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

AbstractInfectious 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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Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

10.1101/2020.03.31.019190 ◽

2020 ◽

Author(s):

Nicholas F. Page ◽

Michael Gandal ◽

Myka Estes ◽

Scott Cameron ◽

Jessie Buth ◽

...

Keyword(s):

Immune Activation ◽

Molecular Mechanisms ◽

Brain Regions ◽

Repetitive Behaviors ◽

Anterior Cingulate ◽

Psychiatric Disease ◽

Primate Model ◽

Maternal Immune Activation ◽

Transcriptomic Changes ◽

And Control

AbstractBackgroundMaternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. 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 mechanistic dissection.MethodsWe performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring—an age comparable to mid adolescence in humans.ResultsWe identify 266 unique genes differentially expressed (DE) 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. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1st or 2nd trimester MIA exposures, including for the top DE genes—PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring.ConclusionsTogether, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

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Preliminary evidence that maternal immune activation specifically increases diagonal domain volume in the rat brain during early postnatal development

10.1101/432450 ◽

2018 ◽

Author(s):

Tobias C. Wood ◽

Michelle E. Edye ◽

Michael K. Harte ◽

Joanna C. Neill ◽

Eric P. Prinssen ◽

...

Keyword(s):

Rat Brain ◽

Immune Activation ◽

Diffusion Tensor ◽

Ex Vivo ◽

Morphological Changes ◽

Female Offspring ◽

Preliminary Evidence ◽

Poly I:C ◽

Maternal Immune Activation ◽

The Impact

AbstractMaternal immune activation (MIA) is consistently associated with elevated risk for multiple psychiatric disorders in the affected offspring. Related to this, an important goal of our work is to explore the impact of MIA effects across the lifespan. In this context, we recently reported the effects of poly (I:C)-induced MIA at gestational day (GD)15, immediately prior to birth, at GD21 and again at post-natal day (PD)21, providing a systematic assessment of plasma IL-6, body temperature and weight alterations in pregnant rats following poly (I:C) exposure and preliminary evidence for gross morphological changes and microglial neuropathology in both male and female offspring at GD21 and PD21. Here, we sought to complement and extend these data by characterising in more detail the meso-scale impact of gestational poly (I:C) exposure at GD15 on the neuroanatomy of the juvenile (PD21) rat brain using high-resolution, ex vivo anatomical magnetic resonance imaging (MRI) in combination with atlas-based segmentation. Our preliminary data suggest subtle neuroanatomical effects of gestational poly (I:C) exposure (n=10) relative to saline controls (n=10) at this time-point. Specifically, we report here preliminary evidence for a significant increase in the relative volume of the diagonal domain in poly (I:C) offspring (p<0.01; q<0.1), particularly in female offspring. This occurred in the absence of any microstructural alterations as detectable using diffusion tensor imaging (DTI). Longitudinal in vivo studies, informed by the effect sizes from this dataset are now required to establish both the functional relevance and cellular mechanisms of the apparent DD volume increase.

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Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: an integrated neuroimaging, behavioural, and transcriptional study

10.1101/2020.12.03.406454 ◽

2020 ◽

Author(s):

Elisa Guma ◽

Pedro Bordignon ◽

Gabriel Allan Devenyi ◽

Daniel Gallino ◽

Chloe Anastassiadis ◽

...

Keyword(s):

