Fetal Nervous System Development Research Articles

HDAC1/2/3-mediated downregulation of neurogranin is involved in cognitive impairment in offspring exposed to maternal subclinical hypothyroidism.

Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane-associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS-275 (an HDAC1/2/3-specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3-H3K9ac-Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism-mediated cognitive impairment in the offspring.

Effects of prenatal exposure to THC on hippocampal neural development in offspring

Cannabis use is a worldwide issue with the development of legalization. Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, is related to affect fetal nervous system development. In our present study, we administered THC to pregnant mice from gestational day 5.5–12.5. Differences in neuronal cell composition and organization between the two groups were found by staining sections of the offspring hippocampus at PND21. In addition, RNA-seq of hippocampal tissue also suggested differences in gene expression due to THC treatment, especially significant enrichment to neurogenesis and neural differentiation. Subsequently, the effect of THC treatment on the proliferation and differentiation capacity of neural stem cells (NSCs) was confirmed. Based on the RNA-seq results, we selected the differentially expressed transcription factor MEF2C for validation. The effect of THC treatment on NSCs differentiation was found to be regulated by knocking down the expression of MEF2C in NSCs. Considering that THC is an agonist of cannabinoid receptor (CB1R), the differentiation outcome of NSC after THC treatment was significantly rescued, by pretreating with the CB1R inhibitor Rimonabant. Notably, pretreatment with Rimonabant restored the expression of MEF2C. Taken together, the present results suggested that THC regulated the MEF2C pathway through CB1R and had an impact on hippocampal neurodevelopment.

35.1 Links Between Maternal Gestational Depression, Corticosteroids, and Fetal Heart Rate Variability: Predicting Early Markers of Infant Inhibition and Regulation

Maternal depression during gestation adversely affects fetal nervous system development and may lead to childhood behavioral problems. Mechanisms of adverse effects are less understood, although cortisol secretion is a potential mediator. Limited research has evaluated links between maternal depression, corticosteroids, and early markers of nervous system development, such as fetal heart rate variability (FHRV), cerebral inhibition, or temperament characteristics. Thus, the objectives were to: 1) evaluate associations between maternal depression, corticosteroids, and FHRV; and 2) test whether FHRV predicts markers of infant inhibition and regulatory capacity. Maternal depression and hair concentrations of cortisol and cortisone were measured during gestation. Heart rate was recorded in 23 fetuses by transabdominal Doppler. The SD of interbeat intervals over 20 minutes was computed to assess FHRV. Higher FHRV values reflect greater physiological regulation. Maternal depression, corticosteroid, and FHRV measurement occurred between 28 and 33 weeks gestation. Subsequent markers of infant nervous system development and temperament were assessed. Newborn development of cerebral inhibition was evaluated at 44 weeks gestation through an auditory sensory gating paradigm. Parents rated their infant’s temperamental regulatory capacity when infants were 3 months of age. Maternal depression was associated with lower FHRV, especially for male fetuses (β = –0.633; p = 0.045). Maternal depression was associated with lower cortisol to total corticosteroids ratios (β = –0.519; p = 0.033). Higher cortisol ratios were associated with increased FHRV (β = 0.485; p = 0.019). Higher FHRV was associated with decreased newborn sensory gating deficits (β = –0.992; p = 0.035), indicating better development of cerebral inhibition. Higher FHRV was also related to increased infant regulatory capacity (r = 0.454; p = 0.029). Maternal depression is associated via corticosteroids with decreased FHRV. Decreased FHRV predicted worse infant inhibition and infant regulatory capacity. Conclusions are limited due to the small sample size. Interventions addressing gestational depression may mitigate biologically mediated adverse effects on infants and thus need further study.

Prenatal Stress in Maternal Hyperhomocysteinemia: Impairments in the Fetal Nervous System Development and Placental Function.

