Fetal Nervous System Research Articles

Human neural stem/progenitor cells derived from embryonic stem cells and fetal nervous system present differences in immunogenicity and immunomodulatory potentials in vitro

To develop cell therapies for damaged nervous tissue with human neural stem/progenitor cells (hNPCs), the risk of an immune response and graft rejection must be considered. There are conflicting results and lack of knowledge concerning the immunocompetence of hNPCs of different origin. Here, we studied the immunogenicity and immunomodulatory potentials of hNPCs cultured under equivalent conditions after derivation from human embryonic stem cells (hESC-NPCs) or human fetal spinal cord tissue (hfNPCs). The expression patterns of human leukocyte antigen, co-stimulatory and adhesion molecules in hESC-NPCs and hfNPCs were relatively similar and mostly not affected by inflammatory cytokines. Unstimulated hfNPCs secreted more transforming growth factor-β1 (TGF-β1) and β2 but similar level of interleukin (IL)-10 compared to hESC-NPCs. In contrast to hfNPCs, hESC-NPCs displayed 4–6 fold increases in TGF-β1, TGF-β2 and IL-10 under inflammatory conditions. Both hNPCs reduced the alloreaction between allogeneic peripheral blood mononuclear cells (PBMCs) and up-regulated CD4+CD25+forkhead box P3 (FOXP3)+ T cells. However, hESC-NPCs but not hfNPCs dose-dependently triggered PBMC proliferation, which at least partly may be due to TGF-β signaling. To conclude, hESC-NPCs and hfNPCs displayed similarities but also significant differences in their immunocompetence and interaction with allogeneic PBMCs, differences may be crucial for the outcome of cell therapy.

703: Association between psychosocial disorder during pregnancy and childhood attention deficit hyperactivity disorder by gestational age and race/ethnicity

pregnancy and childhood attention deficit hyperactivity disorder by gestational age and race/ethnicity Darios Getahun, Michael Fassett, Steven Jacobsen Kaiser Permanente Southern California, Research and Evaluation, Pasadena, CA, West Los Angeles Medical Center, Kaiser Permanente Southern California, Department of Obstetrics and Gynecology, Los Angeles, CA OBJECTIVE: Psychosocial distress disorder (PSD) during pregnancy is known to increase the risk of adverse perinatal outcomes. Because stressors during pregnancy may alter development of the fetal nervous system function and behavior later in life, we examined the association between PSD and childhood ADHD and whether the risk varies by gestational age and maternal race/ethnicity. STUDY DESIGN: A nested case-control study of singleton born children age 3-11 years delivered at 28 weeks of gestation (n 81,678) in Kaiser Permanente Southern California (KPSC) hospitals (1991-2006) was performed using the Perinatal Service System, Hospital Inpatient, Outpatient physician encounter, and Pharmacy records. ICD-9 codes from hospitalizations during pregnancy and infant birth certificates as well as pharmacy records on medication specific for PSD were used to ascertain the exposure and outcomes of interest. Adjusted odds ratio (OR) and 95% confidence interval (CI) were used to quantify the associations. RESULTS: Five percent of pregnancies were complicated by PSD. Compared with control children, case children were more likely to be male and of White or African-American race/ethnicity. Case children were more likely than control children to be exposed to PSD (OR 1.6, 95%CI 1.41.8). A stratified analysis by gestational age revealed that case children born at 34-36, and 37-42 weeks of gestation, were significantly more likely to be exposed to PSD (1.8-fold [95%CI 1.3, 2.5], and 1.6-fold [95%CI 1.4-1.8], respectively). PSD was associated with increased odds of ADHD across all racial/ethnic groups except Asian/Pacific Islanders. CONCLUSION: The results suggest that maternal PSD during pregnancy is associated with increased risk of childhood ADHD. Identification of at-risk children may provide the opportunity for early diagnosis and initiate treatment when it is more effective.

