Brain Development In Newborns Research Articles

Bone Marrow-Derived Mesenchymal Stem Cells and γ-Secretase Inhibitor Treatments Suppress Amyloid-β25-35-Induced Cognitive Impairment in Rat Dams and Cortical Degeneration in Offspring.

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and ensuing cognitive impairment. Progressive deposition of extracellular amyloid beta (Aβ) aggregates (plaques) and intracellular hyperphosphorylated Tau protein (p-Tau) are the core pathological markers of AD but may precede clinical symptoms by many years, presenting a therapeutic window of opportunity. Females are more frequently afflicted by AD than males, necessitating evaluation of novel treatments for the female population. The current study examined the protective efficacies of intravenous bone marrow-derived mesenchymal stem cells (BM-MSCs) and oral gamma-secretase inhibitor-953 (GSI-953) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring induced by intracerebroventricular injection of Aβ25-35 prior to pregnancy. The Aβ25-35 (AD) group exhibited significant (P < 0.001) impairments in the Y-maze and novel object recognition test performance prior to conception. Histological analysis of the offspring cortex revealed substantial dendritic shrinkage and activation of microglial cells, while neurochemical analysis demonstrated significant increases in the proinflammatory cytokine interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). In contrast, BM-MSC or GSI-953 treatment of dams following Aβ25-35 injection significantly (P < 0.001) reduced the number and size of activated microglial cells, markedly increased dendrite length, and reversed proinflammatory cytokine elevations in offspring. Moreover, BM-MSC or GSI-953 treatment reversed the Aβ25-35-induced amyloid precursor protein and p-Tau elevations in the offspring brain; these changes were accompanied by upregulation of the brain-derived neurotrophic factor and downregulation of glycogen synthase kinase-3β in the serum and brain. Treatment with BM-MSCs or GSI-953 also reversed Aβ25-35-induced elevations in different gene expressions in the neonatal cortex. Finally, treatment of dams with BM-MSCs or GSI-953 prevented the Aβ25-35-induced disruption of newborn brain development. Thus, BM-MSC and GSI-953 treatments have broad-spectrum effects against Aβ25-35-induced brain pathology, including the suppression of neural inflammation, restoration of developmental plasticity, and promotion of neurotrophic signaling.

How does the convergence of prematurity and congenital heart disease impact the developing brain?

Prematurity and congenital heart disease (CHD) are individually associated with increased risk of brain injury and adverse neurodevelopmental outcomes. Delayed brain development in newborns with CHD has been documented to begin in utero and predisposes newborns with CHD to brain injury. Little is known about the combined risks when prematurity and CHD co-occur. The purpose of this review is to highlight the unique vulnerability of preterm newborns with CHD to brain dysmaturation and brain injury, and the urgent need for prospective research.

Identification of regulated proteins by resveratrol in glutamate-induced cortical injury of newborn rats.

Glutamate induces neuronal damage by generating oxidative stress and neurotoxicities. The neurological damage caused by glutamate is more severe during brain development in newborns than in adults. Resveratrol is naturally present in a variety of fruits and medicinal plants and exerts a neuroprotective effect against brain damage. The goal of this study was to evaluate the neuroprotective effects of resveratrol and to identify changed proteins in response to resveratrol treatment during glutamate-induced neonatal cortical damage. Sprague-Dawley rat pups (7 days old) were randomly divided into vehicle, resveratrol, glutamate, and glutamate and resveratrol groups. The animals were intraperitoneally injected with glutamate (10 mg/kg) and/or resveratrol (20 mg/kg) and their brain tissue was collected 4 hr after drug administration. Glutamate exposure caused severe histopathological changes, while resveratrol attenuated this damage. We identified regulated proteins by resveratrol in glutamate-induced cortical damaged tissue using two-dimensional gel electrophoresis and mass spectrometry. Among identified proteins, we focused on eukaryotic initiation factor 4A2, γ-enolase, protein phosphatase 2A subunit B, and isocitrate dehydrogenase. These proteins decreased in the glutamate-treated group, whereas the combination treatment of glutamate and resveratrol attenuated these protein reductions. These proteins are anti-oxidant proteins and anti-apoptotic proteins. These results suggest that glutamate induces brain cortical damage in newborns; resveratrol exerts a neuroprotective effect by controlling expression of various proteins with anti-oxidant and anti-apoptotic functions.

Prenatal exposure to hesperidin improves reflexive motor behaviors in mice offspring.

