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Maternal antioxidant treatment prevents behavioural and neurological changes in offspring exposed to prenatal social stress [RNA-seq]

ABSTRACT: Maternal exposure to social stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. How the effects of maternal social stress are transmitted to the developing foetus is unclear. Using a rat model of maternal social stress during pregnancy, we explored the mechanisms by which maternal stress is conveyed to the foetus and the potential for targeted treatment to prevent disease in the offspring. Maternal stress induced oxidative stress in the placenta, but not in the foetal brain, which was prevented by a single administration of nanoparticle-bound antioxidant prior to the stress exposure. Moreover, this antioxidant treatment prevented prenatal stress-induced anxiety-like behaviour in juvenile male offspring, along with neurological and gene expression changes in the offspring brain. In vitro, placental conditioned medium or foetal plasma from stressed pregnancies caused changes to cultured cortical neurons, similar to those observed in the brains of juvenile offspring exposed to prenatal stress, and were found to contain altered levels of extracellular microRNAs but not corticosterone. The present study highlights the crucial role of the placenta, and molecules secreted from the placenta, in foetal brain development and provides evidence of the potential for treatment that can prevent maternal stress-induced foetal programming of neurological disease.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE131040 | GEO | 2024/04/22

REPOSITORIES: GEO

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Project description:Prenatal development is a critical period for programming of neurological disease. Preeclampsia, a pregnancy complication involving oxidative stress in the placenta, has been associated with long-term health implications for the child, including an increased risk of developing schizophrenia and autism spectrum disorders in later life. We have shown previously, in a rodent model of placental oxidative stress, that culture medium conditioned by the placenta alters neuronal characteristics when applied to primary cortical cultures in vitro and mimics many of the neurodevelopmental changes observed in the offspring brain. To further investigate if molecules released by the placenta may be important mediators in foetal programming of the brain, we analysed if placental tissue delivered from patients with preeclampsia secreted molecules that could affect cortical cells in culture. Application of culture medium conditioned by preeclamptic placentae to mixed cortical cultures caused changes in neurons and astrocytes that were related to key changes observed in brains of patients with schizophrenia and autism, including effects on dendrite lengths, astrocyte number as well as glutamate and GABA receptors. Treatment of the placental explants with an antioxidant prevented neuronal abnormalities. Furthermore, we identified that bidirectional communication between neurons and astrocytes, potentially via glutamate, is required to produce the effects of preeclamptic placenta medium on cortical cells. Analysis of possible signalling molecules in the placenta conditioned medium showed that the secretion profile of extracellular microRNA, small posttranscriptional regulators, was altered in preeclampsia and partially rescued by antioxidant treatment of the placental explants. Predicted targets of these differentially abundant microRNAs were linked to neurodevelopment and the placenta. The presented study provides further evidence that the diseased placenta may release factors that damage cortical cells in the brain and suggests the possibility of targeted antioxidant treatment of the placenta to prevent neurodevelopmental disorders.

Project description:The aim of this work was to evaluate the influence of maternal and embryonic genotype of two lines of rabbit selected by growth rate (line R) and litter size at weaning (line A) on foetal and placental growth. Embryos were recovered at 48 h of gestation from line R (46) and line A (40) donors and transferred to nulliparous recipient does (26 R and 24 A). Each recipient doe received six embryos into one oviduct from line R and six embryos form line A into the other. Laparoscopy was performed at day 14 to determine implantation rate. Recipient females were slaughter at day 14, 24 and 30 (12, 24, 14, respectively) to determine the number of live fetuses and the weight of live foetuses, foetal placenta and maternal placenta. To analyze endocrine levels, blood serum was collected from 14 females at 14, 21 and 28 days of gestation. A transcriptome analysis was performed to search for differences between foetal placentas at day 14 and 24 of development. Foetal survival at Days 14, 24 and 30, and weight at Day 14 was higher for line A embryos, being the weight higher for AA genotype (0.29Â±0.01g vs. 0.19Â±0.01g ,for RR genotype). Only the R embryonic genotype showed higher foetal weight at Day 30 (53.4 Â± 1.74 vs. 48.5 Â± 1.81, for line R and line A foetuses). However, foetal and maternal placentas were higher for RR genotype on Day 24 and 30. No differences in foetal placenta at transcriptome level were found. Additionally, both progesterone and IGF-I levels were similar between lines. In conclusion, line R presented reproductive troubles, with higher gestational losses at embryonary level at Day 14 and 24, and uterine environment problems at least at last part of gestation which reduced survival rate of A line foetuses. Embryos were recovered at 48 h of gestation from line R and line A donors and transferred to nulliparous recipient does. Recipient females were slaughter at Day 14 and 24, and a transcriptomic comparison analysis was performed from foetal placenta tissue.

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Maternal antioxidant treatment prevents behavioural and neurological changes in offspring exposed to prenatal social stress [RNA-seq]

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