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

Animals Behavior, Animal Disease Models, Animal Female Mice Neuroimaging Poly I-C Pregnancy Prenatal Exposure Delayed Effects
Gestational timing Imaging Maternal immune activation Neurodevelopmental disorders transcription Risk factor

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 09 2021
Historique:
received: 04 01 2021
revised: 23 02 2021
accepted: 15 03 2021
pubmed: 1 6 2021
medline: 28 9 2021
entrez: 31 5 2021
Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.biopsych.2021.03.017 PMID: 34053674
pubmed: 34053674
pii: S0006-3223(21)01176-8
doi: 10.1016/j.biopsych.2021.03.017
pii:
doi:

Substances chimiques

Poly I-C O84C90HH2L

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

328-341

Subventions

Organisme : CIHR
Pays : Canada

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Auteurs

Elisa Guma (E)

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.

Pedro do Couto Bordignon (PDC)

Department of Psychology, McGill University, Montreal, Quebec, Canada; Ludmer Center for Neuroinformatics and Mental Health, Montreal, Quebec, Canada.

Gabriel A Devenyi (GA)

Department of Psychiatry, McGill University, Montreal, Quebec, Canada; Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada.

Daniel Gallino (D)

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

Chloe Anastassiadis (C)

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.

Vedrana Cvetkovska (V)

Department of Psychology, McGill University, Montreal, Quebec, Canada.

Amadou D Barry (AD)

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.

Emily Snook (E)

Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Jurgen Germann (J)

Computational Brain Imaging Lab, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, Quebec, Canada; University Health Network, Toronto, Ontario, Canada.

Celia M T Greenwood (CMT)

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.

Bratislav Misic (B)

Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Rosemary C Bagot (RC)

Department of Psychology, McGill University, Montreal, Quebec, Canada; Ludmer Center for Neuroinformatics and Mental Health, Montreal, Quebec, Canada.

M Mallar Chakravarty (MM)

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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Early or Late Gestational Exposure to Maternal...
questionsmedicales.fr › Comportement et mécanismes comportementaux › Comportement › Comportement animal › Early or Late Gestational Exposure to Maternal...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Early or Late Gestational Exposure to Maternal...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Early or Late Gestational Exposure to Maternal...
questionsmedicales.fr › Techniques d'investigation › Neuroimagerie › Early or Late Gestational Exposure to Maternal...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Polynucléotides › Polyribonucléotides › Poly I › Poly I-C › Early or Late Gestational Exposure to Maternal...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Reproduction › Grossesse › Early or Late Gestational Exposure to Maternal...
questionsmedicales.fr › Maladies urogénitales › Maladies de l'appareil urogénital féminin et complications de la grossesse › Complications de la grossesse › Lésions prénatales › Effets différés de l'exposition prénatale à des facteurs de risque › Early or Late Gestational Exposure to Maternal...