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Glia. 2016 Dec;64(12):2306-2320. doi: 10.1002/glia.23079. Epub 2016 Sep 30.

Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction.

Author information

1
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.
2
Assistance Publique - Hôpitaux de Paris, Service de Réanimation et Pédiatrie Néonatales, Groupe Hospitalier Robert Debré, Paris, France.
3
Université Paris Diderot, Paris, France.
4
Fondation PremUp, Paris, France.
5
Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
6
Division of Development and Growth, Department of Child and Adolescent Medicine, Geneva University Hospital and School of Medicine, Geneva, Switzerland.
7
Institut Langevin, CNRS UMR 7587, Inserm U979, ESPCI ParisTech, PSL Research University, Paris, France.
8
Université Paris-Descartes, Paris, France.
9
Assistance Publique - Hôpitaux de Paris, Service de Médecine et Réanimation Néonatales de Port-Royal, Groupe Hospitalier Cochin, Broca, Hôtel-Dieu, Paris, France.
10
Institut Cochin, Inserm U1016, UMR8104 CNRS, Paris, France.
11
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France. olivier.baud@rdb.aphp.fr.
12
Assistance Publique - Hôpitaux de Paris, Service de Réanimation et Pédiatrie Néonatales, Groupe Hospitalier Robert Debré, Paris, France. olivier.baud@rdb.aphp.fr.
13
Université Paris Diderot, Paris, France. olivier.baud@rdb.aphp.fr.
14
Fondation PremUp, Paris, France. olivier.baud@rdb.aphp.fr.

Abstract

Fetal growth restriction (FGR) 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 FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low-protein-diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. 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. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition-induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth-restricted human infants. GLIA 2016;64:2306-2320.

KEYWORDS:

myelination; neuroinflammation; neuroprotection; prenatal insult

PMID:
27687291
DOI:
10.1002/glia.23079
[Indexed for MEDLINE]

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