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Recurrent apneas are important causes of hospitalization and morbidity in newborns. Gestational stress (GS) compromises fetal brain development. Maternal stress and anxiety during gestation are linked to respiratory disorders in newborns; however, the mechanisms remain unknown. Here, we tested the hypothesis that repeated activation of the neuroendocrine response to stress during gestation is sufficient to disrupt the development of respiratory control and augment the occurrence of apneas in newborn rats. Pregnant dams were displaced and exposed to predator odor from days 9 to 19 of gestation. Control dams were undisturbed. Experiments were performed on male and female rats aged between 0 and 4 d old. Apnea frequency decreased with age but was consistently higher in stressed pups than controls. At day 4, GS augmented the proportion of apneas with 02 desaturations by 12%. During acute hypoxia (12% 02), the reflexive increase in breathing augmented with age; however, this response was lower in stressed pups. Instability of respiratory rhythm recorded from medullary preparations decreased with age but was higher in stressed pups than controls. GS reduced medullary serotonin (5-HT) levels in newborn pups by 32%. Bath application of 5-HT and injection of 8-OH-DPAT [(±)-8-hydroxy-2-di-(n-propylamino) tetralin hydrobromide; 5-HT1A agonist; in vivo] reduced respiratory instability and apneas; these effects were greater in stressed pups than controls. Sex-specific effects were observed. We conclude that activation of the stress response during gestation is sufficient to disrupt respiratory control development and promote pathological apneas in newborn rats. A deficit in medullary 5-HT contributes to these effects. [ABSTRACT FROM AUTHOR]

To better understand serotonergic modulation of air breathing during bullfrog development, we measured changes in fictive lung ventilation frequency associated with focal stimulation of the rostral region of the medullary Raphé neurons. Electrical (3 to 33 Hz) and chemical (glutamate microinjections; 0.5 mol l-1, 0.3-10 nl) activation of Raphé neurons was performed in brainstem preparations from three developmental stages (pre- and metamorphic tadpoles and adult frogs). Fictive lung ventilation was recorded extracelluarly from the Vth and Xth cranial nerves. Electrical stimulation of Raphé neurons caused a frequency-dependent increase in lung burst frequency in pre-metamorphic tadpoles only. In metamorphic tadpoles, an increase in fictive lung ventilation was observed at 20 Hz only. Electrical stimulation had no effect in preparations from adult frogs. Glutamate microinjections elicited similar responses as a lung burst frequency increase was observed in the pre- metamorphic group only. Regardless of the stimulation technique used, the increase in fictive lung ventilation was attenuated by the selective 5-HT3 antagonist tropisetron (5-20 µmoI l-1). Results from immunohistochemical analysis of the Raphé region stimulated do not correlate with functional data as the number of 5-HT immunoreactive neurons within this region increases during development. We conclude that, in this preparation, stimulation of lung ventilation by the medullary Raphé is restricted to early (pre-metamorphic) stages. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that 5-HT2A/C receptors contribute to the modulation of respiratory motor output elicited by serotonin bath-application in the in vitro brainstem preparation from bullfrog tadpoles. Preparations were superfused with (1) a selective 5-HT2A/C receptor agonist (DOI, 0.5–25 μM) or (2) 5-HT in presence of a non-selective 5-HT2A/C receptor antagonist (methysergide maleate, 10 μM). Stage-related differences in 5-HT2A/C modulation were assessed by performing experiments on two groups: pre- and post-metamorphic tadpoles. 5-HT2A/C receptor activation with DOI did not alter either gill or lung burst frequency. Methysergide did not prevent the gill burst frequency attenuation elicited by 5-HT. Our results show no apparent contribution of the 5-HT2A/C receptor subtypes to the serotonergic modulation of either gill- or lung-related neural activity in either group. While 5-HT2A/C receptors are involved in the modulation of respiratory motor output in mammals, these receptor subtypes do not appear to play a significant role in this species. [ABSTRACT FROM AUTHOR]

Human and animal studies on sleep-disordered breathing and respiratory regulation show that the effects of sex hormones are heterogeneous. Because neonatal stress results in sex-specific disruption of the respiratory control in adult rats, we postulate that it might affect respiratory control modulation induced by ovarian steroids in female rats. The hypoxic ventilatory response (HVR) of adult female rats exposed to neonatal maternal separation (NMS) is ∼30% smaller than controls (24), but consequences of NMS on respiratory control in aging female rats are unknown. To address this issue, whole body plethysmography was used to evaluate the impact of NMS on the HVR (12% O2, 20 min) of middle-aged (MA; ∼57 wk old) female rats. Pups subjected to NMS were placed in an incubator 3 h/day for 10 consecutive days (P3 to P12). Controls were undisturbed. To determine whether the effects were related to sexual hormone decline or aging per se, experiments were repeated on bilaterally ovariectomized (OVX) young (∼12 wk old) adult female rats. OVX and MA both reduced the HVR significantly in control rats but had little effect on the HVR of NMS females. OVX (but not aging) reduced the anapyrexic response in both control and NMS animals. These results show that hormonal decline decreases the HVR of control animals, while leaving that of NMS female animals unaffected. This suggests that neonatal stress alters the interaction between sex hormone regulation and the development of body temperature, hormonal, and ventilatory responses to hypoxia., (Copyright © 2015 the American Physiological Society.)

Recent medical advances have made it possible for babies to survive premature birth at increasingly earlier developmental stages. This population requires costly and sophisticated medical care to address the problems associated with immaturity of the respiratory system. In addition to pulmonary complications, respiratory instability and apnea reflecting immaturity of the respiratory control system are major causes of hospitalization and morbidity in this highly vulnerable population. These medical concerns, combined with the curiosity of physiologists, have contributed to the expansion of research in respiratory neurobiology. While most researchers working in this field commonly use rodents as an animal model, recent research using in vitro brainstem preparation from bullfrogs (Rana catesbeiana) have revealed the technical advantages of this animal model, and shown that the basic principles underlying respiratory control and its ontogeny are very similar between these two groups of vertebrates. The present review highlights the recent advances in the area of research with a focus on intermittent (episodic) breathing and the role of serotonergic and GABAergic modulation of respiratory activity during development.