Early-life enteric infections are increasingly recognized as a major driver of adverse neurodevelopmental outcomes. However, the cell-type-specific mechanisms linking intestinal inflammation to persistent cognitive deficits in the developing brain remain poorly defined. Here, we demonstrate that transient Citrobacter rodentium infection in mice, which models human pathogenic Escherichia coli infection, disrupts hippocampal development and impairs cognitive function. These phenotypes were observed only during a critical postnatal window, coinciding with transient intestinal permeability. Hippocampal transcriptomics revealed persistent dysregulation of neurogenic pathways, and cellular analyses confirmed alterations in neurons, microglia, and endothelial cells. Critically, we identified accumulation of the microbial metabolite D-lactate in the hippocampus. Oral D-lactate supplementation in a gut barrier disruption model, exacerbated both behavioral deficits and hippocampal neuronal loss. Finally, in the presence of inflammatory stimuli, exposing primary neurons to D-lactate reduced the ratio of NeuN expressing neurons. Together, these findings identify age-dependent intestinal barrier dysfunction as a potential route linking early-life enteric infection with increased D-lactate exposure, hippocampal neuronal alterations, and persistent behavioural impairment.
Maternal immune activation (MIA) is a major environmental risk factor for schizophrenia, yet the early neuronal mechanisms linking embryonic immune challenges to neurodevelopmental disruption remain poorly defined. Here, we provide a detailed mechanistic characterization of primary cortical neurons derived from a Poly(I:C)-induced MIA model, revealing mitochondrial dysfunction as a central feature of the pathological phenotype. Cortical neurons cultured from the offspring of Poly(I:C)-treated females (embryonic day 14) exhibited a severely constrained bioenergetic state, characterized by increased basal respiration and ATP levels coupled with a significant reduction in both maximal respiration and spare respiratory capacity, indicating limited metabolic flexibility. This bioenergetic failure was accompanied by elevated mitochondrial superoxide production, consistent with a sustained redox imbalance. Concomitant alterations in mitochondrial proteins, including a marked reduction in NDUFS2 levels, further support the involvement of respiratory chain Complex I instability. Moreover, mitochondrial dynamics and content were profoundly disrupted, as evidenced by dysregulated OPA1, DRP1, and TOM20/TOM40 expression, which correlated with a reduced functional pool and a maladaptive remodeling toward enlarged, rounded, or fragmented mitochondria. Notably, these mitochondrial deficits directly paralleled a simplified dendritic arborization and impaired synaptic organization, thereby linking early bioenergetic and redox disturbances to structural neuronal impairments. Collectively, our findings identify mitochondrial dysfunction as a key mechanistic axis connecting prenatal inflammation to neurodevelopmental vulnerability, offering a cell-autonomous framework for how gestational immune challenges translate into structural deficits relevant to schizophrenia.
In response to peripheral inflammation, such as the intraperitoneal administration of lipopolysaccharide (LPS), inflammatory cytokines recruit afferent neurons that communicate the inflammation to the brain and, in addition, cytokines are released to the bloodstream and reach circumventricular organs in the brain, such as the area postrema (AP). The nucleus of the solitary tract (NTS) perceives peripheral inflammatory stimuli both directly from afferent peripheral nerves and indirectly through its bidirectional connection to the AP. Norepinephrine (NE) neurons within the NTS are known to mediate behavioral and physiological responses to stress, especially stress related to inflammatory challenges in the periphery. However, the restrictions of traditional pain assays limit the understanding of the influence of NTS NE neurons on pain. Here, we used the Blackbox, a machine-learning assisted behavioral analysis apparatus that was developed specifically for the study of pain in rodents. First, we determined the Blackbox variables that correlate to allodynia in mice submitted to intraperitoneal injection of LPS. IP injection of LPS caused several changes to behavior and posture. Most notably, the distance travelled, hind paw toe spread and hind paw distance significantly decreased in response to LPS and strongly correlated with decreased von Frey mechanosensitivity threshold. Selective chemogenetic activation of NTS NE neurons caused similar pain-related behaviors, while inhibition of NTS NE neurons partially reversed the impact of LPS on pain-related behaviors. Taken together, these data show that the NE neurons within the NTS mediate allodynia in response to peripheral inflammation, contributing to the nociception aspect of sickness behaviors.
While maternal histories of adverse childhood experiences (ACEs) have been linked to altered immune signaling during pregnancy, the specific inflammatory pathways underlying these associations remain poorly characterized. We leveraged high-dimensional proteomics to examine associations between maternal ACEs and pregnancy-associated inflammatory signaling pathways defined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and tested whether these associations were moderated by neighborhood-level social vulnerability during pregnancy. Participants included pregnant individuals enrolled in the Environmental influences on Child Health Outcomes (ECHO) Cohort (N = 770). Circulating inflammatory proteins were assayed from maternal plasma using the Olink Target 96 Inflammation panel. Protein markers were mapped to Human Genome Organisation (HUGO) Gene Nomenclature Committee gene symbols and aggregated into KEGG pathway scores using curated definitions. Linear regression models evaluated associations between continuous maternal ACE scores and each pathway score. Following correction for multiple comparisons, higher maternal ACE exposure was associated with higher activity across 12 KEGG-annotated protein pathways, including AGE–RAGE, non-alcoholic fatty liver disease, chemokine, Th17 differentiation, HIF-1, cellular senescence, Rap1, NOD-like receptor signaling, transcriptional misregulation in cancer, and infection-related pathway signaling. Domain-specific analyses identified the most consistent associations for childhood household dysfunction. Neighborhood-level social vulnerability during pregnancy did not moderate ACE–inflammation associations but was independently associated with higher KSHV infection and NOD-like receptor signaling pathway scores. Together, these findings indicate that maternal ACEs and prenatal social vulnerability are independently associated with small, but directionally consistent, differences in overlapping inflammatory and growth-related protein signals during pregnancy.
