Inflammatory modulation of the associations between prenatal maternal depression and neonatal brain

Yonghui Wu,Michael J Meaney,Birit F P Broekman,Marielle V Fortier,Han Zhang,Peter D Gluckman,Anqi Qiu,Lynette P Shek,Yap-Seng Chong,Changqing Wang

doi:10.1038/s41386-020-0774-0

Abstract

Inflammatory signaling has a role in sensing intrauterine environment, which may be moderators in altering fetal brain development upon maternal environment. This study integrated cytokine transcriptome of post-mortem fetal brains, neonatal brain imaging and genetic variants (n = 161) to examine whether cytokines are candidates for modulating the relationship between prenatal maternal depression and fetal brain development. This study obtained the transcriptome data of 208 cytokine genes in 12 fetal brain regions from the BrainSpan database. We also included 161 mother–child dyads with prenatal maternal depressive symptoms assessed at 26 weeks of gestation, cytokine genotype data extracted from umbilical cord specimens, and neonatal brain images from a longitudinal prospective birth cohort. We revealed that 22 cytokine genes are expressed in specific brain regions in utero, whose variants have roles in modulating the effects of the prenatal environment on the accelerated fetal development of the hippocampus, auditory, parietal, orbitofrontal, and dorsal prefrontal cortex. Neonates high in the genetic expression score (GES) of TNFRSF19 and IL17RB showed a larger right hippocampal volume, high in the GES of BMPR1B showed the thicker thickness of the sensorimotor cortex, and high in the GES of IL1RAP and CXCR4 demonstrated the thicker thickness of the dorsal and orbital prefrontal cortex in relation with greater prenatal maternal depressive symptoms. Our findings suggest that in humans, the cytokine genes are expressed in a brain region-specific manner in utero and may have potential roles in modulating the fetal development of the corresponding brain regions in response to the maternal environment.

Highlights

Emerging evidence arising from observational studies in humans reveals that fetal exposure to maternal depression during pregnancy has a long-term impact on the brain development of the offspring, especially brain regions related to affective disorders [1,2,3]
Cytokine genes expressed in specific post-mortem brain regions in utero Robust regression identified 22 cytokine genes whose expression levels in specific brain regions were significantly associated with the post-conceptual age
Our findings showed the upregulation or downregulation of the cytokine gene expressions in utero, suggesting that this small set of the cytokine genes might potentially be functional in a specific brain region in utero

Summary

Introduction

Emerging evidence arising from observational studies in humans reveals that fetal exposure to maternal depression during pregnancy has a long-term impact on the brain development of the offspring, especially brain regions related to affective disorders [1,2,3]. The altered functional connectivity between the amygdala and prefrontal cortex is observed in infants and children exposed to greater prenatal maternal depressive symptoms [9]. Thickness in the inferior frontal and temporal cortex and microstructure in the white matter of the inferior frontal area are correlated with prenatal maternal depressive symptoms in children aged between 2.6 and 5.1 years old [7]. These brain regions are implicated in psychiatric disorders such as depression and anxiety [10]. These findings suggest that maternal depressive symptoms during pregnancy appear to affect brain development in a manner that influences the vulnerability to affective psychopathology

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Conclusion