Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

Project description:Zika virus (ZIKV) has emerged as a significant public health concern due to its association with severe neurological outcomes in infants, including microcephaly and congenital Zika syndrome (CZS). However, while the majority of ZIKV infections during pregnancy do not result in CZS, the potential long-term neurological effects of mild or inapparent maternal infections remain poorly understood. In this study, we adapted a model of maternal ZIKV infection in human STAT2 knock-in (hSTAT2) mice to investigate the effects of ZIKV infection during mid-gestation, aiming to mirror typical asymptomatic infections as they occur in humans. We found that maternal ZIKV infection at mid-gestation leads to vertical transmission without causing overt developmental deficits or clinical signs in dams or offspring. Despite the absence of immediate clinical signs, transcriptomic analyses revealed significant changes in the developing fetal brain, particularly in genes related to synaptic function and neuronal development. These molecular alterations were associated with increased synaptic density in the hippocampus and heightened susceptibility to chemically induced seizures in offspring, suggesting subtle yet significant long-term neurological consequences. Using motion sequencing (MoSeq), an unsupervised machine learning approach that profiles naturalistic motor behavior, we also identified persistent, sex-biased alterations in the content and structure of spontaneous behavior in offspring exposed to maternal ZIKV infection. Our findings highlight that even mild maternal ZIKV infections can disrupt fetal neurodevelopment, underscoring the need for enhanced monitoring and public health measures for children exposed to ZIKV in utero but who do not experience severe developmental alterations at birth. Additionally, our study provides a valuable animal model and comprehensive, cell type-specific transcriptomic datasets that will facilitate new lines of investigation into the impact of inapparent maternal ZIKV infections on fetal and childhood brain development.

Project description:Activation of the maternal immune system during pregnancy can fetal development, which can lead to postnatal susceptibility to a wide range of diseases, including cardiovascular, metabolic and psychiatric disorders. During maternal immune activation (MIA), the maternal body must balance its ressources between mounting an immune response and investing resources into continued metabolism and growth : both essential for survival of the fetus and a successful pregnancy. How the placenta responds to MIA over time and how it can protect the fetus is not well understood, and neither are the fetal consequences of MIA. Here, we characterised the response to an induced acute inflammation in maternal lungs over time across maternal and fetal organs, using a combination of omics-methods, imaging and integrative computational analysis. We found that the placenta, unlike other maternal organs, did not react by inducing a typical inflammatory response, but instead initially induced genes associated to strengthen tissue integrity and simultaneously reduced growth to prevent exposure to potential infections. Afterwards, a return to homeostasis was observed, with heightened biosynthesis and expression of endoplasmic reticulum (ER) stress genes. This mechanism likely protects the fetus from inflammation, as we observed no immune response in the fetal liver transcriptome. Instead, we observed metabolic adaptations in the fetus, including a release of docosahexaenoic acid (DHA) Notably, DHA has a crucial function for fetal brain development , and levels of triglyceride and phosphatidylcholine lipids that are necessary for transportation of DHA to the brain were also increased. This metabolic response is likely a combination of the placental MIA response and temporary maternal fasting, caused by MIA-induced fever and lack of nutrient intake. Our study shows, for the first time, the temporal and systemic response to MIA in lungs across maternal and fetal organs.

			Action	DRS
	SRR11348219_1.fastq.gz	Fastqsanger.gz
	SRR11348219_2.fastq.gz	Fastqsanger.gz
	SRR11348220_1.fastq.gz	Fastqsanger.gz
	SRR11348220_2.fastq.gz	Fastqsanger.gz
	SRR11348221_1.fastq.gz	Fastqsanger.gz

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Maternal microbiome modulation of fetal brain development and sensory behavior

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