Role of thyroid hormones in normal and abnormal central nervous system myelination in humans and rodents.

Thyroid hormones (THs) are instrumental in promoting the molecular mechanisms which underlie the complex nature of neural development and function within the central nervous system (CNS) in vertebrates. The key neurodevelopmental process of myelination is conserved between humans and rodents, of which both experience peak fetal TH concentrations concomitant with onset of myelination. The importance of supplying adequate levels of THs to the myelin producing cells, the oligodendrocytes, for promoting their maturation is crucial for proper neural function. In this review we examine the key TH distributor and transport proteins, including transthyretin (TTR) and monocarboxylate transporter 8 (MCT8), essential for supporting proper oligodendrocyte and myelin health; and discuss disorders with impaired TH signalling in relation to abnormal CNS myelination in humans and rodents. Furthermore, we explore the importance of using novel TH analogues in the treatment of myelination disorders associated with abnormal TH signalling.

Hippocampal neurogenesis and memory in adolescence following intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short-term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long-lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36-44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain-derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety-like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba-1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro-BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long-lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal-dependent learning and memory in adolescence.

Caffeine for apnea of prematurity: Effects on the developing brain.

Caffeine is a methylxanthine that is widely used to treat apnea of prematurity (AOP). In preterm infants, caffeine reduces the duration of respiratory support, improves survival rates and lowers the incidence of cerebral palsy and cognitive delay. There is, however, little evidence relating to the immediate and long-term effects of caffeine on brain development, especially at the cellular and molecular levels. Experimental data are conflicting, with studies showing that caffeine can have either adverse or benefical effects in the developing brain. The aim of this article is to review current understanding of how caffeine ameliorates AOP, the cellular and molecular mechanisms by which caffeine exerts its effects and the effects of caffeine on brain development. A better knowledge of the effects of caffeine on the developing brain at the cellular and/or molecular level is essential in order to understand the basis for the impact of caffeine on postnatal outcome. The studies reviewed here suggest that while caffeine has respiratory benefits for preterm infants, it may have adverse molecular and cellular effects on the developing brain; indeed a majority of experimental studies suggest that regardless of dose or duration of administration, caffeine leads to detrimental changes within the developing brain. Thus there is an urgent need to assess the impact of caffeine, at a range of doses, on the structure and function of the developing brain in preclinical studies, particularly using clinically relevant animal models. Future studies should focus on determining the maximal dose of caffeine that is safe for the preterm brain.