Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats

Abstract

Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of neurodevelopment is a major risk factor for behavioral deficits and psychiatric illness in offspring. A spectrum of behavioral abnormalities can be recapitulated in rodents by inducing MIA using the viral mimetic, PolyI:C. Many studies have focused on long-term changes in brain structure and behavioral outcomes in offspring following maternal PolyI:C exposure, but acute changes in prenatal development are not well-characterized. Using RNA-Sequencing, we profiled acute transcriptomic changes in rat conceptuses (decidua along with nascent embryo and placenta) after maternal PolyI:C exposure during early gestation, which enabled us to capture gene expression changes provoked by MIA inclusive to the embryonic milieu. We identified a robust increase in expression of genes related to antiviral inflammation following maternal PolyI:C exposure, and a corresponding decrease in transcripts associated with nervous system development. At mid-gestation, regions of the developing cortex were thicker in fetuses prenatally challenged with PolyI:C, with females displaying a thicker ventricular zone and males a thicker cortical mantle. Along these lines, neural precursor cells (NPCs) isolated from fetal brains prenatally challenged with PolyI:C exhibited a higher rate of self-renewal. Expression of Notch1 and the Notch ligand, delta-like ligand 1, which are both highly implicated in maintenance of NPCs and nervous system development, was increased following PolyI:C exposure. These results suggest that MIA elicits rapid gene expression changes within the conceptus, including repression of neurodevelopmental pathways, resulting in profound alterations in fetal brain development.

COVID-19 in pregnancy: implications for fetal brain development

“…Several candidate mechanisms have been proposed in models of MIA which may apply to maternal SARS-CoV-2 infection as well (Figure 1). particularly in the setting of activation via Toll-like receptor (TLR) 7/8 signaling pathways, and to a lesser extent for immune activation via TLR3/TLR4 signaling pathways [42,[88][89][90][91]. (ii) Dysregulated placental serotonin signaling, as the placenta is the primary source of serotonin for the developing fetal brain [92,93].…”

“…(iii) Maternal and placental immune activation are also associated with other alterations in fetal brain neurotransmitter signaling, including the dopaminergic, cholinergic, GABAergic, glutamatergic, and melanocortinergic systems (the latter mediated primarily by dysregulated leptin signaling) that influence fetal brain development and future risk for conditions such as schizophrenia, addiction, and disordered eating [49,[98][99][100][101][102][103]. (iv) Maternal and placental immune activation are associated with placental and fetal brain mitochondrial dysfunction, oxidative stress, and disrupted protein homeostasis [88,91,104,105].…”

Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells

“…These 513 predicted miRNA–mRNA interactions were highly enriched in nervous system development functions and the 85 mRNAs common in the significantly activated nervous system development functions ( Table 1 ) and their predicted interactions with DE miRNAs shown in Figure 4 identified several regulatory networks. The upregulated miR-10a-5p miRNA family was the second most abundant in our NSCs after miR-92a-3p and was predicted to regulate the expression of genes, PRKCI whose down-regulation promotes NOTCH signaling and NSC self-renewal [ 36 ], pro-neural genes RORB, BDNF and RNF112 [ 37 , 38 , 39 ], and HCN1 associated with differentiation of sympathetic neurons [ 40 ]. miR-10a-5p along with miR-30c-5p and miR342-3p, was also predicted to down-regulate the pro-apoptotic gene CASP3 .…”

A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway

“…In addition to placental inflammation and neonatal viremia, the transfer of pro-inflammatory cytokines across the placenta could lead to fetal brain cortical malformations, and changes in macrophages function that may be even sustained up to adulthood in accordance with the so-called “ Barker hypothesis of the fetal origin of adult disease ” (Barker, 2001 ). Novel preclinical findings indicate that MIA alters fetal brain development, with implications for long-term cognitive function and behavioral phenotype (Baines et al, 2020 ; Easterlin et al, 2020 ).…”