Embryonic and adult synaptic proteome analysis following maternal immune activation
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Brain
SUBMITTER: 
Anna Y. Yotova
LAB HEAD: David Slattery
PROVIDER: PXD043094 | Pride | 2024-07-31
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| 23122023_LLi_AYotova_MIA_reports_ADULTS.xlsx | Xlsx | |||
| 23122023_LLi_AYotova_MIA_reports_EMBRYOS.xlsx | Xlsx | |||
| A0_M0.raw | Raw | |||
| A2-5_M2-5.raw | Raw | |||
| A5_M5.raw | Raw |
Items per page: 5 1 - 5 of 22 |
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Project description:Maternal immune activation (MIA) is reported to increase the risk of psychiatric disorders in the offspring. However, the underlying mechanism remains unclear. Here, we constructed an MIA mouse model by intraperitoneal injection of LPS into pregnant mice and evaluated the behaviors and gene expression profiles in the brains of the female and male offspring, respectively. We found that the MIA female offspring exhibited increased anxiety and a large number of differentially expressed genes (DEGs) in the brain, which were enriched with disease genes of psychiatric disorders and immune functions. In contrast, the MIA male offspring exhibited no significant abnormal behaviors and only a small number of DEGs, which were not enriched with disease genes and immune functions. Therefore, we further pursued the downstream study on the molecular mechanism underlying the increased anxiety in the female offspring. We identified the lncRNA AU020206-IRFs-STAT1-cytokine axis by integrating lncRNA-protein interaction data and TF-promoter interaction data and verified the axis in vitro and in vivo. The female mice with overexpression of AU020206 in the prefrontal cortex exhibited anxiety behaviors. This study illustrates that MIA upregulates the AU020206-IRFs-STAT1 axis in controlling the brain immunity linked to abnormal behaviors, providing a basis for understanding the role of MIA in psychiatric disorders.
2024-10-09 | GSE233424 | GEO
Project description:BACKGROUND: Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly un- derstood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates. METHODS: We performed RNA sequencing across psychiatrically relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus) and primary visual cortex for comparison from 3.5- to 4-year-old male MIA-exposed and control offspring—an age comparable to mid adolescence in humans. RESULTS: We identify 266 unique genes differentially expressed in at least one brain region, with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Although we observed temporal and regional differences, transcriptomic changes were shared across first- and second-trimester exposures, including for the top differentially expressed genes—PIWIL2 and MGARP. In addition to PIWIL2, several other regulators of retrotransposition and endogenous transposable elements were dysregulated following MIA, potentially connecting MIA to retrotransposition. CONCLUSIONS: Together, these results begin to elucidate the brain-level molecular processes through which MIA may impart risk for psychiatric disease
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Project description:Background: Environmental insults that activate the maternal immune system are potent primers of developmental neuropathology and maternal immune activation (MIA) has emerged as a risk factor for neurodevelopmental and psychiatric disorders. Animal models of MIA provide an opportunity to identify molecular pathways that initiate disease processes and lead to neuropathology and behavioral deficits in offspring. MIA-induced behaviors are accompanied by anatomical and neurochemical alterations in adult offspring that parallel those seen in affected human populations. Methods: We performed transcriptional profiling and neuroanatomical characterization in a time course across mouse embryonic cortical development, following MIA via single injection of the viral mimic polyinosinic:polycytidylic acid (polyI:C) at E12.5. Transcriptional changes identified in the cortex of MIA offspring at E17.5 were validated and mapped to cortical neuroanatomy and cell types via protein analysis and immunohistochemistry. Results: MIA induced strong transcriptomic signatures, including induction of genes associated with hypoxia, immune signaling, and angiogenesis. The acute response identified 6h after the MIA insult was followed by changes in proliferation, neuronal and glial differentiation, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cell types in germinal zones and alterations in neuronal and glial cell types across cortical lamina were identified in the MIA-exposed cortex. Conclusions: MIA-induced transcriptomic signatures in fetal offspring overlap significantly with perturbations identified in neurodevelopmental disorders (NDDs), and provide novel insights into alterations in molecular and developmental timing processes linking MIA and neuropathology, potentially revealing new targets for development of novel approaches for earlier diagnosis and treatment of these disorders.
