Stéphane Sizonenko

Primary cortical folding in the human newborn: an early marker of later functional development.

In the human brain, the morphology of cortical gyri and sulci is complex and variable among individuals, and it may reflect pathological functioning with specific abnormalities observed in certain developmental and neuropsychiatric disorders. Since cortical folding occurs early during brain development, these structural abnormalities might be present long before the appearance of functional symptoms. So far, the precise mechanisms responsible for such alteration in the convolution pattern during intra-uterine or post-natal development are still poorly understood. Here we compared anatomical and functional brain development in vivo among 45 premature newborns who experienced different intra-uterine environments: 22 normal singletons, 12 twins and 11 newborns with intrauterine growth restriction (IUGR). Using magnetic resonance imaging (MRI) and dedicated post-processing tools, we investigated early disturbances in cortical formation at birth, over the developmental period critical for the emergence of convolutions (26-36 weeks of gestational age), and defined early endophenotypes of sulcal development. We demonstrated that twins have a delayed but harmonious maturation, with reduced surface and sulcation index compared to singletons, whereas the gyrification of IUGR newborns is discordant to the normal developmental trajectory, with a more pronounced reduction of surface in relation to the sulcation index compared to normal newborns. Furthermore, we showed that these structural measurements of the brain at birth are predictors of infants outcome at term equivalent age, for MRI-based cerebral volumes and neurobehavioural development evaluated with the assessment of preterm infants behaviour (APIB).

Prenatal Nicotine Exposure Alters Early Pancreatic Islet and Adipose Tissue Development with Consequences on the Control of Body Weight and Glucose Metabolism Later in Life

Despite medical advice, 20-30% of female smokers continue to smoke during pregnancy. Epidemiological studies have associated maternal smoking with increased risk of obesity and type-2 diabetes in the offspring. In the present study, we investigated the impact of prenatal nicotine exposure (3 mg/kg in Sprague Dawley rats via osmotic Alzet minipumps) on the early endocrine pancreas and adipose tissue development in rat pups before weaning. Body weight, fat deposition, food intake and food efficiency, cold tolerance, spontaneous physical activity, glucose utilization, and insulin sensitivity were also examined at adulthood. Prenatal nicotine exposure led to a decrease in endocrine pancreatic islet size and number at 7 d of life (postnatal d 7), which corroborates with a decrease in gene expression of specific transcription factors such as pancreatic and duodenal homeobox 1, Pax-6, Nkx6.1, and of hormones such as insulin and glucagon. The prenatal nicotine exposure also led to an increase in epididymal white adipose tissue weight at weaning (postnatal d 21), and marked hypertrophy of adipocytes, with increased gene expression of proadipogenic transcription factors such as CAAT-enhancer-binding protein-alpha, peroxisome proliferator activated receptor-gamma, and sterol regulatory element binding protein-1C. These early tissue alterations led to significant metabolic consequences, as shown by increased body weight and fat deposition, increased food efficiency on high-fat diet, cold intolerance, reduced physical activity, and glucose intolerance combined with insulin resistance observed at adulthood. These results prove a direct association between fetal nicotine exposure and offspring metabolic syndrome with early signs of dysregulations of adipose tissue and pancreatic development.

Impact of intrauterine growth restriction and glucocorticoids on brain development: Insights using advanced magnetic resonance imaging

There are now a number of evidences showing that the developing organism adapts to the environment it finds itself. Short- and long-term adjustments, referred as programming, take place and will initially induce intrauterine growth retardation but will also have consequences that will appear later in life. The use of magnetic resonance imaging (MRI) techniques in IUGR babies has delineated changes in the central nervous system (CNS) development that correlate with altered neurodevelopment and could be implicated in the development of neuropsychiatric disorders in adult life. Similarly, the use of corticosteroid treatment in preterm infants has also been implicated in abnormal CNS development. In this review, we will focus on the modifications of CNS development that occur after exposition to adverse environment such as undernutrition or corticosteroid treatment that can now be studied in vivo with advanced MRI technology.

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

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

IJDN Special issue on developmental brain injury

Developmental brain injury remains a vast field of research with cerebral responses that are different according to the initial trigger, brain maturation at onset and intrinsic factors induced in repair and plasticity. Prematurity with acute hypoxia-ischemia and inflammation are the main source of developmental injury but poor intrauterine growth also leads to more subtle changes in the developmental programming of the brain. Further, medical interventions are not without effect on brain development. The brain facing injury reacts with several mechanisms that lead to acute damage and healing but also to long-term developmental changes due to its high capacity of plasticity. Better understanding of injury, reducing the initial damage and supporting the subsequent development is needed to protect the developing brain and reduce neurodevelopmental disabilities in these infants. The aim of this special issue is to expose recent advances in developmental brain injury through new experimental and imaging approaches, mechanisms of damage, analysis of anaesthetics effects, adaptation of the brain to adverse conditions and neuroprotection strategies.

