Birth elicits a conserved neuroendocrine response with implications for perinatal osmoregulation and neuronal cell death

Abstract

Long-standing clinical findings report a dramatic surge of vasopressin in umbilical cord blood of the human neonate, but the neural underpinnings and function(s) of this phenomenon remain obscure. We studied neural activation in perinatal mice and rats, and found that birth triggers activation of the suprachiasmatic, supraoptic, and paraventricular nuclei of the hypothalamus. This was seen whether mice were born vaginally or via Cesarean section (C-section), and when birth timing was experimentally manipulated. Neuronal phenotyping showed that the activated neurons were predominantly vasopressinergic, and vasopressin mRNA increased fivefold in the hypothalamus during the 2–3 days before birth. Copeptin, a surrogate marker of vasopressin, was elevated 30-to 50-fold in plasma of perinatal mice, with higher levels after a vaginal than a C-section birth. We also found an acute decrease in plasma osmolality after a vaginal, but not C-section birth, suggesting that the difference in vasopressin release between birth modes is functionally meaningful. When vasopressin was administered centrally to newborns, we found an ~ 50% reduction in neuronal cell death in specific brain areas. Collectively, our results identify a conserved neuroendocrine response to birth that is sensitive to birth mode, and influences peripheral physiology and neurodevelopment.

Vasopressin but Not Oxytocin Responds to Birth Stress in Infants

“…Animal models support the findings of a perinatal surge in AVP and copeptin with higher levels in plasma after a vaginal than a Cesarean section (Hoffiz et al, 2021). In parallel to the increase in the peripheral blood circulation also central AVP mRNA levels and AVP protein levels rise significantly at birth (Spoljaric et al, 2017;Hoffiz et al, 2021). Hypoxic events, which in human fetuses accompany regularly uterine contractions before birth, have been identified in animal models as large driver of AVP and copeptin release into the peripheral blood circulation and in specific brain regions (L'Abate et al, 2013;Coldren et al, 2017;Summanen et al, 2018).…”

“…In fact, mild uterine contractions are sufficient to trigger fetal copeptin release (Wellmann et al, 2016) and a large multicenter randomized controlled trial is underway to study the clinical effect of mild uterine contractions prior to ECS on infants and mothers outcome after birth (Wellmann et al, 2021). Animal models support the findings of a perinatal surge in AVP and copeptin with higher levels in plasma after a vaginal than a Cesarean section (Hoffiz et al, 2021). In parallel to the increase in the peripheral blood circulation also central AVP mRNA levels and AVP protein levels rise significantly at birth (Spoljaric et al, 2017;Hoffiz et al, 2021).…”

“…Hypoxic events, which in human fetuses accompany regularly uterine contractions before birth, have been identified in animal models as large driver of AVP and copeptin release into the peripheral blood circulation and in specific brain regions (L'Abate et al, 2013;Coldren et al, 2017;Summanen et al, 2018). Whereas increased AVP levels in plasma were found to be associated with decreased plasma osmolality after a vaginal, but not Cesarean section birth (Hoffiz et al, 2021), central AVP increase is related to reduced neuronal cell death in specific brain areas (Hoffiz et al, 2021) and suppress energetically expensive correlated network events under conditions of reduced oxygen supply at birth (Spoljaric et al, 2017). To what extent peripheral or central AVP mechanisms may contribute to birth related natural analgesia in human neonates is under discussion (Kasser et al, 2019).…”

First Encounters: Effects of the Microbiota on Neonatal Brain Development

“…We also found that the expression of pro-inflammatory cytokines, especially interleukin 1β and tumor necrosis factor α, was markedly higher in the brains of mice born in the presence of a microbiota than in those born GF ( Castillo-Ruiz et al, 2018 ). More recently, we reported neural activation 3 h after birth in the PVN ( Hoffiz et al, 2021 ), a brain region that receives input from the vagus nerve and has a central role in immune regulation and the stress response. This timing coincides with the arrival of microbiota to the newborn gut, although we have yet to demonstrate that the two events are causally linked.…”

Copeptin and Stress

“…The main stimulus for copeptin release at birth is represented by neuronal hypoxia due to transient cerebral hypoperfusion caused by maternal uterine contractions: as a consequence of this, naturally delivered infants exhibit up to 100-fold higher copeptin levels than children born by cesarean section, regardless of gestational age at birth [122]; moreover, the latter show higher copeptin levels and if affected by intra-uterine growth restriction or if the cesarean section was needed due to complications than elective, thus strengthening the role for copeptin as a stress biomarker [124][125][126]. Activation of the AVP system at birth is aimed at providing to the newborn natural analgesia, tuning neurobehavior in complex interactions between central and peripheral nervous systems and preventing excessive dehydration and weight loss in the first postnatal days [8]: a correlation between copeptin levels and all these phenomena has been recently highlighted in studies involving humans (after-birth nociception and osmoregulation) or animals (after-birth osmoregulation and neurobehavior) [127][128][129].…”