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

Elisa Guma; Pedro do Couto Bordignon; Gabriel A Devenyi; Daniel Gallino; Chloe Anastassiadis; Vedrana Cvetkovska; Amadou D Barry; Emily Snook; Jurgen Germann; Celia M T Greenwood; Bratislav Misic; Rosemary C Bagot; M Mallar Chakravarty

doi:10.1016/j.biopsych.2021.03.017

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

Biol Psychiatry. 2021 Sep 1;90(5):328-341. doi: 10.1016/j.biopsych.2021.03.017. Epub 2021 Mar 23.

Affiliations

¹ Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada. Electronic address: elisa.guma@mail.mcgill.ca.
² Department of Psychology, McGill University, Montreal, Quebec, Canada; Ludmer Center for Neuroinformatics and Mental Health, Montreal, Quebec, Canada.
³ Department of Psychiatry, McGill University, Montreal, Quebec, Canada; Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada.
⁴ Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada.
⁵ 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.
⁶ Department of Psychology, McGill University, Montreal, Quebec, Canada.
⁷ 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.
⁸ Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁹ Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; University Health Network, Toronto, Ontario, Canada.
¹⁰ 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.
¹¹ Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
¹² 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. Electronic address: mallar.chakravarty@mcgill.ca.

PMID: 34053674
DOI: 10.1016/j.biopsych.2021.03.017

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: Gestational timing; Imaging; Maternal immune activation; Neurodevelopmental disorders transcription; Risk factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal*
Disease Models, Animal
Female
Mice
Neuroimaging
Poly I-C
Pregnancy
Prenatal Exposure Delayed Effects*

Substances

Poly I-C

Grants and funding

CIHR/Canada