Abstract
Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring’s neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.
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Acknowledgements
These studies were supported by the University of California Davis Conte Center to CSC (National Institutes of Health; P50MH106438). Development of the nonhuman primate model and behavioral characterization of the offspring were supported by P50MH106438-04S1 to MDB. Cytokine analysis was supported by the Biological and Molecular Analysis Core of the MIND Institute Intellectual and Developmental Disabilities Research Center (P50HD103526). The authors would like to thank Dr Thorsten Feiweier from Siemens AG, Healthcare, for providing the prototype software package for advanced diffusion imaging used to acquire data in the present study. Additional support was provided by the base grant (RR00169) of the California National Primate Research Center (CNPRC). We thank the veterinary and animal services staff of the CNPRC for care for the animals. Dr Andres Salazar, MD, Oncovir, Washington D.C, kindly provided poly ICLC.
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TAL contributed to study design, performed diffusion neuroimaging analyses, and wrote the majority of the paper. CSC as the grant principal investigator contributed to study design, edited, and reviewed the paper. AMI designed the analytic plan and performed statistical analyses, paper writing, and paper review. CT and RMV contributed to data analysis of diffusion and structural data as well as paper review. AMR, CEH, and JB were involved in NHP husbandry, NHP measurement and monitoring, NHP scanning, as well as paper review. RJM, DHG, AKM, and MAS contributed to study design and reviewed the paper. JVW contributed to study design, processed and measured cytokine data, and reviewed the paper. MDB contributed to study design, oversaw the entirety of NHP husbandry, housing, and measurement, and reviewed the paper.
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Lesh, T.A., Iosif, AM., Tanase, C. et al. Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model. Mol Psychiatry 28, 4185–4194 (2023). https://doi.org/10.1038/s41380-023-02213-w
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DOI: https://doi.org/10.1038/s41380-023-02213-w
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