The article presents current views on maternal hyperhomocysteinemia (HHcy) as an important factor causing prenatal stress and impaired nervous system development in fetuses and newborns in early ontogenesis, as well as complications in adulthood. Experimental data demonstrate that prenatal HHcy (PHHcy) affects the morphological maturation of the brain and activity of its neurotransmitter systems. Cognitive deficit observed in the offspring subjected to PHHcy in experimental studies can presumably cause the predisposition to various neurodegenerative diseases, as the role of maternal HHcy in the pathogenesis such diseases has been proven in clinical studies. The review also discusses molecular mechanisms of the HHcy neurotoxic action on the nervous system development in the prenatal and early postnatal periods, which include oxidative stress, apoptosis activation, changes in the DNA methylation patterns and microRNA levels, altered expression and processing of neurotrophins, and neuroinflammation induced by an increased production of pro-inflammatory cytokines. Special attention is given to the maternal HHcy impact on the placenta function and its possible contribution to the brain function impairments in the offspring. Published data suggest that some effects of PHHcy on the developing fetal brain can be due to the disturbances in the transport functions of the placenta resulting in an insufficient supply of nutrients necessary for the proper formation and functioning of brain structures.

Zika virus infection induces MiR34c expression in glioblastoma stem cells: new perspectives for brain tumor treatments

Zika virus (ZIKV) is a flavivirus with a marked effect on fetal nervous system development. ZIKV treatment has recently been found to also have a benefit against glioblastoma, a highly aggressive brain tumor with a poor prognosis. The reported data do not completely explain the mechanism beyond this effect. Nevertheless, in the majority of the cases no adverse effect has been found in healthy adult humans. In this study, we characterized the ZIKV infection mechanism on glioblastoma stem cells, which are considered responsible for the tumor progression and resistance to conventional therapies. Moreover, we explain why the action of this virus is directed to the stem cells in the nervous system counterpart. Our results confirm the effectiveness of ZIKV treatment against glioblastoma, indicating novel molecular targets that can be introduced for more powerful therapies.

Assessment of squalene eligibility in bettering some maternal and fetal disorders instigated by gamma irradiation of rats at mid gestation

Purpose: Squalene is an eminent vital part of the synthesis of steroid hormones in the body as well as the first specific intermediate in cholesterol biosynthesis that plays an essential role in normal embryogenesis. The present work was designed to test the maternal and embryonic response to the modulating capacity of squalene (0.4 ml/kg/d), when supplemented to rats from days 1 to 18 of pregnancy, against the damaging consequences induced by maternal subjection to 3 Gy gamma irradiation on day 10 post-conception.Materials and methods: The experimental protocol comprised of four different pregnant groups, namely: (1) control, (2) squalene supplemented, (3) irradiated and (4) squalene supplemented + irradiated.Results: It has been detected that radiation has increased the maternal blood lactate dehydrogenase (as a marker of tissue injury), cholesterol, triglycerides, estradiol and progesterone and has also provoked the oxidative stress that has been demonstrated by the increased malondialdehyde (MDA) and the decreased glutathione (GSH) and superoxide dismutase (SOD). These maternal changes were associated with high embryonic lethality, growth retardation, severe developmental abnormalities and defective neural tube closure expressed by exencephaly. However, squalene treatment has significantly improved the radiation imposed maternal variations and reduced the embryonic mortality, although it has not been able to attenuate the embryonic neural tube defects.Conclusions: It has been presumed that the maternal mid-gestational irradiation (day 10) has affected the fetal nervous system development with concomitant maternal oxidative stress, hyperlipidemia, and increased progesterone and estradiol levels. Squalene uptake has improved the maternal variations and reduced the embryonic mortality while could not stop or improve the embryonic neural tube defects imposed by radiation at this exact radiation timing.

Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure.

Placental transfer of Δ9-tetrahydrocannabinol (THC) during pregnancy has the potential to interfere with endogenous cannabinoid regulation of fetal nervous system development in utero. Here we examined the effect of maternal cannabinoid intake on mouse hippocampal interneurons largely focusing on cholecystokinin containing interneurons (CCK-INTs), a prominent cannabinoid subtype 1 receptor (CB1R) expressing neuronal population throughout development. Maternal treatment with THC or the synthetic CB1R agonist WIN55,212-2 (WIN) produced a significant loss of CCK-INTs in offspring. Further, residual CCK-INTs in animals prenatally treated with WIN displayed decreased dendritic complexity. Consistent with these anatomical deficits, pups born to cannabinoid treated dams exhibited compromised CCK-INT mediated feedforward and feedback inhibition. Moreover, pups exposed to WIN in utero lacked constitutive CB1R mediated suppression of inhibition from residual CCK-INTs, and displayed altered social behavior. Our findings add to a growing list of potential cell/circuit underpinnings that may underlie cognitive impairments in offspring of mothers that abuse marijuana during pregnancy.

