Hippocampal Changes Elicited by Metabolic and Inflammatory Stressors following Prenatal Maternal Infection

Abstract

The hippocampus participates in spatial navigation and behavioral processes, displays molecular plasticity in response to environmental challenges, and can play a role in neuropsychiatric diseases. The combined effects of inflammatory prenatal and postnatal challenges can disrupt the hippocampal gene networks and regulatory mechanisms. Using a proven pig model of viral maternal immune activation (MIA) matched to controls and an RNA-sequencing approach, the hippocampal transcriptome was profiled on two-month-old female and male offspring assigned to fasting, mimetic viral, or saline treatments. More than 2600 genes presented single or combined effects (FDR-adjusted p-value < 0.05) of MIA, postnatal stress, or sex. Biological processes and pathways encompassing messenger cyclic adenosine 3′,5′-monophosphate (cAMP) signaling were enriched with genes including gastric inhibitory polypeptide receptor (GIPR) predominantly over-expressed in the MIA-exposed fasting males relative to groups that differed in sex, prenatal or postnatal challenge. While this pattern was amplified in fasting offspring, the postnatal inflammatory challenge appeared to cancel out the effects of the prenatal challenge. The transcription factors C-terminal binding protein 2 (CTBP2), RE1 silencing transcription factor (REST), signal transducer and activator of transcription 1 (STAT1), and SUZ12 polycomb repressive complex 2 subunit were over-represented among the genes impacted by the prenatal and postnatal factors studied. Our results indicate that one environmental challenge can influence the effect of another challenge on the hippocampal transcriptome. These findings can assist in the identification of molecular targets to ameliorate the effects of pre-and post-natal stressors on hippocampal-associated physiology and behavior.

Prenatal and postnatal challenges affect the hypothalamic molecular pathways that regulate hormonal levels

“…The over-representation of genes annotated to neurotransmitter regulation and transport processes that are affected by prenatal challenge interacting with postnatal challenge and sex is aligned with reports that MIA disrupts the development of neurotransmission in dopaminergic pathways underlying schizophrenia spectrum disorder phenotypes [ 58 ]. Neurotransmitters are commonly found in neurons alongside neuropeptides [ 59 ] and differential expression of neuropeptide genes was detected in the hippocampus of 60-day-old pigs exposed to PRRSV-elicited MIA [ 27 ]. Also aligned with the present findings, a study of MIA in mice detected a higher inhibitory synaptic tone of males and females, whereas changes in the excitatory synapse transmission were only detected in females relative to controls [ 60 ].…”

“…A transcriptome study of the basolateral amygdala of male mice exposed to the chronic stress of repeated housing with an aggressive mouse identified the enrichment of SUZ12 upstream of differentially expressed genes [ 63 ]. SUZ12 was also enriched among genes in the hippocampus of 60-day-old pigs exposed to PRRSV-elicited MIA [ 27 ]. The present results are aligned with reports that mutations in Suz12 have been associated with MIA-related autism spectrum disorder phenotypes [ 64 ].…”

“…The AUCs, estimated in the top 3% of the homotypic motif clusters across 10 vertebrate species, were standardized in the iRegulon NES. The NES > 3 threshold that corresponds to a 0.03 < FDR p-value < 0.09 were applied in the present study [ 26 , 27 ].…”

Influence of Maternal Immune Activation and Stressors on the Hippocampal Metabolome

“…The joint effects of prenatal and postnatal stressors have been reasoned under the double-hit hypothesis studied in rodent, pig, and primate models [ 9 , 21 , 22 , 23 ]. The combination of weaning stress and MIA affects serum indicators [ 24 ], metabolomics [ 25 ], the amygdala and hippocampus transcriptome [ 26 , 27 , 28 , 29 , 30 ], and the behavior of pigs [ 31 ]. MIA and postnatal challenges have [ 9 , 21 , 22 , 23 ] been associated with changes in serum indicators and neurodevelopmental disorders, including schizophrenia and autism spectrum disorders in humans [ 18 , 19 ].…”

Genes Participating in the Ensheathment of Neurons Are Affected by Postnatal Stress and Maternal Immune Activation in the Pituitary Gland

“…The mRNAs of the receptors of the cytokine interleukins 17 IL-17rc and IL-17rd are abundant in the pituitary, making this gland susceptible to cytokine signaling [14]. Moreover, the physiological and behavioral response to postnatal stress can be affected by MIA [15]. While the effects of MIA and its stress on specific molecules in the pituitary gland have been reported, there is limited information on the simultaneous effect of MIA and weaning on the pituitary gland's transcriptome.…”