The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring

Hameete, Bart C.; Fernández-Calleja, José M. S.; Groot, Martje W G D M de; Oppewal, Titia Rixt; Tiemessen, Machteld M.; Hogenkamp, Astrid; Vries, Rob B. M. de; Groenink, Lucianne

doi:10.1016/j.bbih.2020.100192

Cited by 25 publications

(23 citation statements)

References 82 publications

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“…Several genes and gene families in the cell adhesion molecules pathway that presented differential expression across MIA groups have been previously associated with a prenatal immune challenge ( Table 2 ). Consistent with our findings on selectin genes, including SELP , SELL , and SELE , MIA disrupted the expression of genes SELP and SELL in mice brains [ 61 ]. Moreover, consistent with the detected patterns of multiple integrins including ITGB2 , ITGA4 , ITGB7 , and ITGAL , detected in the present study, the expression of the neurodevelopmental gene ITGB2 was altered in the brain of individuals diagnosed with SSD or ASD [ 62 ].…”

Section: Discussionsupporting

confidence: 91%

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure

Rymut

Rund

Southey

et al. 2022

Genes

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The influence of proinflammatory challenges, such as maternal immune activation (MIA) or postnatal exposure to drugs of abuse, on brain molecular pathways has been reported. On the other hand, the simultaneous effects of MIA and drugs of abuse have been less studied and sometimes offered inconsistent results. The effects of morphine exposure on a pig model of viral-elicited MIA were characterized in the prefrontal cortex of males and females using RNA-sequencing and gene network analysis. Interacting and main effects of morphine, MIA, and sex were detected in approximately 2000 genes (false discovery rate-adjusted p-value < 0.05). Among the enriched molecular categories (false discovery rate-adjusted p-value < 0.05 and −1.5 > normalized enrichment score > 1.5) were the cell adhesion molecule pathways associated with inflammation and neuronal development and the long-term depression pathway associated with synaptic strength. Gene networks that integrate gene connectivity and expression profiles displayed the impact of morphine-by-MIA interaction effects on the pathways. The cell adhesion molecules and long-term depression networks presented an antagonistic effect between morphine and MIA. The differential expression between the double-challenged group and the baseline saline-treated Controls was less extreme than the individual challenges. The previous findings advance the knowledge about the effects of prenatal MIA and postnatal morphine exposure on the prefrontal cortex pathways.

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Section: Discussionsupporting

confidence: 91%

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure

Rymut

Rund

Southey

et al. 2022

Genes

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“…Research indicates that PAX6, and other transcriptional regulators of neurogenesis, may be directly controlled by inflammatory mediators which are upregulated in the MIA offspring brain ( Loayza et al, 2022 ), such as microglia ( Cunningham et al, 2013 ) and cytokines ( Walter et al, 2011 ; Borsini et al, 2015 ). However, a number of studies report no changes to inflammation status within the fetal MIA offspring brain (see Hameete et al, 2021 ), yet neurogenesis is defective across the prenatal timeline ( Tables 1 – 3 ). Epigenetic mechanisms are believed to mediate the prolonged effects of MIA on the offspring brain and behavioral phenotypes ( Bergdolt and Dunaevsky, 2019 ), and hence, considering epigenetics is critical for healthy neurogenesis ( Albert et al, 2017 ; Albert and Huttner, 2018 ), could provide a basis for putative causative mechanisms.…”

Section: Causative Mechanismsmentioning

confidence: 99%

The impact of maternal immune activation on embryonic brain development

2023

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The adult brain is a complex structure with distinct functional sub-regions, which are generated from an initial pool of neural epithelial cells within the embryo. This transition requires a number of highly coordinated processes, including neurogenesis, i.e., the generation of neurons, and neuronal migration. These take place during a critical period of development, during which the brain is particularly susceptible to environmental insults. Neurogenesis defects have been associated with the pathogenesis of neurodevelopmental disorders (NDDs), such as autism spectrum disorder and schizophrenia. However, these disorders have highly complex multifactorial etiologies, and hence the underlying mechanisms leading to aberrant neurogenesis continue to be the focus of a significant research effort and have yet to be established. Evidence from epidemiological studies suggests that exposure to maternal infection in utero is a critical risk factor for NDDs. To establish the biological mechanisms linking maternal immune activation (MIA) and altered neurodevelopment, animal models have been developed that allow experimental manipulation and investigation of different developmental stages of brain development following exposure to MIA. Here, we review the changes to embryonic brain development focusing on neurogenesis, neuronal migration and cortical lamination, following MIA. Across published studies, we found evidence for an acute proliferation defect in the embryonic MIA brain, which, in most cases, is linked to an acceleration in neurogenesis, demonstrated by an increased proportion of neurogenic to proliferative divisions. This is accompanied by disrupted cortical lamination, particularly in the density of deep layer neurons, which may be a consequence of the premature neurogenic shift. Although many aspects of the underlying pathways remain unclear, an altered epigenome and mitochondrial dysfunction are likely mechanisms underpinning disrupted neurogenesis in the MIA model. Further research is necessary to delineate the causative pathways responsible for the variation in neurogenesis phenotype following MIA, which are likely due to differences in timing of MIA induction as well as sex-dependent variation. This will help to better understand the underlying pathogenesis of NDDs, and establish therapeutic targets.

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“… 120–122 Maternal cytokine elevation results in subsequent production of inflammatory mediators in the fetal brain, 123 and increased concentrations of some cytokines can be detected during postnatal development, 124 though precisely which mediators are altered at which time points vary between studies. 125 Microglia from MIA offspring display an altered phenotype characterized by premature induction of the mature gene signature in neonatal pups, as well as decreased phagocytosis and higher basal expression of inflammatory genes in adulthood. 11 , 126 While these results in combination with human data suggest that microglial dysfunction can promote ASD pathogenesis, the exact contribution of microglia to cognitive and behavioral outcomes is still unclear, and many studies report conflicting results with regard to microglial reactivity following MIA.…”

Section: Microbiome-microglia Interactionsmentioning

confidence: 99%

Regulation of microglial physiology by the microbiota

Cook

Prinz

2022

Gut Microbes

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The mammalian gut contains a large, complex community of microorganisms collectively termed the microbiota. It is increasingly appreciated that gut microbes are closely integrated into mammalian physiology, participating in metabolic symbiosis, promoting immune function and signaling to a wide variety of distant cells, including the brain, via circulating metabolites. Recent advances indicate that microglia, the brain’s resident immune cells, are influenced by microbial metabolites at all stages of life, under both physiological and pathological conditions. The pathways by which microbiota regulate microglial function are therefore of interest for investigating links between neurological disorders and gut microbiome changes. In this review, we discuss the effects and mechanisms of microbiota-microglia signaling in steady state, as well as evidence for the involvement of this signaling axis in CNS pathologies.

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The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring

Cited by 25 publications

References 82 publications

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure

The impact of maternal immune activation on embryonic brain development

Regulation of microglial physiology by the microbiota

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