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Project description:Maternal infection and inflammation during pregnancy is associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. We leveraged single-cell RNA sequencing to profile transcriptional changes in the rodent fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis, and stress signaling. We found that MIA specifically activated the integrated stress response (ISR) in male, but not female, MIA offspring, thereby reducing global mRNA translation and altering nascent proteome synthesis. Moreover, genetic blockade of ISR activation rescued the social behavior phenotype in MIA male offspring. Our data suggest that therapeutic targeting of the ISR may be beneficial in reducing maternal inflammation-associated neurodevelopmental disorders.
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Project description:Infection during pregnancy is strongly implicated as an environmental risk factor for autism spectrum disorder (ASD), with activation of the maternal immune system (MIA) identified in the causative pathway. Maternal exposure to viral and bacterial mimics at midgestation leads to the development of core ASD behaviors in rodent offspring. However, the fundamental pathogenic mechanisms coupling MIA to persistent changes in brain function and behavior are incompletely understood.The medial prefrontal cortex (mPFC) is a major locus of pathology in ASD and highly associated with behaviors dysregulated by MIA. Transcriptomic profiling of the mPFC from adult MIA and control offspring provides insight into molecular pathways persistently disrupted by prenatal exposure to maternal inflammation.
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Project description:In this study, we aim to demonstrate the immunomodulatory mechanisms of maternal VitD on the offspring. We found that high maternal VitD levels rescue the abnormal immune phenotype caused by maternal immune activation (MIA), and inhibit the transformation of CD4+ T cells into a pro-inflammatory phenotype through a maternal VitD concentration-dependent regulation of metabolism and epigenetic reprogramming. Furthermore, we identified critical windows for maternal VitD regulation of offspring immunity, as well as the long-term impacts of MIA.
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Project description:Early-life exposure to high-fat diet (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by Barnes maze test were observed both in 6-month-old male and female mice. Multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies, that were confirmed by regulon analysis, showing that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.
2024-01-26 | PXD045639 | Pride
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.
2024-06-13 | PXD039402 | Pride
Project description:Introduction: Maternal immune activation (MIA), characterized by increased circulating inflammatory mediators during pregnancy, is associated with adverse pregnancy outcomes and neurodevelopmental deficits in offspring. These health outcomes often manifest differently depending on fetal-placental sex. A well-established model of MIA involves administration of a viral mimetic, polyinosinic:polycytidilic acid (PolyI:C), to pregnant rodents. Placental responses to PolyI:C contribute to the detrimental effects of MIA on offspring, but these responses have not yet been well characterized. In the present study, we profiled acute gene expression changes in male and female placentas following PolyI:C administration to pregnant rats. Methods: Pregnant rats received 4 mg/kg PolyI:C or saline intravenously on gestational day 18.5, and tissues were harvested 4-5 hours later. Gene expression profiling on placental tissue was performed. Enzyme immunoassays and immunohistochemistry were conducted to determine levels of select proteins in maternal blood and placental tissue, respectively. Results: Maternal PolyI:C exposure caused a robust increase in levels of inflammatory markers in maternal blood and placental tissue. There were more genes differentially expressed in female placentas after PolyI:C exposure (765) than male placentas (221), including reduced expression of genes associated with maternal-fetal communication. Placentas also had increased expression of genes linked with vascular dysfunction after PolyI:C-induced MIA. Discussion: PolyI:C elicited a powerful inflammatory response in the placenta along with vascular dysfunction, likely contributing to the adverse pregnancy outcomes triggered by MIA. Female placentas responded to PolyI:C more vigorously than male placentas, which could underlie the differential outcomes of MIA depending on sex.
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2018-10-26 | PXD004073 | Pride