Fetal development of complex autonomic control evaluated from multiscale heart rate patterns

Development of the fetal autonomic nervous system's integrative capacity in relation to gestational age and emerging behavioral pattern is reflected in fetal heart rate patterns. Conventional indices of vagal and sympathetic rhythms cannot sufficiently reflect their complex interrelationship. Universal behavioral indices of developing complex systems may provide additional information regarding the maturating complex autonomic control. We investigated fetal magnetocardiographic recordings undertaken at 10-min intervals in active (n = 248) and quiet (n = 111) states between 22 and 39 wk gestational age. Standard deviation of heartbeat intervals, skewness, contribution of particular rhythms to the total power, and multiscale entropy were analyzed. The multiscale entropy methodology was validated for 10-min data sets. Age dependence was analyzed by linear regression. In the quiet state, contribution of sympathovagal rhythms and their complexity over a range of corresponding short scales increased with rising age, and skewness shifted from negative to positive values. In the active state, age dependencies were weaker. Skewness as the strongest parameter shifted in the same direction. Fluctuation amplitude and the complexity of scales associated with sympathovagal rhythms increased. We conclude that in the quiet state, stable complex organized rhythms develop. In the active state, however, increasing behavioral variability due to multiple internal coordinations, such as movement-related heart rate accelerations, and external influences develop. Hence, the state-selective assessment in association with developmental indices used herein may substantially improve evaluation of maturation age and early detection and interpretation of developmental problems in prenatal diagnosis.

Experimental gestational hypothyroidism evokes hypertension in adult offspring rats

Gestational hypothyroidism is a prevalent disorder in pregnant women. We aimed to investigate the impact of experimental gestational hypothyroidism (EGH) on cardiovascular and autonomic nervous systems (ANS) in the offspring of rats. EGH was induced with methimazole (MMI) 0.02% in drinking water from day 9 of gestation until birth. Sixty day old offspring from MMI-treated dams (OMTD, n=13) or water-treated dams (OWTD, n=13) had femoral arteries surgically assessed for the measurements of heart rate (HR), mean (MAP), systolic (SAP) and diastolic arterial pressure (DAP), and spontaneous baroreflex sensitivity (BRS). To investigate the balance of ANS, we established the high (HF) and low frequency (LF) bands of pulse interval (PI) and LF band of SAP spectrum. OMTD had increased MAP (130.2 ± 2.0 vs 108.8 ± 3.0 mmHg, p<0.001), SAP (157.3 ± 2.9 vs 135.7 ± 4.5mm Hg, p<0.001) and DAP (109.7 ± 1.9 vs 88.4 ± 2.6 mmHg, p<0.001) when compared to OWTD, and had lower HR (355.1 ± 8.9 vs 386.8 ± 9.2 bpm, p<0.05). After spectral analysis of PI and SAP, only LF band of SAP spectrum was higher (7.2 ± 0.8 vs 4.0 ± 0.6 mmHg(2), p<0.01) in OMTD under spontaneous condition. Despite bradycardia, EGH promotes spontaneous hypertension in 60 day old offspring, probably due to increased sympathetic modulation of vessels, which is suggested by the higher LF of SAP. These findings suggest a critical role of maternal THs in the development of fetal cardiovascular and autonomic nervous systems.

Development of integrative autonomic nervous system function: an investigation based on time correlation in fetal heart rate patterns

