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Neuroinflammation as a basis for brain damage caused by fetal growth restriction

Presented at the Neonatal Society 2016 Summer Meeting.

Rideau Batista Novais A1-4, Pham H1,4, van de Looij 5,6, Bernal M7, Zana-Taieb E1,4,8,9, Pansiot J1,4, Dumont F10, Gressens P1,3,4, Charriaut-Marlangue C1,3,4, Tanter M7, Demene C7, Vaiman D10, Baud O1-4

1 Inserm U1141
2 APHP, Service de Réanimation et Pédiatrie Néonatales, CHU Robert Debré
3 Université Paris Diderot
4 Fondation PremUp
5 EPFL, Lausanne, Switzerland
6 Geneva University Hospital and School of Medicine, Geneva, Switzerland
7 Institut Langevin, Inserm U979
8 Université Paris-Descartes
9 APHP, Service de Médecine et Réanimation Néonatales de Port-Royal
10 Inserm U1016

Background: Fetal growth restriction is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by fetal growth restriction in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo.

Methods: We investigated a model of fetal growth restriction induced by low-protein-diet malnutrition during pregnancy using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology.

Results: We show that myelination and brain function are both significantly altered in our model of fetal growth restriction. These alterations, detected first by advanced magnetic resonance imaging and then by ultrafast ultrasound imaging of cerebral cortical connectivity, are accompanied by white matter dysmaturation as shown by the immunohistochemical profiles of differentiating oligodendrocytes. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth-restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia.

Conclusion: Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition-induced fetal growth restriction, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth-restricted human infants.

Corresponding author: olivier.baud@aphp.fr

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