Prenatal exposure during the embryonic period has positive or adverse effect on newborn brain development. Neuroprotective activity of the hesperidin is well documented but there is no evidence for maternal exposure to hesperidin on offspring reflexive motor behaviors. So, the aim of the current study was to determine the prenatal exposure to hesperidin on reflexive motor behaviors in mice offspring. Forty pregnant female NMRI mice (8-10weeks old) were allocated into four groups. Group 1 kept as control and groups 2-4 intraperitoneal (i.p) injected with hesperidin (0.1, 0.5, and 1mg/kg) on days of 5, 8, 11, 14, and 17 of pregnancy. The control group injected with saline at the same days. Following delivery, 20 pups from each litter were selected and reflexive motor behaviors determined using ambulation, hind-limb foot angle, surface righting, hind-limb strength, grip strength, front-limb suspension, and negative geotaxis tests. At the end of the study serum Malondialdehyde (MDA), Superoxide dismutase (SOD), Glutathione peroxidase (GPx), and total antioxidant status (TAS) levels were determined. According to the results, maternal exposure to hesperidin (0.1, 0.5, and 1mg/kg) increased ambulation score, front-limb suspension time, and hind-limb suspension score in mice offspring compared to the control group (p<.05). Hesperidin (0.1, 0.5, and 1mg/kg) decreased hind-limb foot angle in mice offspring compared to the control group (p<.05). Prenatal exposure to hesperidin (0.5 and 1mg/kg) significantly increased the surface righting and grip strength in comparison to the control group (p<.05). Hesperidin (0.1, 0.5, and 1mg/kg) decreased MDA and increased SOD and GPx levels in mice offspring (p<.05). These results suggested hesperidin exposure during pregnancy has positive effect on reflexive motor behaviors in mice offspring may be due to its antioxidant activity.

Investigating the Brain Development in Newborns by Information-Based Analysis of Electroencephalography (EEG) Signal

In this paper, we employ the information theory to analyze the development of brain as the newborn ages. We compute the Shannon entropy of Electroencephalography (EEG) signal during sleep for 10 groups of newborns who are aged 36 weeks to 45 weeks (first to the last group). Based on the obtained results, EEG signals for newborns in 36 weeks have the lowest information content, whereas EEG signals for newborns in 45 weeks show the greatest information content. Therefore, we concluded that the information content of EEG signal increases as the age of newborn increases. Th result of statistical analysis demonstrated that the influence of increment of age of newborn on the variations of informant content of their EEG signals was significant.

The Effects of Low-Dose Bisphenol A and Bisphenol F on Neural Differentiation of a Fetal Brain-Derived Neural Progenitor Cell Line

Environmental chemicals are known to disrupt the endocrine system in humans and to have adverse effects on several organs including the developing brain. Recent studies indicate that exposure to environmental chemicals during gestation can interfere with neuronal differentiation, subsequently affecting normal brain development in newborns. Xenoestrogen, bisphenol A (BPA), which is widely used in plastic products, is one such chemical. Adverse effects of exposure to BPA during pre- and postnatal periods include the disruption of brain function. However, the effect of BPA on neural differentiation remains unclear. In this study, we explored the effects of BPA or bisphenol F (BPF), an alternative compound for BPA, on neural differentiation using ReNcell, a human fetus-derived neural progenitor cell line. Maintenance in growth factor-free medium initiated the differentiation of ReNcell to neuronal cells including neurons, astrocytes, and oligodendrocytes. We exposed the cells to BPA or BPF for 3 days from the period of initiation and performed real-time PCR for neural markers such as β III-tubulin and glial fibrillary acidic protein (GFAP), and Olig2. The β III-tubulin mRNA level decreased in response to BPA, but not BPF, exposure. We also observed that the number of β III-tubulin-positive cells in the BPA-exposed group was less than that of the control group. On the other hand, there were no changes in the MAP2 mRNA level. These results indicate that BPA disrupts neural differentiation in human-derived neural progenitor cells, potentially disrupting brain development.