To describe the development of the integrative capacity of the fetal autonomic nervous system (ANS) according to gestational age and emerging behavioral states, assuming that developing integrative ANS functions are reflected in increasing autocorrelation of fetal heart rate and fetal heart rate variability markers. Magnetocardiograms of 114 healthy fetuses (21-40 weeks of gestation) were recorded. Level of fetal activity (quiet/active sleep) was estimated according to characteristic heart rate patterns. Autocorrelation functions of (i) fetal heart rate and (ii) time patterns of SDNN (standard deviation of normal-to-normal intervals) and RMSSD (root mean square of successive differences in normal-to-normal intervals) were calculated and autocorrelation was determined over different time scales. Age and activity related changes were examined using linear regression and non-parametric tests. During pregnancy, autocorrelation increased in fetal heart rate signals and time patterns of SDNN and RMSSD. Short-time correlation (0-20 s) changed between 21 and 31 gestational weeks. Long-time correlation (75-300 s) accelerated later in pregnancy and did not increase in quiet heart rate patterns. Strong state-dependent changes were found with time patterns of SDNN. Emerging integrative ANS functions are reflected in increasing autocorrelation of fetal heart rate fluctuations over increasing time scales. The period from 21 to 31 gestational weeks seems to be critical to ANS development. Increasing long-time correlation is specific to active sleep states.

Maternal stress in pregnancy: considerations for fetal development.

There is significant current interest in the degree to which prenatal exposures, including maternal psychological factors, influence child outcomes. Studies that detect an association between prenatal maternal psychological distress and child developmental outcomes are subject to a number of interpretative challenges in the inference of causality. Some of these are common to many types of prenatal exposures that must necessarily rely on observational designs. Such challenges include the correlation between prenatal and postnatal exposures and the potential role of other sources of shared influence, such as genetic factors. Others are more specific to this area of research. These include confounding between maternal report of child outcomes and the maternal psychological attributes under study, difficulties in distinguishing maternal stress from more ubiquitous aspects of maternal personality, and the lack of association between cortisol and measures of maternal psychological stress. This article considers these methodological issues and offers an additional methodology focused on fetal neurobehavior for discerning potential mechanisms that may mediate associations between maternal psychological functioning and the developing fetal nervous system.

Effect of malaria in pregnancy on foetal cortical brain development: a longitudinal observational study

BackgroundMalaria in pregnancy has a negative impact on foetal growth, but it is not known whether this also affects the foetal nervous system. The aim of this study was to examine the effects of malaria on foetal cortex development by three-dimensional ultrasound.MethodsBrain images were acquired using a portable ultrasound machine and a 3D ultrasound transducer. All recordings were analysed, blinded to clinical data, using the 4D view software package. The foetal supra-tentorial brain volume was determined and cortical development was qualitatively followed by scoring the appearance and development of six sulci. Multilevel analysis was used to study brain volume and cortical development in individual foetuses.ResultsCortical grading was possible in 161 out of 223 (72%) serial foetal brain images in pregnant women living in a malaria endemic area. There was no difference between foetal cortical development or brain volumes at any time in pregnancy between women with immediately treated malaria infections and non-infected pregnancies.ConclusionThe percentage of images that could be graded was similar to other neuro-sonographic studies. Maternal malaria does not have a gross effect on foetal brain development, at least in this population, which had access to early detection and effective treatment of malaria.

Thyroid hormones and cognitive function

Iodine is essential for the synthesis of thyroxine (T4), which is critical for the maturation of the fetal brain and nervous system. Maternal circulating T4 deficiency (as in severe iodine deficien...

Phase-rectified signal averaging as a new method for surveillance of growth restricted fetuses

Objective: This study aims to compare average acceleration capacity (AAC), a new parameter to assess the dynamic capacity of the fetal autonomous nervous system, and short term variation (STV) in fetuses affected by intrauterine growth restriction (IUGR) and healthy fetuses. Methods: A prospective observational study was performed, including 39 women with IUGR singleton pregnancies (estimated fetal weight <10th percentile and umbilical artery resistance index >95th percentile) and 43 healthy control pregnancies matched according to gestational age at recording. Ultrasound biometries and Doppler examination were performed for identification of IUGR and control fetuses, with subsequent analysis of fetal heart rate, resulting in STV and AAC. Follow-up for IUGR and control pregnancies was done, with perinatal outcome variables recorded. Results: AAC [IUGR mean value 2.0 bpm (interquartile range = 1.6–2.1), control 2.7 bpm (2.6–3.0)] differentiates better than STV [IUGR 7.4 ms (5.3–8.9), control 10.9 ms (9.2–12.7)] between IUGR and control. The area under the curve for AAC is 97 % [95% CI = (0.95–1.0)], for STV 85 % (CI = 0.76–0.93; p < 0.01). Positive predictive value for STV is 77% and negative predictive value is 81%. For AAC both positive and negative predictive values are 90%. Conclusions: AAC shows an improvement to discriminate between normal and compromised fetuses at a single moment in time, in comparison with STV.