Decabrominated diphenyl ether and methylmercury impair fetal nervous system development in mice at documented human exposure levels.

The central nervous system (CNS) is extremely vulnerable to the toxic effects of environmental pollutants during development. Polybrominated diphenyl ethers (PBDEs) are persistent contaminants, increasingly present in the environment and in human tissues. Recent investigations identified a correlation between maternal exposure to PBDEs and impairment in fetal neurobehavioral development, suggesting that these contaminants pose a potential risk for children. We investigated on the potential effects of environmental decabrominated diphenyl ether (decaBDE, the fully brominated congener) on key neurodevelopmental molecules (e.g., synaptic proteins and immature neuron markers) in fetal mouse neurons. Methylmercury was used as reference neurotoxic contaminant and to evaluate its possible synergism with decaBDE. The neurotoxic effects of decaBDE and methylmercury were determined in developing cultured neurons from mouse fetal hippocampus and cerebellum. Neuron death, dendritic branching, synaptic protein expression, markers of immature neurons, and microglia activation were evaluated by immunocytochemistry. Brain samples from prenatally treated embryos were also examined for neurotoxicity signs by immunoblotting and histochemistry. DecaBDE significantly affected (down to 0.4 nM) the number of dendritic branches, and the levels of synaptic proteins and doublecortin in cultured neurons. Prenatal exposure to decaBDE decreased the synaptic proteins and increased the expression of the immature neuron and microglial markers in mouse fetuses. In conclusion, prenatal exposure to realistic (relevant for human exposure) concentrations of decaBDE induces impairment of fetal CNS development in mice, suggesting a potential risk of fetotoxicity in humans.

Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats

Major depression is one of the most prevalent mental disorders in the population. In addition to genetic influences, disturbances in fetal nervous system development might be a contributing factor. Maternal infection during pregnancy may affect fetal brain development and consequently lead to neurological and mental disorders. Previously, we used low-dose lipopolysaccharide (LPS) exposure on embryonic day 10.5 to mimic mild maternal infection in rats and found that dopaminergic and serotonergic neurons were reduced in the offspring. The offspring also showed more anxiety-like behavior and an enhanced stress response. In the present study we used forced swim test and chronic mild stress challenge to assess depression-like behaviors in the affected offspring and examined their adult hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) concentration. Our results showed that prenatally LPS-exposed rats (LPS rats) displayed more depression-like behaviors and had reduced adult neurogenesis and BDNF. The behavioral abnormalities and reduction in adult neurogenesis could be reversed by chronic fluoxetine (FLX) treatment. This study demonstrates that during the critical time of embryonic development LPS exposure can produce long-term behavioral changes and reduction in adult neurogenesis. The findings of enhanced depression-like behaviors, reduced adult neurogenesis, and their responsiveness to chronic antidepressant treatment suggest that prenatal LPS exposure could serve as an animal model of depression.

What should Medical Students Know and Understand about Fetal Ultrasonography of the Nervous System?

Abstract Evaluation of the developing nervous system is a standard and relatively sensitive component of routine fetal ultrasonography. Medical school learning objectives should direct students to consolidate core concepts related to normal and abnormal fetal nervous system development through critical observation of this commonly performed clinical procedure.

Maternal Diesel Exhaust Exposure Damages Newborn Murine Brains

To examine pathologically the influence of diesel exhaust (DE) exposure on fetal nervous system development, brain tissue (cerebral cortex and hippocampus) was collected from newborn mice whose mothers were exposed to DE during pregnancy. After DE exposure, these brain tissues showed evidence of numerous caspase 3-positive cells (a common enzymatic biomarker of apoptosis). Some cells were found to contain crescent-shaped spaces, which are suggestive of apoptotic processes. Granular perithelial (GP) cells, scavenger cells surrounding cerebral vessels of the blood-brain barrier, showed signs of apoptosis; furthermore, the GP cytoplasmic granules had degenerated and showed evidence of what appeared to be ultrafine, DE particles. Additionally, the swelling of astrocyte endfoot that surround capillaries showed degenerative changes similar to myelin figures. Furthermore, the apoptosis of endothelial cells and stenosis of some capillaries were observed. These findings varied in severity, depended on DE concentration, and were not observed in the control group. These observations suggest that exposure of pregnant mice to DE might carry a risk of cellular atrophy and might affect fetal brain development. Our findings also reveal that inhalation of DE might be hazardous to the general health of fetuses.