Post-Hypoxic Recovery of Respiratory Rhythm Generation Is Gender Dependent

Abstract

The preBötzinger complex (preBötC) is a critical neuronal network for the generation of breathing. Lesioning the preBötC abolishes respiration, while when isolated in vitro, the preBötC continues to generate respiratory rhythmic activity. Although several factors influence rhythmogenesis from this network, little is known about how gender may affect preBötC function. This study examines the influence of gender on respiratory activity and in vitro rhythmogenesis from the preBötC. Recordings of respiratory activity from neonatal mice (P10–13) show that sustained post-hypoxic depression occurs with greater frequency in males compared to females. Moreover, extracellular population recordings from the preBötC in neonatal brainstem slices (P10–13) reveal that the time to the first inspiratory burst following reoxygenation (TTFB) is significantly delayed in male rhythmogenesis when compared to the female rhythms. Altering activity of ATP sensitive potassium channels (KATP) with either the agonist, diazoxide, or the antagonist, tolbutamide, eliminates differences in TTFB. By contrast, glucose supplementation improves post-hypoxic recovery of female but not male rhythmogenesis. We conclude that post-hypoxic recovery of respiration is gender dependent, which is, in part, centrally manifested at the level of the preBötC. Moreover, these findings provide potential insight into the basis of increased male vulnerability in a variety of conditions such as Sudden Infant Death Syndrome (SIDS).

The physiological determinants of Sudden Infant Death Syndrome

“…This is followed by a post-hypoxic augmentation of the eupneic rhythm (Fig. 2A, (Blitz and Ramirez, 2002; Pena et al, 2004; Hill et al, 2011; Garcia et al, 2013a)). Moreover, this stereotypical post-hypoxic response can be mimicked by adding hydrogen peroxide, a reactive oxygen species and by-product commonly encountered during reoxygenation from hypoxia (Garcia et al, 2011).…”

“…However, a third and potentially critical, yet often overlooked phase of respiratory vulnerability occurs upon reoxygenation. During reoxygenation, a silent period termed the post-hypoxic ventilatory depression creates a transition between gasping and eupnea (Lieske et al, 2000; Hill et al, 2011; Garcia et al, 2013a). Any impairment that increases the length of the post-hypoxic ventilatory depression or otherwise impairs the reestablishment of eupnea may contribute to SIDS.…”

“…Of great interest is the finding that gene polymorphisms regulating glucose metabolism are also disturbed in SIDS (Forsyth et al, 2005). Glucose concentration affects the hypoxic response of the respiratory network and may contribute to the known gender difference in SIDS (Garcia et al, 2013b). Ultimately, all of these factors could disturb homeostatic mechanisms that are required for an adequate response of the respiratory network to respond to a challenge for example posed by the prone position.…”

“…During discrete periods of development, respiratory control and function undergo changes both at the cellular and systems level (Wong-Riley and Liu, 2005; Holley et al, 2012; Garcia et al, 2013a). In rodents, the second postnatal week is a critical period of brainstem development when chloride homeostasis (Lee et al, 2005; Liu and Wong-Riley, 2012), NMDA receptor expression (Wong-Riley and Liu, 2005), and GABA A receptor subunit expression (Liu and Wong-Riley, 2006) change.…”

“…For more examples the reader is referred to the review by Behan and Wenninger (2008). In addition to such differences, during hypoxia Garcia et al (2013a) reported that during reoxygenation the post-hypoxic respiratory depression is significantly longer in males when compared to females at P10–13. This difference in post-hypoxic recovery appeared to involve the preBötC.…”