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Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Adult_MACS]

ABSTRACT: Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naïve microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.

ORGANISM(S): Mus musculus

PROVIDER: GSE201812 | GEO | 2022/07/01

REPOSITORIES: GEO

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Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Adult_ATAC-seq]

Project description:Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naïve microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.

2022-07-01 | GSE201815 | GEO

Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Adult_scRNA-seq]

Project description:Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naïve microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.

2022-07-01 | GSE201814 | GEO

Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Adult_FACS]

2022-07-01 | GSE201813 | GEO

Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Adult_Rescue]

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Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Neonatal_MACS]

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Prenatal exposure to environmental toxins induces sexually dimorphic transcriptome changes in neonatal offspring

Project description:Purpose: Gestational exposure to environmental toxins and socioeconomic stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism. We modeled these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activated the maternal immune system. Only male offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminished microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Genetic ablation of microglia during the same critical period mimicked the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development.

2020-10-29 | GSE160344 | GEO

Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Neonatal_MACS]

Project description:Prenatal immune stress blunts microglia reactivity which impairs neurocircuitry [Neonatal_MACS]

| PRJNA833084 | ENA

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

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.

2018-07-26 | GSE117327 | 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

Microglia development follows a stepwise program to regulate brain homeostasis - ChIP-seq

Project description:Microglia play important roles in life-long brain maintenance and in pathology, but are also crucial in the developing central nervous system; yet their regulatory dynamics during development have not been fully elucidated. Genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development reveal that microglia undergo three temporal developmental stages in synchrony with the brain: early, pre-, and adult microglia, which are under the control of distinct regulatory circuits. Knockout of the transcription factor MafB caused disruption of homeostasis in adulthood and increased inflammation. Environmental perturbations, such as the microbiome or prenatal immune activation, led to dysregulation of the developmental program, particularly in terms of inflammation. Together, our work identifies a stepwise developmental program of microglia integrating immune response pathways that may be associated with several neurodevelopmental disorders.

2016-07-13 | GSE79816 | GEO

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