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

Elham Ahmadzadeh; Ingrid Dudink; David W Walker; Amy E Sutherland; Yen Pham; Vanesa Stojanovska; Graeme R Polglase; Suzanne L Miller; Beth J Allison

doi:10.1113/JP284971

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

J Physiol. 2023 Aug 28. doi: 10.1113/JP284971. Online ahead of print.

Authors

Elham Ahmadzadeh^{1

2}, Ingrid Dudink^{1

2}, David W Walker³, Amy E Sutherland^{1

2}, Yen Pham^{1

2}, Vanesa Stojanovska^{1

2}, Graeme R Polglase^{1

2}, Suzanne L Miller^{1

2}, Beth J Allison^{1

2}

Affiliations

¹ The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
² Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
³ School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.

PMID: 37641535
DOI: 10.1113/JP284971

Abstract

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 raphé 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 raphé 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. KEY POINTS: Early-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.

Keywords: FGR; brain injury; brainstem; cardiorespiratory centres; fetal hypoxia; medullary raphe nuclei; placental 5-HT; placental insufficiency; serotonergic neurons; vagal nuclei.

Abstract

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