Drosophila CYP6g1 and its human homolog CYP3A4 confer tolerance to methylmercury during development

Methylmercury (MeHg) is a persistent environmental toxicant that is commonly encountered through dietary fish and seafood. While the fetal nervous system is a well-known primary target for MeHg toxicity, the risks of MeHg exposures that are commonly experienced today through diet and environmental exposure remain uncertain. Despite knowledge of numerous cellular processes that are affected by MeHg, the mechanisms that ultimately influence tolerance or susceptibility to MeHg in the developing fetus are not well understood. Using transcriptomic analyses of developing brains of MeHg tolerant and susceptible strains of Drosophila, we previously identified members of the cytochrome p450 (CYP) family of monooxygenases/oxidoreductases as candidate MeHg tolerance genes. While CYP genes encode Phase I enzymes best known for xenobiotic metabolism in the liver, several classes of CYPs are required for synthesis or degradation of essential endobiotics, such as hormones and fatty acids, that are critical to normal development. We now demonstrate that variation in expression CYP genes can strongly influence MeHg tolerance in the developing fly. Importantly, modulating expression of a single CYP, CYP6g1, specifically in neurons or the fat body (liver equivalent) is sufficient to rescue development in the presence of MeHg. We also demonstrate a conserved function for CYP3A4, a human homolog of CYP6g1, in conferring MeHg tolerance to flies. Finally, we show that pharmacological induction of CYPs with caffeine parallels an increase in tolerance to MeHg in developing flies. These findings establish a previously unidentified role for CYPs in MeHg toxicity and point to a potentially conserved role of CYP genes to influence susceptibility to MeHg toxicity across species.

Change of Spectral Analysis of Fetal Heart Rate During Clinical Hypnosis: a Prospective Randomised Trial from the 20th Week of Gestation Till Term.

Objective: To investigate the functional adaptive process of the fetal autonomic nervous system during hypnosis from the 20th week of gestation till term. Are there changes in the power spectrum analysis of fetal heart rate when the mother is having a clinical hypnosis or control period? Study Design: Fourty-nine FHR recordings were analysed. Included recordings were from singletons and abdominal fetal ECG-monitored pregnancies. All women were randomised to receive clinical hypnosis followed by a period with no intervention or vice versa. Statistical analyses were performed with the Wilcoxon signed ranks and Spearman rho correlation tests. Results: There was a significant difference found between fetal heart rate at baseline (144.3 ± 6.0) and hypnosis (142.1 ± 6.4). A difference was also detected between the standard deviation of the heart rate between baseline (6.7 ± 1.9) and hypnosis (6.8 ± 3.5). LFnu was smaller during baseline (80.2 ± 5.3) than during hypnosis (82.1 ± 5.7), whereas HFnu was significantly larger (19.8 ± 5.3 vs. 17.9 ± 5.7). There was no correlation between the gestation age and the change in LFnu, HFnu or ratio LF/HF due to the hypnosis intervention. Conclusion: The functional adaptive process of the fetal autonomic system during hypnosis is reflected by a sympathovagal shift towards increased sympathetic modulation.

