Oligodendrocytes: Cells of origin for white matter injury in the developing brain

A prominent pattern of brain injury in preterm born infants involves damage to white matter with impaired oligodendrocyte maturation. This results in diffuse deficits in myelination that are associated with later development of cerebral palsy. While numerous experimental animal models of perinatal white matter injury have been developed, they show a spectrum of effects. This review proposes that adopting a more standard approach to defining white matter injury is important for validating experimental findings against the bona fide human condition. This chapter will describe the pathology of perinatal white matter injury and a general methodological approach for assessing white matter injury experimentally

Effect of postnatal progesterone therapy following preterm birth on neurosteroid concentrations and cerebellar myelination in guinea pigs

Allopregnanolone protects the fetal brain and promotes normal development including myelination. Preterm birth results in the early separation of the infant from the placenta and consequently a decline in blood and brain allopregnanolone concentrations. Progesterone therapy may increase allopregnanolone and lead to improved oligodendrocyte maturation. The objectives of this study were to examine the efficacy of progesterone replacement in augmenting allopregnanolone concentrations during the postnatal period and to assess the effect on cerebellar myelination - a region with significant postnatal development. Preterm guinea pig neonates delivered at 62 days of gestation by caesarean section received daily s.c. injections of vehicle (2-Hydroxypropyl-β-cyclodextrin) or progesterone (16 mg/kg) for 8 days until term-equivalent age (TEA). Term delivered controls (PND1) received vehicle. Neonatal condition/wellbeing was scored, and salivary progesterone was sampled over the postnatal period. Brain and plasma allopregnanolone concentrations were measured by radioimmunoassay; cortisol and progesterone concentrations were determined by enzyme immunoassay; and myelin basic protein (MBP), proteolipid protein (PLP), oligodendroctye transcription factor 2 (OLIG2) and platelet-derived growth factor receptor-α (PDGFRα) were quantified by immunohistochemistry and western blot. Brain allopregnanolone concentrations were increased in progesterone-treated neonates. Plasma progesterone and cortisol concentrations were elevated in progesterone-treated male neonates. Progesterone treatment decreased MBP and PLP in lobule X of the cerebellum and total cerebellar OLIG2 and PDGFRα in males but not females at TEA compared with term animals. We conclude that progesterone treatment increases brain allopregnanolone concentrations, but also increases cortis

Intrauterine growth restriction and development of the hippocampus: implications for learning and memory in children and adolescents

Intrauterine growth restriction (IUGR) is often the result of compromised placental function and suboptimal uteroplacental blood flow. Children born with IUGR have impaired cognitive functioning and specific memory deficits, indicating long-lasting impairments in hippocampal functioning; indeed, hippocampal volume is reduced in infants with IUGR. Animal studies have provided valuable insight into the nature of deficits in hippocampal-dependent functions observed in children born with IUGR; outcomes of experimental IUGR reveal reduced neuron numbers and morphological alterations in the cornu ammonis fields 1 and 3 and dentate gyrus subregions of the hippocampus. However, whether such early and ongoing structural changes in the hippocampus could account for deficits in spatial memory reported in adolescent rats with IUGR is yet to be established. Understanding the association between hippocampal structural and functional alterations in IUGR will aid in the development of interventions to minimise the effect of IUGR on the hippocampus and long-term cognitive outcomes

Limitations of two-component diffusion models for axon diameter density estimation

Two component models of diffusion-weighed signal decay in Magnetic Resonance Imaging have been advocated for use in the estimation of axon diameter distributions. In this work, we demonstrate that axon diameters are not distinguishable under the short pulse approximation, even at high gradient strengths available on pre-clinical MRI systems. We instead investigate the long pulse regime under which axon diameters are maximally separated, as are the two hindered and restricted diffusion components. Through simulation and experimental MRI of the ovine optic nerve, we show that a simplistic two-component model is incapable of capturing experimental decay behaviour, calling into question the utility of these models for axon diameter density estimation

Caffeine and the developing brain: molecular and cellular effects

[No abstract available

Development of the cerebral cortex and the effect of the intrauterine environment

The human brain is one of the most complex structures currently under study. Its external shape is highly convoluted, with folds and valleys over the entire surface of the cortex. Disruption of the normal pattern of folding is associated with a number of abnormal neurological outcomes, some serious for the individual. Most of our knowledge of the normal development and folding of the cerebral cortex (gyrification) focuses on the internal, biological (i.e. genetically driven) mechanisms of the brain that drive gyrification. However, the impact of an adverse intrauterine and maternal physiological environment on cortical folding during fetal development has been understudied. Accumulating evidence suggests that the state of the intrauterine and maternal environment can have a significant impact on gyrification of the fetal cerebral cortex. This review summarises our current knowledge of how development in a suboptimal intrauterine and maternal environment can affect the normal development of the folded cerebral cortex

HGF regulates the development of cortical pyramidal dendrites

Although hepatocyte growth factor (HGF) and its receptor tyrosine kinase MET are widely expressed in the developing and mature central nervous system, little is known about the role of MET signaling in the brain. We have used particle-mediated gene transfer in cortical organotypic slice cultures established from early postnatal mice to study the effects of HGF on the development of dendritic arbors of pyramidal neurons. Compared with untreated control cultures, exogenous HGF promoted a highly significant increase in dendritic growth and branching of layer 2 pyramidal neurons, whereas inactivation of endogenous HGF with function-blocking, anti-HGF antibody caused a marked reduction in size and complexity of the dendritic arbors of these neurons. Furthermore, pyramidal neurons transfected with an MET dominant-negative mutant receptor likewise had much smaller and less complex dendritic arbors than did control transfected neurons. Our results indicate that HGF plays a role in regulating dendritic morphology in the developing cerebral cortex

Intrauterine growth restriction: Effects on neural precursor cell proliferation and angiogenesis in the foetal subventricular zone

Exposure to adverse prenatal factors can result in abnormal brain development, contributing to the aetiology of several neurological disorders. Intrauterine insults could occur during neurogenesis and gliogenesis, disrupting these events. Here we investigate the effects of chronic placental insufficiency (CPI) on cell proliferation and the microenvironment in the subventricular zone (SVZ). At 30 days of gestation (DG; term ∼67 DG), CPI was induced in pregnant guinea pigs via unilateral uterine artery ligation to produce growth-restricted (GR) foetuses (n = 7); controls (n = 6) were from the unoperated horn. At 60 DG, foetal brains were stained immunohistochemically to identify proliferating cells (Ki67), immature neurons (polysialylated neuronal cell adhesion molecule), astrocytes (glial fibrillary acidic protein), microglia (ionised calcium-binding adaptor molecule-1, Iba-1) and the microvasculature (von Willebrand factor) in the SVZ. There was no overall difference (p > 0.05) in the total number of Ki67-immunoreactive (IR) cells, the percentage of SVZ occupied by blood vessels or the density of Iba-1-IR microglia in control versus GR foetuses. However, regression analysis across both groups revealed that both the number of Ki67-IR cells and the percentage of SVZ occupied by blood vessels in the ventral SVZ were negatively correlated (p < 0.05) with brain weight. Furthermore, in the SVZ (dorsal and ventral) the density of blood vessels positively correlated (p < 0.05) with the number of Ki67-IR cells. Double-labelling immunofluorescence suggested that the majority of proliferating cells were likely to be neural precursor cells. Thus, we have demonstrated an association between angiogenesis and neurogenesis in the foetal neurogenic niche and have identified a window of opportunity for the administration of trophic support to enhance a neuroregenerative response