Altered brain metabolites in male nonhuman primate offspring exposed to maternal immune activation - PubMed (original) (raw)

doi: 10.1016/j.bbi.2024.07.011. Epub 2024 Jul 18.

Roza M Vlasova 2, Shuai Chen 3, Ana-Maria Iosif 3, Jeffrey Bennett 4, Costin Tanase 4, Amy M Ryan 4, Takeshi Murai 4, Casey E Hogrefe 5, Cynthia D Schumann 4, Daniel H Geschwind 6, Judy Van de Water 7, David G Amaral 8, Tyler A Lesh 4, Martin A Styner 9, A Kimberley McAllister 10, Cameron S Carter 11, Melissa D Bauman 12

Affiliations

Altered brain metabolites in male nonhuman primate offspring exposed to maternal immune activation

Richard J Maddock et al. Brain Behav Immun. 2024 Oct.

Abstract

Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.

Keywords: Adolescence; Childhood; Gestational immune activation; Macaque; Magnetic resonance spectroscopy; Myo-inositol; N-acetylaspartate; Prefrontal; Resilience.

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.

Fig. 1.

An example of voxel locations from the same animal (in MIA group) at age 6 months (row A) and 45 months (row B). The spatial scaling of the brain and voxel is equal at both ages. An example PRESS spectrum (TE/TR 33/1500) from the same animal is shown at 6 months (panel C) and 45 months of age (panel D). An example off-resonance MEGA-PRESS spectrum (TE/TR 131/2000) from the same animal is shown at 6 months (panel E) and 45 months of age (panel F). Smoother, thick red lines are LCModel fits. Lighter black lines are raw data. Wavy lines under spectrum are estimated baselines. Residual signal is shown above each spectrum.

Fig. 2.

Fig. 2.

MEGA-PRESS difference spectra at 6 months (A) and 45 months of age (B). The edited glutathione cysteine resonance at 2.95 PPM is shown in gray. Co-editing resonances, including an NAA aspartate resonance at 2.67 PPM, are also visible. Panel A shows the average difference spectrum across all 6-month-old offspring (MIA and Control). Panel B shows an example difference spectrum from one 45-month-old MIA offspring.

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