Exploring the Caffeine-Induced Teratogenicity on Neurodevelopment Using Early Chick Embryo

Caffeine consumption is worldwide. It has been part of our diet for many centuries; indwelled in our foods, drinks, and medicines. It is often perceived as a “legal drug”, and though it is known to have detrimental effects on our health, more specifically, disrupt the normal fetal development following excessive maternal intake, much ambiguity still surrounds the precise mechanisms and consequences of caffeine-induced toxicity. Here, we employed early chick embryos as a developmental model to assess the effects of caffeine on the development of the fetal nervous system. We found that administration of caffeine led to defective neural tube closures and expression of several abnormal morphological phenotypes, which included thickening of the cephalic mesenchymal tissues and scattering of somites. Immunocytochemistry of caffeine-treated embryos using neural crest cell markers also demonstrated uncharacteristic features; HNK1 labeled migratory crest cells exhibited an incontinuous dorsal-ventral migration trajectory, though Pax7 positive cells of the caffeine-treated groups were comparatively similar to the control. Furthermore, the number of neurons expressing neurofilament and the degree of neuronal branching were both significantly reduced following caffeine administration. The extent of these effects was dose-dependent. In conclusion, caffeine exposure can result in malformations of the neural tube and induce other teratogenic effects on neurodevelopment, although the exact mechanism of these effects requires further investigation.

Exposure of foetal neural progenitor cells to IL‐1β impairs their proliferation and alters their differentiation – a role for maternal inflammation?

During pregnancy, activation of the maternal immune system results in inflammation in the foetal nervous system. The causative agents are pro-inflammatory cytokines like interleukin-1β (IL-1β), produced by the foetus. In this study, we examine the effect of IL-1β on the proliferation and differentiation of neural progenitor cells (NPCs) to better understand its potential effects on the developing brain. We find that the IL-1β receptor (IL-1R1) is expressed in the ventral mesencephalon of the developing brain. Furthermore, IL-1R1 is expressed on Nestin-positive, Sox-2-positive NPCs. IL-1β treatment reduced the numbers of proliferating NPCs, an effect prevented by the IL-1R1 receptor antagonist. LDH and MTT assays, and western blot analysis for cleaved caspase 3 and poly(ADP-ribose) polymerase, confirmed that this was not due to an increase in cell death but rather an induction of differentiation. To further study the effects of IL-1β on cell fate determination, we differentiated NPCs in the presence and absence of IL-1β. Il-1β promoted gliogenesis and inhibited neurogenesis, an effect that required p38-MAPK kinase signalling. In summary, these data show that exposure of NPCs to IL-1β affects their development. This necessitates an examination of the consequences that maternal immune system activation during pregnancy has on the cellular architecture of the developing brain.

Familiäre Holoprosencephalie – Späte Diagnose trotz Wiederholungsfall

Holoprosencephaly (HPE) is a serious malformation of the central nervous system which occurs between the 18th and 28th day of gestation. HPE can appear in different manifestations within one family. The diagnosis of HPE can be performed in an early sonographic scan between the 12th and the 14th week of gestation, according to the guidelines for the examination of the foetal nervous system. The history of a pregnant woman with a previous birth of a foetus with cerebral malformation and having a partner with minor signs for HPE justifies an intensified sonographic examination and molecular analysis. An amniocentesis was done just for the basic analysis, not for further genetic testing. However, it is very important to have information about a recurrency risk for every subsequent pregnancy.

The effects of methylmercury on Notch signaling during embryonic neural development in Drosophila melanogaster

Methylmercury (MeHg) is a ubiquitous toxicant that targets the developing fetal nervous system. MeHg interacts with the Notch signaling pathway, a highly-conserved intercellular signaling mechanism required for normal development. Notch signaling is conveyed by activation of the genes in the enhancer of split (E(spl)) locus in Drosophila. We have previously shown that acute high doses of MeHg upregulate several E(spl) genes in Drosophila neural-derived C6 cells. Furthermore, MeHg induction of E(spl) can occur independent of the Notch receptor itself. We now show that MeHg, unlike inorganic mercury (HgCl2), preferentially upregulates E(spl)mδ and E(spl)mγ in Drosophila C6 cells. This is distinct from Delta ligand-induced Notch signaling in which no induction of E(spl)mδ is seen. MeHg is also seen to specifically upregulate E(spl)mδ in Drosophila embryos where HgCl2 showed no such effect. Additionally, treatment of embryos with MeHg caused a consistent failure in axonal outgrowth of the intersegmental nerve (ISN). This ISN phenotype was partially replicated by genetic activation of the Notch pathway, but was not replicated by increasing expression of E(spl)mδ. These data suggest a role for Notch signaling and the E(spl)mδ target gene in MeHg toxicity, however, the site of action for E(spl)mδ in this system remains to be elucidated.