O-013 Lactoferrin In Inflammatory Neonatal Rat Brain Injury: A Nutrient For Neuroprotection?

Introduction Lactoferrin (Lf) is an iron-binding glycoprotein secreted in milk with anti-oxydant, anti-inflammatory and anti-microbial properties. The aim of this work was to assess the neuroprotective effect of Lf in P3 rat pup brain exposed to Lypopolysaccharide (LPS) using high-field (9.4 T) 1H-MR Spectroscopy. Materials and methods At birth, dams received either a Lf-enriched food (1 g/kg/day) or a diet isocaloric (iso) to the Lf during lactation. Rat pups received Lf through breastfeeding. P3 pups were then divided in 4 groups: sham-iso, LPS-iso, sham-Lf and LPS-Lf (n = 10/group). P3 pups from LPS groups were injected in the subcortical white matter with 0.5 µL saline containing LPS (10 µg) and the sham groups with vehicle. Metabolic profile was measured by 1H-MRS in the Hippocampus (Hp) and Striatum (St), 24 h (P4) and 21 days (P24) after LPS. A Mann-Whitney test was used to compare values between the different groups (significance: p < 0.05). Results At 24h, no evidence for ventriculomegaly was observed. At P24 LPS-Iso and LPS-Lf presented significant ventriculomegaly, but ventricle volumes of the LPS-Lf rats (25 ± 2 mm3) tended to be lower than the one of the LPS-Iso group (34 ± 3 mm3) (mean ± SEM) At 24 h, LPS groups (i.e. -Lf and -Iso) exhibited altered metabolism compared to sham groups involving modification of [Glc]-energy source, [Glu+Gln]-neurotransmission and [GPC+PCho]-components of cell membranes. In addition, LPS-Iso group presented also changes in [Mac]-tissue integrity marker, [GABA]-neurotransmitter, [NAA+NAAG]-neuronal marker and [PCr]/[Cr]-energy metabolism compared to sham groups. Interestingly LPS-Iso group presented also differences with the LPS-Lf group: [Mac], [PE]-cell membranes and [Cr+PCr]-energetic metabolism. At P24 the brain metabolism of LPS-exposed rats continued to be disturbed but in a lesser extent for LPS-Lf rats. Further MRI derived data (volumetry and diffusion MRI) are under investigation. Discussion and conclusion Supplemented in the food during the lactation, Lf appears to have a neuroprotective effect: this result could be of high interest for preterm’s brain neuroprotection.

338 Nutrient for Neuroprotection: MRI Assessment of Lactoferrin Supplementation after HI Injury in the P3 Rat Brain

Background Animal models of preterm brain injury can be achieved by Hypoxia-Ischemia (HI). Lactoferrin (Lf) is an iron-binding glycoprotein with anti-oxidant, anti-inflammatory and anti-infectious activities. In rodents, after oral administration, Lf is rapidly transferred from the intestine into the brain. Aim The aim of this work was to assess the neuroprotective effect of Lf supplementation trough lactation after P3 HI brain injury by using MRI. Methods At birth, rat pups were divided in 3 groups: The dams of the HI-Lf group (n=6) received Lf-enriched food, HI-Iso received a diet isocaloric to the Lf (n=6) and a Sham group (n=3). At P3 pups from HI-Lf and HI-Iso groups underwent HI injury. At P25, T2W images, 1H-MRS and DTI were performed. A Mann-Whitney test was used to compare values between the different groups. Results When compared to HI-Iso group, the number of rats injured (51% vs. 61%), the percentage of injured cortex at P3 (4.9±3.6% vs. 15.0±7.1%, P=0.02) as well as the percentage of cortical loss at P25 (4.6±4.8% vs. 16.7±11.9%, P=0.09) were reduced in the HI-Lf group. At P25, using 1H-MRS, brain metabolites of HI-Lf rats is almost normalized with [Glu+Gln] only remaining decreased whereas the Iso-HI group showed also decreased levels of [Asp] and [totalNAA]. With DTI, white matter FA values tend to be higher in the HI-Lf group than in the HI-Iso group and were comparable to Sham. Conclusion This study shows a potential neuroprotection from maternal nutritional supplementation with Lf after HI in the developing brain of progeny.

583 Lactoferrin Supplementation Protects Brain Development in Rat Pups Exposed to Prenatal Dexamethasone

583 Lactoferrin Supplementation Protects Brain Development in Rat Pups Exposed to Prenatal Dexamethasone