Morphine exposure and maternal deprivation during the early postnatal period alter neuromotor development and nerve growth factor levels

The objective of this study was to verify whether repeated morphine administration and maternal deprivation in early life alter neurobehavioral development and central nerve growth factor (NGF) levels. A total of 58 male Wistar rat pups were used in our study. From postnatal day 1 (P1), litters were daily deprived of their mother for 3h; this was continued for the first 10days of life. Animals were divided into 5 groups: total control (C), did not receive any intervention; saline (S), received saline solution; morphine (M), received morphine; deprived-saline group (DS), were subjected to maternal deprivation and received saline solution; and deprived-morphine (DM), were subjected to maternal deprivation and received morphine. From P8, newborns received subcutaneous (s.c.) injections of morphine or saline (5μg) once daily for 7days. Righting reflex, negative geotaxis and gait were chosen as postural parameters to evaluate neuromotor reflexes. In the righting reflex test, a delay in the development of animals was evidenced in the M group. Performance of negative geotaxis was slower in the M and DM groups. In the gait test, all groups showed a daily improvement in performance in terms of locomotion frequency. An increased frequency of rearing was observed in the M, DS, and DM groups from P16 to P20. The DM group presented an increase in NGF levels in the brainstem. An increase in cerebral cortex NGF levels in the M, DS, and DM groups was observed as well. Our results suggest that changes in environmental conditions and the disruption of mother–infant interactions during the neonatal period can produce changes in the neurobiology, physiology, and emotional behavior of rats. This finding has important implications for the maternal-neonate interaction needed for normal brain development in newborns.

Extraction of features from sleep EEG for Bayesian assessment of brain development.

Brain development can be evaluated by experts analysing age-related patterns in sleep electroencephalograms (EEG). Natural variations in the patterns, noise, and artefacts affect the evaluation accuracy as well as experts’ agreement. The knowledge of predictive posterior distribution allows experts to estimate confidence intervals within which decisions are distributed. Bayesian approach to probabilistic inference has provided accurate estimates of intervals of interest. In this paper we propose a new feature extraction technique for Bayesian assessment and estimation of predictive distribution in a case of newborn brain development assessment. The new EEG features are verified within the Bayesian framework on a large EEG data set including 1,100 recordings made from newborns in 10 age groups. The proposed features are highly correlated with brain maturation and their use increases the assessment accuracy.

MRI reveals increased superior vena caval blood flow in human fetuses with congenital heart disease, abnormal placental pathology and neonatal brain white matter changes

Background Delayed brain development in newborns with congenital heart disease (CHD) results in increased vulnerability to white matter injury before and after cardiac surgery [1]. Doppler showing reductions in pulsatility index (PI) in the middle cerebral arteries (MCA) of fetuses with CHD is interpreted as evidence of “brain sparing physiology”. It supports the hypothesis that in utero brain dysmaturation in CHD is due to reduced cerebral oxygen delivery [2]. We were interested in the relationship between cerebral blood flow, placental pathology and white matter changes in CHD fetuses using ultrasound and MRI.

Assessment of MRI parameters for studying brain development in newborns with congenital heart disease

Background Microstructural evidence of white matter (WM) dysmaturation in the brains of newborns with congenital heart disease (CHD) using MRI has been previously shown [1]. Further, delayed WM development confers an increased risk of WM injury before and after neonatal cardiac surgery [2]. WM injury is associated with a high incidence of subsequent neurodevelopmental deficits and fetal interventions to improve brain development in the setting of CHD are currently being investigated. We wished to compare the utility of our previously described parameters in another cohort of CHD newborns, and assess the performance of a new parameter (WM T2 relaxation) for discerning differences in WM maturation.

MiRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma

BackgroundMicroRNAs (miRNAs) and their role during tumor development have been studied in great detail during the last decade, albeit their expression pattern and regulation during normal development are however not so well established. Previous studies have shown that miRNAs are differentially expressed in solid human tumors. Platelet-derived growth factor (PDGF) signaling is known to be involved in normal development of the brain as well as in malignant primary brain tumors, gliomas, but the complete mechanism is still lacking. We decided to investigate the expression of the oncogenic miR-21 during normal mouse development and glioma, focusing on PDGF signaling as a potential regulator of miR-21.MethodsWe generated mouse glioma using the RCAS/tv-a system for driving PDGF-BB expression in a cell-specific manner. Expression of miR-21 in mouse cell cultures and mouse brain were assessed using Northern blot analysis and in situ hybridization. Immunohistochemistry and Western blot analysis were used to investigate SOX2 expression. LNA-modified siRNA was used for irreversible depletion of miR-21. For inhibition of PDGF signaling Gleevec (imatinib mesylate), Rapamycin and U0126, as well as siRNA were used. Statistical significance was calculated using double-sided unpaired Student´s t-test.ResultsWe identified miR-21 to be highly expressed during embryonic and newborn brain development followed by a gradual decrease until undetectable at postnatal day 7 (P7), this pattern correlated with SOX2 expression. Furthermore, miR-21 and SOX2 showed up-regulation and overlapping expression pattern in RCAS/tv-a generated mouse brain tumor specimens. Upon irreversible depletion of miR-21 the expression of SOX2 was strongly diminished in both mouse primary glioma cultures and human glioma cell lines. Interestingly, in normal fibroblasts the expression of miR-21 was induced by PDGF-BB, and inhibition of PDGF signaling in mouse glioma primary cultures resulted in suppression of miR-21 suggesting that miR-21 is indeed regulated by PDGF signaling.ConclusionsOur data show that miR-21 and SOX2 are tightly regulated already during embryogenesis and define a distinct population with putative tumor cell of origin characteristics. Furthermore, we believe that miR-21 is a mediator of PDGF-driven brain tumors, which suggests miR-21 as a promising target for treatment of glioma.