Antidepressants and the developing nervous system

Antidepressants and the developing nervous system

Protecting Children From Toxicants

Protecting Children From Toxicants

Fetal Neuroimaging

Although ultrasound remains the screening modality of choice in evaluation of the fetal nervous system, magnetic resonance imaging with its multiplanar imaging ability and high signal-to-noise ratio is highly accurate in illustrating the morphologic changes of the developing brain and fetal brain abnormalities. Fetal magnetic resonance imaging is an established powerful tool for obtaining additional information in evaluation of anomalies of the fetal face, neck, and spine. It is helpful to patients and their health care professionals in making vital management decisions and aids in genetic counseling for future pregnancies.

Abstract 1855: Maternal consumption of long chain omega 3 fatty acids decreases risk for mammary gland cancer in the female C(3)1 TAg mouse

Abstract Omega 3 fatty acids have been shown to reduce incidence and slow growth of mammary gland cancer in rodent models. Omega 3 fatty acids in the maternal diet are important for normal fetal brain, eye and nervous system development. Since exposure to dietary components during the critical developmental times of gestation and lactation may alter risk for mammary gland cancer in females, we tested whether exposure to increased levels of long chain omega 3 fatty acids (from fish oils) would be preventive or promotional to mammary gland cancer in the offspring. Normal SV40 female mice were fed AIN 76 diets containing either 10% corn oil (control) or 5% of an omega 3 fatty acid concentrate + 5% canola oil. Females were then mated with C(3)1 TAg transgenic mice. Transgene hemizygous offspring were the experimental mice not the original SV40 female mice. On a normal diet the hemizygous mice are expected to have about 100% tumor incidence by 150 days of age. At weaning (3 weeks) pups were randomized to either the corn oil or the fish oil diet, 15-17 mice per group. At 140 days of age, mice never exposed to fish oil (C/C group) had a significantly higher incidence and multiplicity of mammary gland tumors than mice exposed to fish oil throughout life (F/F group). Mice exposed to fish oil during a portion of life (C/F or F/C) had intermediate incidences and multiplicities. Interestingly, omega 3 in the maternal diet alone decreased tumor multiplicity by 50% compared to no omega 3, even when the mouse received a control diet after weaning. If a mouse, developed a tumor the mean tumor masses were not significantly different though the F/F group had a much smaller mean tumor mass. Adequate omega 3 fatty acids in the maternal diet may reduce risk for mammary gland cancer in the offspring. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1855. doi:10.1158/1538-7445.AM2011-1855

Prenatal Programming of Human Neurological Function

The human placenta expresses the genes for proopiomelanocortin and the major stress hormone, corticotropin-releasing hormone (CRH), profoundly altering the “fight or flight” stress system in mother and fetus. As pregnancy progresses, the levels of these stress hormones, including maternal cortisol, increase dramatically. These endocrine changes are important for fetal maturation, but if the levels are altered (e.g., in response to stress), they influence (program) the fetal nervous system with long-term consequences. The evidence indicates that fetal exposure to elevated levels of stress hormones (i) delays fetal nervous system maturation, (ii) restricts the neuromuscular development and alters the stress response of the neonate, (iii) impairs mental development and increases fearful behavior in the infant, and (iv) may result in diminished gray matter volume in children. The studies reviewed indicate that fetal exposure to stress peptides and hormones exerts profound programming influences on the nervous system and may increase the risk for emotional and cognitive impairment.