Role In Brain Maturation Research Articles

A role for sleep in brain plasticity

The idea that sleep might be involved in brain plasticity has been investigated for many years through a large number of animal and human studies, but evidence remains fragmentary. Large amounts of sleep in early life suggest that sleep may play a role in brain maturation. In particular, the influence of sleep in developing the visual system has been highlighted. The current data suggest that both Rapid Eye Movement (REM) and non-REM sleep states would be important for brain development. Such findings stress the need for optimal paediatric sleep management. In the adult brain, the role of sleep in learning and memory is emphasized by studies at behavioural, systems, cellular and molecular levels. First, sleep amounts are reported to increase following a learning task and sleep deprivation impairs task acquisition and consolidation. At the systems level, neurophysiological studies suggest possible mechanisms for the consolidation of memory traces. These imply both thalamocortical and hippocampo-neocortical networks. Similarly, neuroimaging techniques demonstrated the experience-dependent changes in cerebral activity during sleep. Finally, recent works show the modulation during sleep of cerebral protein synthesis and expression of genes involved in neuronal plasticity.

325 Effect of Triiodothyronine (T3) on Excitotoxic Brain Damage of Newborn Mice

Background: PVL is a major cause of neurodevelopmental delay and lifelong handicaps in preterm infants. Until now effective or causal therapy is not available. Thyroid hormons play essential role in brain maturation and are known to be decreased after brain injuries in adults. Substitution of T3, the metabolically most active thyroid hormone, thus might mitigate brain injuries. Hypotheses: Excitotoxic brain damage of newborn mice decreases thyroid hormon levels. Exogenous T3 administration restores thyroid hormon level and is neuroprotective. Methods: We used a newborn mice model of PVL. We injected ibotenic acid (glutamate-analogue) into one hemisphere of five day old mice to create white and grey matter lesion. 3,3‘,5-Triiodo-L-thyronine (100μg) was injected intraperitoneally in a randomized fashion once at 1 hr or repeatedly at 1/24/48/72/96 hrs after injury. Animals were randomized into 4 groups: 1. hormon level (T3+T4) measurement without intervention 2. ibotenic acid intracranial 3. ibotenic acid intracranial + T3 once intraperitoneal 4. ibotenic acid + T3 repeatedly intraperitoneal. Study time-endpoints were at the time of setting the lesion and 24/120 hrs later. Study endpoints were histological assessement of the lesion size (mean length of rostro-caudal axis of the lesion) and/or hormonlevel measurement. Results: Serum T3 levels decreased significantly while T4 significantly increased with advanced postnatal age. Induced brain damage did not influence serum T3/T4 levels 24/120 hrs after setting the lesion. There was no discernible change in serum T3/T4 levels 24/120 hrs after injection of T3. Neither a single nor repeated injection of T3 had significant effect on lesion size in grey/white matter assessed 24/120 hours after setting the lesion. Summary: Excitotoxic brain damage does not significantly change serum T3 and T4 levels in newborn mice. Supplementary T3 injection at the dosage regimen used was neither neuroprotectiv nor increased regenerative capacities after excititoxic brain damage in newborn mice.

Acetaldehyde cytotoxicity in cultured rat astrocytes

The effect of acetaldehyde on astrocytes have been investigated because not only do they play an important role in brain maturation but also recent reports have shown their delayed proliferation following both `in vivo' and `in vitro' ethanol exposure. Biochemical parameters related to apoptotic and necrotic processes were examined in primary cultures of rat astrocytes exposed for 4 days to acetaldehyde generated from ethanol by co-cultured alcohol dehydrogenase-transfected Chinese hamster ovary cells. Acetaldehyde levels in the culture media attained concentrations of approximately 450 μM. To study ethanol effects, alcohol oxidation was inhibited by 4-methylpyrazole (an inhibitor of alcohol dehydrogenase). Acetaldehyde but not ethanol increased intracellular calcium levels by 155%. Moreover, significant DNA fragmentation was detected using a random oligonucleotide primed synthesis assay, by flow cytometry and when using agar gel electrophoresis. Transglutaminase activity was elevated in the cells treated with acetaldehyde but when acetaldehyde formation was inhibited by 4-methylpyrazole the enzyme activity was unaffected. Nitrate levels in the culture media were unchanged. Additionally, microscopic examination of cell nuclei revealed chromatin condensation in astrocytes exposed to acetaldehyde. It can be concluded, that in `in vitro' acetaldehyde exposed rat astrocytes apoptotic pathways are activated.

Lectin staining in the basal nucleus (Meynert) and the hypothalamic tuberomamillary nucleus of the developing human prosencephalon.

Previous studies have demonstrated that extracellular matrix glycoconjugates, shown by lectin-histochemistry with Vicia villosa agglutinin (VVA) and peanut agglutinin (PNA) as so-called perineuronal nets, play an important role in brain maturation. Concanavalin A (ConA) binding to neuronal surface glycoconjugates may be a marker of synaptic junctions. The present study was done to demonstrate the binding sites of these lectins in two functionally related nuclei of the prosencephalon, the basal nucleus (Meynert) and the hypothalamic tuberomamillary nucleus. Fetal brains of 16-36 weeks of gestation were examined by using VVA, PNA, and ConA to determine appearance and distribution patterns of specific lectin-binding sites on glycoconjugates during fetal brain development. The basal nucleus and the tuberomamillary nucleus showed a characteristic "cellular staining" that may have been due to cytoplasmatic labeling, surface labeling, or both. Lectin-staining occurred much earlier in the basal nucleus than in the tuberomamillary nucleus. Although all three lectins were bound to neurons of the basal nucleus, only ConA-positive neurons were observed in the tuberomamillary nucleus. In conclusion, lectin-labeled cells most probably represent projection neurons that are GABAergic (tuberomamillary nucleus) or cholinergic (basal nucleus). Labeling with the three lectins demonstrated nuclear-specific staining patterns that occur early in fetal development and gradually increase. Binding sites for lectins characterizing perineuronal nets (VVA, PNA) occurred only in the basal nucleus, whereas binding sites for ConA on neuronal-surface glycoconjugates, which seem to play a role in early synaptogenesis, were present in the basal and the tuberomamillary nucleus. The basal nucleus, however, expressed ConA binding sites distinctly earlier, probably indicating early arriving afferents.

