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Neurodevelopmental disorders have been increasingly associated with maternal immune activation (MIA) during pregnancy, particularly in response to viral infections. However, the impact of human respiratory syncytial virus (hRSV) infection during gestation on offspring neurodevelopment remains poorly understood. This study aimed to characterize hRSV-induced MIA and evaluate its effects on fetal brain development and offspring behavior using a murine model. Pregnant mice were infected with hRSV at gestational day 14, and tissues were analyzed at day 19. Infection induced pulmonary inflammation, evidenced by increased neutrophil infiltration, and viral replication was detected in maternal lungs and placental tissue, but not in fetal organs. Placental infection was associated with increased decidual immune cells and a shift toward a pro-inflammatory cytokine profile, including elevated IL-6, TNF-α, IFN-γ, and IL-1β, along with decreased IL-10 and IFN-λ. Increased levels of IL-6, TNF-α, and IL-4 were also detected in maternal serum and fetal brains, suggesting vertical transfer of cytokines. Additionally, reduced brain-derived neurotrophic factor levels and altered expression of tight junction-related genes were observed in fetal brains. Behavioral analyses revealed that offspring of infected dams exhibited impaired short-term memory and altered anxiety-like and repetitive behaviors, which persisted or intensified with age. These findings demonstrate that maternal hRSV infection induces MIA, disrupts the fetal neuroimmune environment, and leads to long-term behavioral alterations in offspring, highlighting hRSV as a potential risk factor for neurodevelopmental disorders. Show less

Maternal physical activity during pregnancy has been shown to confer benefits on the brain functions of offspring. This study investigated the positive effects of maternal exercise during pregnancy on enhancing hippocampal synaptic plasticity and resilience to stress-induced depressive behavior in adult murine offspring. Using a mouse model with mother mice engaged in voluntary wheel running during pregnancy, we assessed changes in long-term potentiation (LTP) in the hippocampal dentate gyrus, synaptic protein expression, and behavioral responses to chronic stress in adult male and female offspring from exercised dams compared with those from sedentary dams. We found that maternal exercise enhanced LTP in offspring of both sexes. Western blot analysis of hippocampal synaptoneurosome extractions revealed significant main effects of maternal exercise on increasing the expression of brain-derived neurotrophic factor (BDNF), PSD-95, synaptophysin, and phosphorylation of N-methyl-D-aspartate receptor subunit GluN2A and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA1. Maternal exercise significantly increased synaptophysin levels in both male and female offspring, with sex-specific effects on increasing PSD-95 levels in male offspring and increased p-GluN2A levels in female offspring from exercised dams. Golgi staining revealed a significant increase in hippocampal dendritic spine density in female offspring only. Maternal exercise-induced improvements in hippocampal synaptic plasticity were associated with reduced depression-like behaviors in both male and female offspring exposed to chronic unpredictable stress. Additionally, male offspring displayed reduced anxiety-like behavior, while female offspring showed no significant anxiolytic changes. These findings elucidate the sex-specific effects of maternal exercise on enhancing hippocampal synaptic plasticity, which may contribute to increased resilience against stress-induced depressive behaviors in adult offspring. Show less

Nearly one third of women of reproductive age in the United States are prescribed opioids annually; 14% of women fill an opioid prescription during pregnancy, and one in five report misuse. Opioid use during pregnancy has given rise to an increasing population of infants born with gestational opioid exposure. Although substantial clinical work has focused on treating these infants as they experience opioid withdrawal symptoms at the time of birth, notably few studies have examined the effects of gestational opioid exposure on brain development and long-term cognitive function. During typical brain development, endogenous opioids and their receptors are highly expressed by neural progenitor cells, neurons, and glia where they modulate cell proliferation, differentiation, and maturation. Thus, any disruption to the endogenous opioid system during the critical period of brain development may have lasting consequences on brain cell populations and the behaviors they influence. Indeed, opioid-exposed infants have smaller brains than age-matched peers and show significant neurodevelopmental impairment; they also have higher rates of learning disability at school age. To investigate how exposure to exogenous opioids during brain development affects neural maturation in the hippocampus, a brain region critical for learning and memory, our lab has developed a clinically relevant perigestational morphine exposure rat model. The current study reports that perigestational exposure to morphine delays postnatal hippocampal neuronal maturation, alters astrocyte and oligodendrocyte proliferation, and alters expression of brain-derived neurotrophic factor (BDNF), a protein crucial for healthy brain growth. Furthermore, we show that environmental enrichment rescues BDNF deficits, offering evidence for the effectiveness of non-invasive, non-pharmacological intervention for developmental consequences of perigestational opioid exposure. Show less

