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Persistent transcriptomic alterations in medial prefrontal cortex after prenatal exposure to maternal inflammation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE117327 | GEO | 2018/07/26

REPOSITORIES: GEO

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Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Project description:Maternal immune activation (MIA)puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through the maternal, placental, and fetal compartments contribute to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, pregnant rat dams were treated with the clinically available 11β-hydroxylase inhibitor metyrapone, alongside administration of the bacterial mimetic lipopolysaccharide (LPS), on gestational day 15. Maternal, placental, and fetal CNS levels of corticosterone and placental 11ßHSD enzymes type 1 and 2 were measured 3-hrs post treatment. Subsequently, offspring social behaviors were measured across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11ßHSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure protected against MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Transcriptomic analyses revealed that metyrapone-exposure triggered opposing effects on gene expression to combat MIA-exposure in males, but not among females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinical drug already provided to pregnant people and neonates for the treatment of hypercortisolism, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.

2023-08-15 | GSE240604 | GEO

Fetal toll-like receptor 3 signalling contributes to the induction of autism-like behaviors in a mouse model of maternal immune activation

Project description:A mouse model of maternal immune activation (MIA) is commonly used to study neurodevelopmental disorders. Gene expression analysis has suggested that fetal brain macrophages may be activated by MIA, but it is unclear whether these transcriptional changes connect to behavioral phenotypes in offspring. Here, we have shown that the induction of autism spectrum disorder (ASD)-like behavioral phenotypes by MIA in male offspring is dependent upon fetal activation of the toll-like receptor 3 (TLR3) signaling molecule TRIF. Using single-cell RNA sequencing, we identified a cluster of border-associated macrophages (BAMs) that was significantly enriched in wild-type fetal brains following TLR3-MIA but not diminished in Trif -/- fetal brains. Moreover, after TLR3-MIA, the number of fetal BAMs in the choroid plexus, but not in the meninges, was increased, and these cells were characterized by increased S100a8/9 expression. Finally, we proposed that activation of fetal TLR3-TRIF signaling was induced by transplacental viral infection. Overall, our data suggest that fetal TLR3 signaling contributes to MIA-induced ASD-like behavioral phenotypes in mice.

2022-02-08 | GSE196151 | GEO

A temporal map of maternal immune activation-induced changes reveals a shift in neurodevelopmental timing and perturbed cortical development in mice

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.

2021-02-09 | GSE166376 | GEO

Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response.

Project description:Maternal immune activation is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment with sub-sequence effects of CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on embryonic day 15. LPS significantly elevated pro-inflammatory cytokines in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-dams exhibited reduced social and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate possible molecular mechanisms by which MIA effects the fetal brain. We observed dysregulation of 3,285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons. 19 Fetal Rat Brain Samples: 10 (-) LPS, 9 (+) LPS.

2012-07-25 | E-GEOD-34058 | biostudies-arrayexpress

Early or Late Gestational Exposure to Maternal Immune Activation Alters Neurodevelopmental Trajectories in Mice: An Integrated Neuroimaging, Behavioral, and Transcriptional Study

Project description:Background: Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear. Methods: We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing. Results: Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation. Conclusions: Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.

2021-06-18 | GSE178403 | GEO

Maternal Immune Activation Disrupts Proteostasis in the Fetal Brain

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.

2020-11-09 | GSE148237 | GEO

Microglial transcriptome of Maternal Immune Activation model at different developmental Stages and after microglia repopulation

Project description:To determine the transcriptomic changes underlying the MIA microglia phenotype and their reversal by PLX, we performed RNA-sequencing of magnetic CD11B beads-isolated microglia from the whole brain in Saline and MIA male and female offspring at E17, P7, P20, and P60, as well as from MG-REP male and female offspring at P60. Microglial transcriptome reveals novel MIA and repopulation modules and overlap of MIA microglial genes with ASD gene network. 14,225 microglial genes from RNA-seq data revealed distinct transcriptional signatures of immature microglia (IM module, 4681 transcripts, enriched in E17 and P7 Saline), MIA immature microglia (MIA-IM module, 2816 transcripts, enriched in E17 and P7 MIA), Juvenile microglia (JM module, 2318 transcripts, enriched in P20 Saline and MIA), Adult microglia (AM module, 3276 transcripts, enriched in P60 Saline + CTRL, P60 MIA + CTRL and P60 MIA + MG-REP), and repopulated adult microglia (REP-AM module, 1,134 transcripts, enriched in P60 Saline + MG-REP)

2020-03-06 | GSE146526 | GEO

Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral organoids

Project description:Maternal obesity raises the risk of high-cholesterol exposure for their offspring. Studies in cohorts and animal models report that maternal obesity could increase the risk of neurodevelopmental disorders (NDDs) in offspring including intellectual disabilities and autism spectrum disorders (ASD). However, whether exposure to high cholesterol is responsible for brain developmental defects, as well as its underlying mechanism, is still unclear. Here, we constructed a cholesterol exposure model utilizing hiPSC-derived cerebral organoids by exogenously adding cholesterol into the culture system. We preformed scRNA sequence analysis to explore the gene expression changes in brain organoids under additional cholesterol exposure.

2022-12-31 | GSE206587 | GEO

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates

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

2022-03-04 | GSE197605 | GEO

Cytogenetics 2.7M and Cytoscan HD 2.8M Microarrays in autistic families in the Lebanese population

Project description:Autism spectrum disorder (ASD) affects these core domains: ritualistic-repetitive behaviors, impaired social interaction, and deficits in non-verbal communication/language development. Although ASD is heritable, its extreme heterogeneity defies genetic analyses. A number of ASD susceptibility genes have been identified. The Lebanese population is ideal for uncovering recessive genes because of a high rate of shared ancestry, consanguineous marriages, and high number of offspring per family. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33). Cytogenetics 2.7M Microarrays/CytoScanâ¢ HD arrays allowed mapping of homozygous regions of the genome.

2017-07-24 | E-MTAB-4963 | biostudies-arrayexpress

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