myelin-basic-protein and Fetal-Growth-Retardation

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.

Topics: Adenomatous Polyposis Coli Protein; Animals; Animals, Newborn; Antigens; Antigens, CD; Brain; Brain Injuries; Cytokines; Female; Fetal Growth Retardation; Gene Expression; Lipopolysaccharides; Microglia; Myelin Basic Protein; Neural Pathways; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Pregnancy; Proteoglycans; Rats; Rats, Sprague-Dawley; Transcriptome

Intra-uterine growth restriction (IUGR) is a significant in utero complication that can have profound effects on brain development including reduced myelination and deficits that can continue into adulthood. Progesterone increases oligodendrocyte proliferation and myelin expression, an action that may depend on the expression of progesterone receptor (PR) isoforms A (PRA) and B (PRB). The objective of this study was to determine the effect of IUGR on PR isoform expression in the brain of male and female fetuses and whether effects were associated with a reduction in myelination. We used a guinea pig model that involves selective reduction in maternal perfusion to the placenta at midgestation (35 days, term 70 days). This resulted in a significant reduction in body weight with marked sparing of brain weight. PRA, PRB and myelin basic protein (MBP) expression were measured in the brains of male and female growth-restricted and control fetuses at late gestation. MBP, as a measure of myelination, was found to decrease in association with IUGR in the CA1 hippocampal region with no change observed in the cortical white matter. There was a marked increase in PRA, PRB and total PR expression in the IUGR fetal brain. Control female fetuses demonstrated significantly higher PRA:PRB ratios than males; however, this sex difference was abolished with IUGR. These data suggest the central nervous system effects of clinical use of progesterone augmentation therapy in late pregnancy should be carefully evaluated. The overall upregulation of PR isoforms in association with IUGR suggests increased progesterone action and a possible neuroprotective mechanism.

Topics: Animals; Brain; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Guinea Pigs; Male; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Pregnancy; Progesterone; Protein Isoforms; Receptors, Progesterone; Sex Characteristics

The effects of intrauterine growth retardation on the development of myelinating oligodendrocytes and astrocytes in the brain and spinal cord of the fetal guinea pig have been examined using immunohistochemical and ultrastructural techniques. As judged by immunoreactivity for myelin basic protein, the extent of myelination in the spinal cord, cerebral cortex, corpus cellosum and cerebellum was reduced in the growth-retarded fetuses compared with controls at both 52 (n = 4) and 62 days (n = 5) of gestation. As assessed by immunoreactivity for glial fibrillary acidic protein, there were no marked differences between control and growth-retarded brains in the extent or distribution of radial glial cells or astrocytes at 52 or 62 days in the cerebellum. However, in the cerebral cortex at 62 days there was a striking proliferation of astrocytes surrounding cortical blood vessels in growth-retarded fetuses. Ultrastructural studies showed that at 52 days, myelination of the corticospinal tract had begun in the control but was virtually absent in growth-retarded fetuses. At 62 days, the total number of myelinated fibres in growth-retarded fetuses was significantly reduced by 56% (P less than 0.01) compared with control fetuses; however, there was no difference between the groups in the total number of fibres in the corticospinal tract. Where fibres were myelinated the myelin sheath was disproportionately reduced relative to axon diameter. Thus, in intrauterine growth retardation there is a delay in the initiation and in the extent of myelination. This could be due to a reduction in the number of myelinating glia formed and the restricted capacity of those which do form to generate myelin.

Topics: Aging; Animals; Astrocytes; Axons; Brain; Female; Fetal Growth Retardation; Glial Fibrillary Acidic Protein; Guinea Pigs; Immunoenzyme Techniques; Microscopy, Electron; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Pregnancy; Spinal Cord