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

• Published in: Molecular psychiatry 2021-02, Vol.26 (2), p.396-410
• Main Authors: Mueller, Flavia S., Scarborough, Joseph, Schalbetter, Sina M., Richetto, Juliet, Kim, Eugene, Couch, Amalie, Yee, Yohan, Lerch, Jason P., Vernon, Anthony C., Weber-Stadlbauer, Ulrike, Meyer, Urs
• Format: Article
• Language: English
• Subjects: 38/39; 59/57; 631/378; 64/60; 692/699/476/1799; 96/21; Adults; Anatomy; Animals; Approach behavior; Behavior; Behavior, Animal; Behavioral Sciences; Biological Psychology; Brain architecture; Brain research; Cytokines; Disease Models, Animal; Environmental aspects; Female; Genetic aspects; Gestation; Health aspects; IL-1β; Immediate Communication; Immune response; Inflammation; Interleukin 6; Magnetic resonance imaging; Medical imaging; Medicine; Medicine & Public Health; Mental illness; Mice; Mice, Inbred C57BL; Nervous system diseases; Neurodevelopmental disorders; Neuroimaging; Neurological diseases; Neurological disorders; Neurosciences; Pharmacotherapy; Polyinosinic:polycytidylic acid; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal influences; Psychiatry; Psychological aspects; Resilience (Personality trait); Risk factors; Sensorimotor gating; Social Behavior; Social interaction; Transcription; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-020-00952-8

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.