Magnetic Resonance Imaging in Congenital Heart Disease

Magnetic resonance imaging (MRI) is increasingly being applied to critically ill newborns with congenital heart disease (CHD) with the hope of understanding mechanisms accounting for adverse neurodevelopmental outcome. This powerful technique has opened an unprecedented window into normal development and pathogenesis during fetal life and surrounding surgery. Much as the technological advances of cardiopulmonary bypass, cardiac intensive care, and transcatheter and surgical techniques have translated into improved survival for neonates with complex congenital heart lesions, MRI promises to elucidate mechanisms and measure outcomes in a way that will inform treatment and establish neurointensive care to lessen neurologic morbidity. Many agree that improving neurodevelopmental outcome in CHD is the preeminent challenge to the field.1 MRI studies in CHD have made the important and surprising observations that (1) brain injury is present before surgery,2 (2) injury is most commonly focal affecting the white matter,3 and (3) brain development is delayed in term infants with CHD.4 Despite its promise as a sensitive early outcome variable that could be used to structure interventional studies with novel trial design,5 success to date has largely been descriptive, identifying clinical risk factors in limited case series. A particular challenge applying these findings to clinical practice is that the incidence of injury and associated risk factors are often unique to each form of CHD.6 For this reason, the approach has not substantially altered clinical care to date. However, several themes have emerged from multiple studies, providing confidence that the identified risk factors are valid and potent. These include the significance of postoperative hypotension,3,6 hypoxemia3 and diminished regional cerebral oxygen saturation.6,7 Although multiple studies have noted the high frequency of preoperative brain injury, particularly in neonates with transposition of the great arteries (TGA),2,6,8 few risk factors have been identified …

Abnormal Brain Development in Newborns With Congenital Heart Disease

Survey of Anesthesiology: June 2008 - Volume 52 - Issue 3 - p 127-128 doi: 10.1097/01.SA.0000307878.52543.ba

Abnormal Brain Development in Newborns with Congenital Heart Disease

Abnormal Brain Development in Newborns with Congenital Heart Disease

The development of potentially better practices to support the neurodevelopment of infants in the NICU

To review the existing evidence used to identify potentially better care practices that support newborn brain development. Literature review. Sixteen potentially better practices are identified and grouped into two operational clinical bundles based upon timing for recommended implementation. Existing evidence supports the implementation of selected care practices that potentially may support newborn brain development.

Abnormal Brain Development in Newborns with Congenital Heart Disease

Congenital heart disease in newborns is associated with global impairment in development. We characterized brain metabolism and microstructure, as measures of brain maturation, in newborns with congenital heart disease before they underwent heart surgery. We studied 41 term newborns with congenital heart disease--29 who had transposition of the great arteries and 12 who had single-ventricle physiology--with the use of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before cardiac surgery. We calculated the ratio of N-acetylaspartate to choline (which increases with brain maturation), the ratio of lactate to choline (which decreases with maturation), average diffusivity (which decreases with maturation), and fractional anisotropy of white-matter tracts (which increases with maturation). We compared these findings with those in 16 control newborns of a similar gestational age. As compared with control newborns, those with congenital heart disease had a decrease of 10% in the ratio of N-acetylaspartate to choline (P=0.003), an increase of 28% in the ratio of lactate to choline (P=0.08), an increase of 4% in average diffusivity (P<0.001), and a decrease of 12% in white-matter fractional anisotropy (P<0.001). Preoperative brain injury, as seen on MRI, was not significantly associated with findings on MRS or DTI. White-matter injury was observed in 13 newborns with congenital heart disease (32%) and in no control newborns. Term newborns with congenital heart disease have widespread brain abnormalities before they undergo cardiac surgery. The imaging findings in such newborns are similar to those in premature newborns and may reflect abnormal brain development in utero.

Deterministic role of the cell cycle in newborn brain development and in brain injury.

Deterministic role of the cell cycle in newborn brain development and in brain injury.