Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring

Kreitz, Silke; Zambon, Alice; Ronovsky, Marianne; Budinský, Luboš; Helbich, Thomas H.; Sideromenos, Spyridon; Ivan, Claudiu; Konerth, Laura; Wank, Isabel; Berger, Angelika; Pollak, Arnold; Heß, Andreas; Pollak, Daniela D.

doi:10.1016/j.bbi.2019.09.011

Cited by 40 publications

(27 citation statements)

References 63 publications

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“…These findings suggest that brain connectivity is more profoundly altered in MIA-exposed offspring that show behavioral impairments, as compared to MIA offspring lacking overt behavioral anomalies. Consistent with this view, Krietz et al [53] provide evidence for abnormal brain functional connectivity in poly(I:C)-exposed mice, as indexed using resting-state functional MRI. Interestingly, the disruption of RSC structural covariance in susceptible MIA-exposed offspring resembles the impairments in RSC connectivity to the anterior cingulate cortex and other default mode network structures in patients with schizophrenia [54] and in individuals with social anhedonia [55].…”

Section: Discussionmentioning

confidence: 78%

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

et al. 2020

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Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.

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Section: Discussionmentioning

confidence: 78%

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

et al. 2020

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“…The injection volume was 10 mL/kg bodyweight in each case. The administration protocol was chosen based upon the authors' own previous studies demonstrating behavioral and neural alterations relevant for depression in the adult MIA offspring [4,9,11,19]. A detailed maternal immune activation checklist [20] is provided in Supplementary Table S1.…”

Section: Breedingmentioning

confidence: 99%

“…Among the environmental factors, maternal infection during pregnancy constitutes a notable example. The fetal period represents an extremely critical stage for the developing brain and different stressors [3], such as activation of the maternal immune system, can impede normal brain development [4,5]. Consequently, it has been postulated that maternal infections predispose offspring to certain neuropsychiatric disorders, including depression, schizophrenia and autism spectrum disorders [6].…”

Section: Introductionmentioning

confidence: 99%

VEGF Treatment Ameliorates Depression-Like Behavior in Adult Offspring after Maternal Immune Activation

Sideromenos

Lindtner

Zambon

et al. 2020

Cells

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Maternal immune activation (MIA) during pregnancy impacts offspring neurodevelopmental trajectories and induces lifelong consequences, including emotional and cognitive alterations. Using the polyinosinic:polycytidilic acid (PIC) MIA model we have previously demonstrated enhanced depression-like behavior in adult MIA offspring, which was associated with reduced expression of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) in the hippocampus. Since VEGF mediates the effects of various antidepressant agents, we here set out to explore whether VEGF administration could rescue the depression-like behavioral deficits in MIA offspring. To test our hypothesis, control and MIA offspring were intracerebroventricularly (i.c.v.) infused with either VEGF or vehicle solution and depression-related behavior was assessed in the sucrose preference test (SPT) and the tail suspension test (TST). As a surrogate of VEGF activity, the phosphorylation of the extracellular signal-regulated kinase (ERK) in hippocampus was quantified. We found that VEGF treatment reduced depression-related behavioral despair in the TST in MIA offspring but had no effect on anhedonia-like behavior in the SPT. While VEGF administration induced the phosphorylation of ERK in the hippocampus of control offspring, this effect was blunted in the MIA offspring. We conclude that VEGF administration, at the dosage tested, beneficially affects some aspects of the depression-like phenotype in the adult MIA offspring, inviting further studies using different dosage regimes to further explore the therapeutic potential of VEGF treatment in MIA-related changes in brain function and behavior.

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“…During administration of B. fragilis, pregnant females of C57Bl/6J were also included as a maternal immune activation (MIA) mouse model. MIA during gestation has been shown to increase the risk of development of neurodevelopmental psychiatric disorders (Conway and Brown, 2019;Kreitz et al, 2020). This is of particular interest in ASD, as GI barrier impairment can lead to inflammatory processes that ultimately might affect the neurodevelopment of the offspring.…”

Section: Animal Models For the Study Of The Relationship Between Gut mentioning

confidence: 99%

Autism Spectrum Disorder Associated With Gut Microbiota at Immune, Metabolomic, and Neuroactive Level

2020

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There is increasing evidence suggesting a link between the autism spectrum disorder (ASD) and the gastrointestinal (GI) microbiome. Experimental and clinical studies have shown that patients diagnosed with ASD display alterations of the gut microbiota. These alterations do not only extend to the gut microbiota composition but also to the metabolites they produce, as a result of its connections with diet and the bidirectional interaction with the host. Thus, production of metabolites and neurotransmitters stimulate the immune system and influence the central nervous system (CNS) by stimulation of the vagal nerve, as an example of the gut-brain axis pathway. In this review we compose an overview of the interconnectivity of the different GI-related elements that have been associated with the development and severity of the ASD in patients and animal models. We review potential biomarkers to be used in future studies to unlock further connections and interventions in the treatment of ASD.

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Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring

Cited by 40 publications

References 63 publications

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

VEGF Treatment Ameliorates Depression-Like Behavior in Adult Offspring after Maternal Immune Activation

Autism Spectrum Disorder Associated With Gut Microbiota at Immune, Metabolomic, and Neuroactive Level

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