Immune Activation ◽

Neurodevelopmental Disorders ◽

Dorsal Hippocampus ◽

Early Adulthood ◽

Sensorimotor Gating ◽

Cingulate Cortex ◽

Late Gestation ◽

Anterior Cingulate ◽

Poly I:C ◽

Maternal Immune Activation

Prenatal maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders. How gestational timing of MIA-exposure differentially impacts downstream development remains unclear. Here, we characterize neurodevelopmental trajectories of mice exposed to MIA induced by poly I:C either early (gestational day [GD]9) or late (GD17) in gestation using longitudinal structural magnetic resonance imaging from weaning to adulthood. Early MIA-exposure associated with accelerated brain volume increases in adolescence/early-adulthood that normalized in later adulthood, in regions including the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety, stereotypic, and sensorimotor gating behaviours observed in adolescence normalized in adulthood. In contrast, MIA-exposure in late gestation had less impact on anatomical and behavioural profiles. Using a multivariate technique to relate imaging and behavioural variables for the time of greatest alteration, i.e. adolescence/early adulthood, we demonstrate that variation in anxiety, social, and sensorimotor gating associates significantly with volume of regions including the dorsal and ventral hippocampus, and anterior cingulate cortex. Using RNA sequencing to explore the molecular underpinnings of region-specific alterations in early MIA-exposed mice in adolescence, we observed the most transcriptional changes in the dorsal hippocampus, with regulated genes enriched for fibroblast growth factor regulation, autistic behaviours, inflammatory pathways, and microRNA regulation. This indicates that MIA in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders. Our findings demonstrate the power of an integrated hypothesis- and data-driven approach in linking brain-behavioural alterations to the transcriptome to understand how MIA confers risk for major mental illness.

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M180. SUSCEPTIBILITY AND RESILIENCE IN A MOUSE MODEL OF MATERNAL IMMUNE ACTIVATION

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.492 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S204-S205

Author(s):

Flavia Müller ◽

Joseph Scarborough ◽

Juliet Richetto ◽

Sina Schalbetter ◽

Ulrike Weber-Stadlbauer ◽

...

Keyword(s):

Mouse Model ◽

Immune Activation ◽

Psychotic Disorders ◽

Sensorimotor Gating ◽

Epidemiological Studies ◽

Poly I:C ◽

Behavioral Testing ◽

Experimental Conditions ◽

Maternal Immune Activation ◽

Mitochondrial Functions

Abstract Background Epidemiological studies over the past decades have repeatedly implicated maternal immune activation (MIA) in the etiology of psychiatric illnesses, including schizophrenia and related psychotic disorders. Not all offspring exposed to MIA, however, develop overt pathologies, suggesting that some are susceptible while others are resilient to MIA. To elucidate susceptibility and resilience in MIA, we used a mouse model that is based on prenatal exposure to the viral mimic poly(I:C). Methods Poly(I:C)-based MIA was induced in C57BL6/N mice on gestation day 12. Control dams received vehicle solution only. Offspring of poly(I:C)- or vehicle-exposed dams were subjected to a comprehensive behavioral testing battery when they reached adulthood (12 weeks of age onwards). Next-generation mRNA sequencing and gene pathway analyses were conducted after behavioral testing to explore the molecular correlates of resilience and susceptibility to MIA. Results Behavioral characterization coupled with unbiased TwoStep cluster analysis of a large number offspring (N >150) revealed that offspring exposed to MIA could be stratified into susceptible and resilient subgroups. While the former was characterized by deficits in social interaction, sensorimotor gating, and working memory, the behavioral profile of the latter was indistinguishable from control offspring. Susceptible and resilient MIA offspring were also dissociable by the presence of distinct molecular profiles in cortical and subcortical brain areas. In the medial prefrontal cortex, susceptible MIA offspring displayed a more profound deregulation of genes relevant for oxidative phosphorylation and mitochondrial functions than resilient MIA offspring. In the amygdala, the susceptible and resilient offspring differed in gene transcription pertinent to opioid signaling, DARPP-32 signaling, and G protein-coupled receptor signaling. Discussion Our data show that MIA can result in substantial phenotypic and transcriptomic variability even in the context of genetic homogeneity and under identical experimental conditions. If extended further, our model system may help to explain why only a subgroup of offspring exposed to MIA develops overt neurodevelopmental sequelae.

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The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

Brain Sciences ◽

10.3390/brainsci11030344 ◽

2021 ◽

Vol 11 (3) ◽

pp. 344

Author(s):

Kinga Gzielo ◽

Agnieszka Potasiewicz ◽

Ewa Litwa ◽

Diana Piotrowska ◽

Piotr Popik ◽

...

Keyword(s):

Immune Activation ◽

Social Play ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Male Rats ◽

Poly I:C ◽

Maternal Immune Activation ◽

Increased Risk ◽

Adolescent Rats ◽

The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

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