Gestational Stress Promotes Pathological Apneas and Sex-Specific Disruption of Respiratory Control Development in Newborn Rat

Abstract

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 O 2 desaturations by 12%. During acute hypoxia (12% O 2 ), 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 [(Ϯ)-8-hydroxy-2-di-(n-propylamino) tetralin hydrobromide; 5-HT 1A 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.

Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood

“…Table 1). However, this did not translate into an increased incidence of overt apnoeas as has been observed in stressed neonates in another model of gestational stress (Fournier et al, 2013). Intriguingly, in PNS animals, ventilatory parameters were dysregulated when the respiratory system was challenged with the classic ventilatory stimulants of hypoxia and hypercapnia.…”

“…Intriguingly, in PNS animals, ventilatory parameters were dysregulated when the respiratory system was challenged with the classic ventilatory stimulants of hypoxia and hypercapnia. Neonatal rats exposed to gestational stress displayed a blunted hypoxic ventilatory response and an enhanced ventilatory response to hypercapnia (Fournier et al, 2013). Enhanced responsiveness to hypercapnia was also observed in adult rats exposed to neonatal maternal separation (Genest et al, 2007).…”

Electrophysiology on Isolated Brainstem-spinal Cord Preparations from Newborn Rodents Allows Neural Respiratory Network Output Recording

“…Solutions 1. Prepare aCSF stock solutions according to the following recipes 7,17 . Other recipes with concentration variations are available in the literature.…”

“…This method can be employed in a wide range of research objectives, targeting inspiratory responses to respiratory variations or pharmacology in both wild type 7 and transgenic 8 animals. Given that experiments are performed at a low temperature, without sensory afferents, and under conditions where the concentrations of glucose and O 2 within the aCSF are high, questions have been raised regarding the physiological relevance of the signal recorded.…”

“…The rhythm generated by brainstem-spinal cord preparations is composed of individual slow bursts that are linked to the inspiratory signal 9 . Isolated brainstem-spinal cord preparations are easily recordable in rats from post-natal day 0 to 4 (P0 -P4) 7 . This approach is commonly used to evaluate the hypoxic response of the respiratory network, and also the response to hypercapnia, acidosis or drugs.…”