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

  • Elisa Guma
    Correspondence
    Address correspondence to Elisa Guma, M.Sc.
    Affiliations
    Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada

    Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada
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  • Pedro do Couto Bordignon
    Affiliations
    Department of Psychology, McGill University, Montreal, Quebec, Canada

    Ludmer Center for Neuroinformatics and Mental Health, Montreal, Quebec, Canada
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  • Gabriel A. Devenyi
    Affiliations
    Department of Psychiatry, McGill University, Montreal, Quebec, Canada

    Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada
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  • Daniel Gallino
    Affiliations
    Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada
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  • Chloe Anastassiadis
    Affiliations
    Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada

    Institute of Medical Science & Collaborative Program in Neuroscience, University of Toronto, Toronto, Ontario, Canada
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  • Vedrana Cvetkovska
    Affiliations
    Department of Psychology, McGill University, Montreal, Quebec, Canada
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  • Amadou D. Barry
    Affiliations
    Departments of Human Genetics and Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada

    Ludmer Center for Neuroinformatics and Mental Health, Montreal, Quebec, Canada
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  • Emily Snook
    Affiliations
    Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada

    Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • Jurgen Germann
    Affiliations
    Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada

    University Health Network, Toronto, Ontario, Canada
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  • Celia M.T. Greenwood
    Affiliations
    Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada

    Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

    Departments of Human Genetics and Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada

    Ludmer Center for Neuroinformatics and Mental Health, Montreal, Quebec, Canada
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  • Bratislav Misic
    Affiliations
    Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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  • Rosemary C. Bagot
    Affiliations
    Department of Psychology, McGill University, Montreal, Quebec, Canada

    Ludmer Center for Neuroinformatics and Mental Health, Montreal, Quebec, Canada
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  • M. Mallar Chakravarty
    Correspondence
    M. Mallar Chakravarty, Ph.D.
    Affiliations
    Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada

    Department of Psychiatry, McGill University, Montreal, Quebec, Canada

    Department of Biological and Biomedical Engineering, McGill University, Montreal, Quebec, Canada

    Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada
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      Abstract

      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.

      Keywords

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      Linked Article

      • Maternal Immune Activation During Pregnancy and Offspring Brain Development
        Biological PsychiatryVol. 90Issue 5
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          One of the principles of fetal programming is that organs undergoing rapid developmental changes are especially vulnerable to organizing and disorganizing influences of environmental conditions. Because the brain is a prominent target for such influences, the prenatal environment may shape mental health across the lifespan. Among gestational conditions that have been extensively studied and shown to increase the risk for neurodevelopmental and psychiatric disorders is maternal infection and maternal immune activation (MIA) (1).
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