novel research opportunity with significant scientific and translational potential. Collectively, these findings will provide important insights to help guide the design of clinical trials using AIH as a therapeutic modality. Elucidating circadian regulation of respiratory plasticity will have both biological and translational significance that may guide development of new strategies to treat severe neuromuscular disorders that compromise breathing.