The medullary serotonergic centres involved in cardiorespiratory control are disrupted by fetal growth restriction

Fetal growth restriction (FGR) is associated with cardiovascular and respiratory complications after birth and beyond. Despite research showing a range of neurological changes following FGR, little is known about how FGR affects the brainstem cardiorespiratory control centres. The primary neurons that release serotonin reside in the brainstem cardiorespiratory control centres and may be affected by FGR. At two time points in the last trimester of sheep brain development, 110 and 127 days of gestation (0.74 and 0.86 of gestation), we assessed histopathological alterations in the brainstem cardiorespiratory control centres of the pons and medulla in early-onset FGR versus control fetal sheep. The FGR cohort were hypoxaemic and asymmetrically growth restricted. Compared to the controls, the brainstem of FGR fetuses exhibited signs of neuropathology, including elevated cell death and reduced cell proliferation, grey and white matter deficits, and evidence of oxidative stress and neuroinflammation. FGR brainstem pathology was predominantly observed in the medullary raphe nuclei, hypoglossal nucleus, nucleus ambiguous, solitary tract and nucleus of the solitary tract. The FGR groups showed imbalanced brainstem serotonin and serotonin 1A receptor abundance in the medullary raphe nuclei, despite evidence of increased serotonin staining within vascular regions of placentomes collected from FGR fetuses. Our findings demonstrate both early and adaptive brainstem neuropathology in response to placental insufficiency.imageKey pointsEarly-onset fetal growth restriction (FGR) was induced in fetal sheep, resulting in chronic fetal hypoxaemia.Growth-restricted fetuses exhibit persistent neuropathology in brainstem nuclei, characterised by disrupted cell proliferation and reduced neuronal cell number within critical centres responsible for the regulation of cardiovascular and respiratory functions. Elevated brainstem inflammation and oxidative stress suggest potential mechanisms contributing to the observed neuropathological changes.Both placental and brainstem levels of 5-HT were found to be impaired following FGR. Abstract figure legend Early-onset fetal growth restriction (FGR) was induced in fetal sheep at 60% gestation (A) and then brainstem structure was compared against control fetuses at two time points in the third pregnancy trimester. FGR was associated with cell death, oxidative stress and inflammation in brainstem medullary 5-HT centres, including the medullary raphe nuclei, nucleus of the solitary tract, solitary tract, hypoglossal nucleus and nucleus ambiguous. (C) Further, we demonstrate increased placental cotyledon 5-HT production (B) and reduced 5-HT density in key brainstem centres.image

Automated summary

Fetal growth restriction (FGR) is associated with cardiovascular and respiratory complications after birth. The brainstem cardiorespiratory control centres, especially in the medulla, may be affected by FGR, leading to neuropathological changes such as cell death, reduced cell proliferation, and oxidative stress and inflammation.