Depression and anxiety during pregnancy are major public health concerns with lasting consequences for mother and child. Although the gut microbiome contributes to stress and mood regulation, its role in preconceptional stress and transgenerational outcomes remains unclear. Here, we examined behavioral, microbial, and thalamic transcriptional effects of preconceptional social isolation rearing (SIR) in female mice and tested whether maternal probiotic supplementation mitigates these alterations. SIR females displayed increased anxiety-like and social-avoidant behavior, reduced gut microbial diversity, depletion of Odoribacter, Tuzzerella, and Alloprevotella, and enrichment of Bacteroides and Lachnospiraceae. A multispecies probiotic (Lactobacillus rhamnosus HN001, L. acidophilus La-14, Bifidobacterium lactis HN019) reversed these behavioral and microbial changes. Adult offspring of SIR dams showed sex-dependent behavioral deficits and microbial alterations partly reflecting maternal patterns. Prenatal SIR was associated with reduced thalamic Bdnf expression in offspring and altered Grin2a/2b selectively in males. In contrast, prenatal probiotic exposure exerted broader transcriptional effects and restored Bdnf levels in SIR offspring. SIR-induced increases in Lachnospiraceae were transmitted to offspring, whereas reductions in Ruminococcaceae were normalized by maternal probiotic treatment. Predicted functional profiling indicated sex-dependent modulation of microbial pathways related to tryptophan and central carbon metabolism. These findings demonstrate enduring transgenerational effects of preconceptional stress on the gut-brain axis and support maternal probiotic supplementation as a potential strategy to mitigate stress-induced dysregulation. Show less

Maternal separation (MS) is a widely used model of early-life stress that induces long-lasting behavioral and neurobiological alterations in offspring. Maternal exercise during pregnancy has been proposed as a non-pharmacological strategy to counteract these adverse effects. Pregnant Wistar rats were assigned to either a sedentary or exercise group, with the exercise group having free access to a running wheel throughout pregnancy. Offspring were divided into four experimental groups: offspring of sedentary mothers without MS (SedMS-), offspring of sedentary mothers with MS (SedMS+), offspring of exercised mothers without MS (ExMS-), and offspring of exercised mothers with MS (ExMS+). Behavioral assessments, conducted in adulthood starting at postnatal day 90 (P90), included the open field, elevated plus maze, forced swim test, and contextual fear conditioning. Morphological analysis of the hippocampus was performed using isotropic fractionation to quantify total neuronal and non-neuronal cells. Epigenetic changes were evaluated through chromatin immunoprecipitation (ChIP) using anti-acetylated histone H3 and H4, followed by amplification of bdnf exons IV and VI. Maternal separation increased depressive-like behavior and impaired hippocampus-dependent memory, effects that were attenuated by maternal exercise. MS also elevated non-neuronal cell numbers and reduced neuronal cells in the hippocampus, whereas prenatal exercise reversed these alterations. No significant group differences were found in histone acetylation at the Bdnf loci examined. Maternal exercise during pregnancy mitigates behavioral and morphological deficits induced by early-life stress, supporting its neuroprotective role in preserving hippocampal integrity and function. Although no significant epigenetic changes were detected, these findings suggest that maternal physical activity may be a promising intervention to mitigate the long-term neurobiological consequences of early-life adversity. Show less