Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants

Abstract

We mapped and characterized changes in the activity of brainstem cell groups under hypoxia in one-day-old newborn mice, an animal model in which the central nervous system at birth is particularly immature. The classical biphasic respiratory response characterized by transient hyperventilation, followed by severe ventilation decline, was associated with increased c-FOS immunoreactivity in brainstem cell groups: the nucleus of the solitary tract, ventral reticular nucleus of the medulla, retrotrapezoid/parafacial region, parapyramidal group, raphe magnus nucleus, lateral, and medial parabrachial nucleus, and dorsal subcoeruleus nucleus. In contrast, the hypoglossal nucleus displayed decreased c-FOS immunoreactivity. There were fewer or no activated catecholaminergic cells activated in the medulla oblongata, whereas ~45% of the c-FOS-positive cells in the dorsal subcoeruleus were co-labeled. Approximately 30% of the c-FOS-positive cells in the parapyramidal group were serotoninergic, whereas only a small portion were labeled for serotonin in the raphe magnus nucleus. None of the c-FOS-positive cells in the retrotrapezoid/parafacial region were co-labeled for PHOX2B. Thus, the hypoxia-activated brainstem neuronal network of one-day-old mice is characterized by (i) the activation of catecholaminergic cells of the dorsal subcoeruleus nucleus, a structure implicated in the strong depressive pontine influence previously reported in the fetus but not in newborns, (ii) the weak activation of catecholaminergic cells of the ventral reticular nucleus of the medulla, an area involved in hypoxic hyperventilation, and (iii) the absence of PHOX2B-positive cells activated in the retrotrapezoid/parafacial region. Based on these results, one-day-old mice could highlight characteristics for modeling the breathing network of premature infants.

Prenatal Hypoxia Induces Cl– Cotransporters KCC2 and NKCC1 Developmental Abnormality and Disturbs the Influence of GABAA and Glycine Receptors on Fictive Breathing in a Newborn Rat

“…Among the pontin respiratory structures impacted by delayed maturation of KCC2, we hypothesised that Kolliker-Fuse nucleus that displayed an increase in calpain-positive neurons played a pivotal role in the alterations of CRD Cl − regulation because of their recognised role in the CRD as the "pontin respiratory group" (Ikeda et al, 2017). It should also be noted that our histological data suggest an impact of prenatal hypoxia on two pontine structures that participate in the adaptation of CRD during hypoxic or hypercapnic challenges: the locus coeruleus and the subcoeruleus nucleus (Coates et al, 1985;Breen et al, 1997;Oyamada et al, 1998;Nitsos and Walker, 1999;Walker et al, 2000;Joubert et al, 2016). Such an observation may suggest that the disregulation of KCC2 induced by prenatal hypoxic in locus coeruleus and subcoeruleus could alter the ability to regulate CRD in a context of gas challenges.…”

Effect of Gender on Chronic Intermittent Hypoxic Fosb Expression in Cardiorespiratory-Related Brain Structures in Mice

“…The VLM is a neuronal column ventral to the ambiguus nucleus that includes the A1C1 group of neurons and extends from the pyramidal decussation to the caudal edge of the facial nucleus (Voituron et al, 2006 , 2011 ; Huckstepp et al, 2015 ). We made a distinction between the caudal part of the VLM (cVLM; from the pyramidal decussation to the caudal edge of the lateral paragigantocellulaire nucleus) and the rostral part of the VLM (rVLM; from the caudal edge of the lateral paragigantocellulaire nucleus to the caudal edge of the facial nucleus) using standard landmarks, as previously described (Voituron et al, 2011 ; Joubert et al, 2016 ).…”

The Role of Maternal Smoking in Sudden Fetal and Infant Death Pathogenesis

“…Furthermore, maternal smoking and substance abuse particularly impair the response to hypoxia in the prone position (22). This maladaptive response can be explained by the infant's chronic exposure to fetal hypoxia, leading to persistent, inappropriate activation of the respiratory neural network underlying the biphasic ventilatory response (21,23). Furthermore, infants exposed to smoking in utero have been shown to display significant arousal abnormalities, taking longer times to wake when exposed to exogenous stressors, such as hypoxia, thus increasing vulnerability to SIDS (24,25).…”