Interference of Polychlorinated Biphenyls in Hepatic and Brain Thyroid Hormone Metabolism in Fetal and Neonatal Rats

The effects of prenatal oral administration of 0.2, 0.6, and 1.8 mg/kg body wt of 3,3′,4,4′,5,5′-hexachlorobiphenyl (HCB) on Day 1 of gestation and a combination of 1 mg/kg 3,3′,4,4′-tetrachlorobiphenyl (TCB) from Day 2 to Day 18 with 0.6 mg HCB/kg body wt on Day 1 of gestation on thyroid hormone status and peripheral thyroid metabolism were studied in pregnant Wistar rats and their fetuses and offspring. Plasma total thyroxine and free thyroxine levels were reduced by HCB in a dose-dependent fashion in pregnant rats (Days 12 and 20 of gestation) and neonates (Day 21 postpartum), while only a combined dose of HCB and TCB was effective in decreasing fetal thyroid hormone levels by 65% on Day 20 of gestation. The activity of type II thyroxine 5′-deiodinase (5′D-II), the enzyme responsible for the deiodination of thyroxine (T4) to biologically active triiodothyronine in the brain, was examined in whole brain homogenates in fetuses and neonates. Decreases in plasma thyroid hormones were accompanied by significant increases, up to 100%, in 5′D-II activity in brain homogenates from fetuses (Day 20 of gestation) and neonates (Days 7 and 21 postpartum). The glucuronidation of 125I-T4 by hepatic microsomes was increased by at least 100% relative to control levels by all treatments in fetuses (Day 20 of gestation) and increased at least 40% in neonates (Days 7 and 21 postpartum) by a dose of 0.6 and 1.8 mg HCB/kg and the combined dose. These data indicate that prenatal HCB and/or TCB administration result in increased peripheral T4 metabolism. The increase in 5′D-II activity suggests that local hypothyroidism occurs in the brains of fetal and neonatal rats exposed to HCB and/or TCB. Since these effects occur during a period in which thyroid hormones play an important role in brain maturation, they may help explain the mechanism of developmental neurotoxicity induced by polychlorinated biphenyls.

Expression of relaxin mRNA and relaxin receptors in postnatal and adult rat brains and hearts. Localization and developmental patterns

Relaxin is a polypeptide hormone best known for its role in parturition. However, high affinity relaxin receptors have been localized in the rat brain and heart in addition to the uterus. Several lines of evidence also suggest that relaxin may be involved in the regulation of blood pressure, heart rate, and the release of oxytocin and vasopressin. We now show by Northern analysis that a 1-kilobase relaxin transcript is detected in the rat brain as well as the ovary of pregnant rats. Using in situ hybridization, relaxin mRNA is localized in discrete regions of the male and female brains, including the anterior olfactory nucleus, tenia tecta, pyriform cortex, neocortex, and hippocampus. Developmental studies show that relaxin mRNA is present in the 1-day postnatal brain, while relaxin receptors are not detectable until 7 days after birth. The relaxin receptor binding affinity was similar in the developing brains, but there was a steady increase in relaxin binding sites during postnatal days 7 to 29, suggesting that relaxin may play a role in brain maturation. While relaxin mRNA is not detected in the heart, high levels of relaxin receptors are detected in the cardiac atrium as early as 1 day after birth. These atrial receptors remained at similar levels throughout postnatal development, suggesting an important role for relaxin in cardiovascular function.

Unilateral naris closure and vascular development in the rat olfactory bulb

The blood supply to the brain has been linked closely to nervous system function and metabolism, thereby possibly playing a direct role in brain maturation. Previously, we demonstrated that closure of an external naris early in life results in large changes within the olfactory bulb, including reductions in laminar volume and cell number and a rapid decline in metabolism and protein synthesis. To understand the role of the blood supply in the dramatic changes following naris closure, the present study examines the development of olfactory bulb vasculature in unilaterally odor-deprived and control rats. On post-partum day 1 (P1; the day after birth), littermate rat pups underwent either unilateral naris occlusion or sham surgery. On P5, P10, P15, P20, P30 and P60, animals were perfused with an india ink-gelatin mixture to assess blood vessel amount and complexity. Densitometric analyses were performed to obtain values of blood vessel area ratios (vessel area/tissue area), branch point number and branch point density. Considerable vessel development in all bulbs occurred over the first two to three weeks post-partum. By P20, large reductions in vessel area ratios were observed in all constituent laminae of deprived bulbs. While similar reductions in number of vessel branch points/tissue area were seen, few changes were noted in the number of branch points/vessel area. The effects were primarily confined to early developmental periods: bulb vasculature in animals deprived at older ages (P40) appeared normal. The results indicate that the vasculature responds to alterations in sensory stimulation early in life, therefore potentially playing an important regulative role in neural development.