Interacting impact of maternal inflammatory response and stress on the amygdala transcriptome of pigs

Abstract

Changes at the molecular level capacitate the plasticity displayed by the brain in response to stress stimuli. Weaning stress can trigger molecular changes that influence the physiology of the offspring. Likewise, maternal immune activation (MIA) during gestation has been associated with behavior disorders and molecular changes in the amygdala of the offspring. This study advances the understanding of the effects of pre-and postnatal stressors in amygdala gene networks. The amygdala transcriptome was profiled on female and male pigs that were either exposed to viral-elicited MIA or not and were weaned or nursed. Overall, 111 genes presented interacting or independent effects of weaning, MIA or sex (FDR-adjusted P-value < 0.05). PIGY upstream reading frame (PYURF) and orthodenticle homeobox 2 (OTX2) are genes associated with MIA-related neurological disorders, and presented significant under-expression in weaned relative to nursed pigs exposed to MIA, with an opposite pattern was observed in non-MIA pigs. Enriched among the genes presenting highly over- or under-expression profiles were 24 KEGG pathways including inflammation, and neurological disorders. Our results indicate that MIA and sex can modulate the effect of weaning stress on the molecular mechanisms in the developing brain. Our findings can help identify molecular targets to ameliorate the effects of pre-and postnatal stressors on behaviors regulated by the amygdala such as aggression and feeding.

Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

“…2. The extreme positive ∆PSI column quantifies the isoform that presented the highest over-expression in MIA relative to control female pigs expressed in proportion. 3 Isoform count indicates the number of isoforms in the gene presenting alternative splicing.…”

“…The experiments were reviewed by the University of Illinois Institutional Animal Care and Use Committee (IACUC) in compliance with the NIH Public Health Service Policy on the Humane Care and Use of Animals and the USDA Animal Welfare Act. The experimental procedures were previously described [3], and the animal and molecular procedures that can influence the results from the alternative splicing analysis are highlighted.…”

“…2 Size = number of distinct genes in the pathway. 3 Enrichment fold = ratio between proportion of pathway genes in the significant splicing list relative to the genome.…”

“…Using a pig model of MIA elicited by a live virus, we reported that three-weekold pigs presented changes in the expression pattern of genes annotated to neurodevel-Immuno 2021, 1 500 opmental disorders, ASD, and SSD in the amygdala [24,25]. Subsequent investigations of the impact of the first challenge by MIA followed by weaning stress at three weeks of age confirmed the higher blood cortisol levels in weaned pigs relative to nursed pigs [7] and uncovered the potential modulating impact of MIA on the effects of weaning on genes annotated to autoimmune diseases and cell adhesion molecules [3]. Lipopolysaccharide (LPS)-elicited MIA in mice led to amygdala dysregulation in fetal and young adult offspring and increased pro-inflammatory markers [26], while MIA elicited by the synthetic viral agent polyinosinic:polycytidylic acid (Poly(I:C)) increased the synaptic strength of glutamatergic projections from the prefrontal cortex to the amygdala in mice [27].…”

“…Infections or other immune challenges during gestation result in the release of inflammatory signals that can reach the developing fetus. These signals can disrupt the offspring's molecular mechanisms [1][2][3] and have been associated with neurodevelopmental, neurodegenerative, immunological, metabolic, and behavioral disorders in humans and model organisms [4][5][6][7][8][9]. Moreover, MIA can alter the response to a challenge that the offspring may experience later in life [10,11].…”