Motoo Yamauchi

Post-sigh breathing behavior and spontaneous pauses in the C57BL/6J (B6) mouse.

The purpose was to examine sighs and spontaneous pauses in regard to the stability of resting breathing in the B6 strain, compared to the A/J strain. A 5-HT1A receptor agonist (buspirone) and a chromosomal substitution strain (B6a1) were used to further alter breathing patterning. Ten-minute recordings of room air breathing were collected from unanaesthetized B6, A/J, and B6a1 mice. Despite no differences between strains in the magnitude and incidence of sighs, post-sigh apneas, the variation for duration of expiration (Te) after sighs, and the number of spontaneous pauses were greater in the B6, while Shannon Entropy (nonlinear metrics) for Te after sighs was lower in B6, compared to the other strains. Buspirone and chromosomal substitution eliminated post-sigh apneas and decreased spontaneous pauses. A greater irregularity and the lower complexity of post-sigh breathing in B6 are reversed by elements on A/J chromosome 1 and by increased 5-HT1A serotonergic tone.

Mouse Models of Apnea: Strain Differences in Apnea Expression and its Pharmacologic and Genetic Modification

Mouse strain differences exist in post-hypoxic ventilatory behavior, specifically, the C57BL/6 J (B6) mouse exhibits irregular breathing including apnea during re-oxygenation after acute hypoxic exposure, while A/J mouse does not. This phenomenon of the B6 mouse responding to the hypoxia-reoxygenation cycle which is a mimic of human sleep apnea syndrome let us consider the B6 mouse as an animal model of sleep apnea. Moreover, the B6 mouse tends to show spontaneous apnea and post-sigh apnea compared to the A/J mouse. In this brief review, we present evidence that pharmacologic approaches as well as genetic modification can improve irregular breathing including apnea in the B6, suggesting that these pharmacologic treatment might be effective for the patients with sleep apnea who cannot tolerate nCPAP. Moreover our findings regarding genetic difference and modification should be helpful to explore the pathogenesis of sleep apnea.

Post-hypoxic Unstable Breathing in the C57BL/6J Mouse: Effects of Acetazolamide

We examined whether acetazolamide (ACZ), a carbonic anhydrase inhibitor, would alter post-hypoxic ventilatory behavior and periodic breathing in the C57BL/6J (B6) mouse. Experiments were performed with unanaesthetized, awake adult male B6 mice (n = 5, 2.5 months old, 21.3 +/- 1.5 g, mean +/- SD) and ventilatory behavior was measured using a flow through body plethysmography. Mice were given an intraperitoneal injection of either vehicle or ACZ (40 mg/kg) and one hour later exposed to 1 min of 8% O2-balance N2 (poikilocapnic hypoxia) or 12%-O2, 3% CO2-balance N2 (non-poikilocapnic hypoxia) followed by rapid reoxygenation (100% O2) of 5 minutes. One minute after reoxygenation, ACZ-treated animals exhibited post-hypoxic frequency decline (p < 0.05), a lower coefficient of variability for frequency (p < 0.001) and no tendency towards periodic breathing (p < 0.05), as compared to vehicle-treated animals. ACZ improves unstable breathing in the B6 model of periodic breathing, despite producing post-hypoxic frequency decline. Our speculation is that periodic breathing occurs through pathways independent of the A5 pontine area.

Loop Gain and Sleep Disordered Breathing

There is a close relationship among the types of sleep apnea (central, obstructive, and mixed) in regard to both the pathogenesis and in the clinical management of sleep apnea syndromes. This review will recount the rationale for the use of animal models in understanding intermediate traits, such as the ventilatory responses to hypoxia and reoxygenation, seen with human sleep apnea. One feature of particular interest will be the dynamic responses of the control system, specifically the instability over time that could operate to produce repetitive apneas. The recurrent nature of clinically significant sleep apnea can be understood in terms of feedback control, or “loop gain”. We will discuss findings in a mouse model for recurrent apneas and propose that there exist genetic mechanisms that could determine loop gain in the respiratory control system.