Gargus, Makenna2026-05-202026-05-202026https://hdl.handle.net/1828/23913Maternal immune activation (MIA) is the maternal exposure to immunogens and stressors that leads to an elevated maternal pro-inflammatory immune response, which has been linked to a significantly increased risk for offspring neurodevelopmental disorders, such as schizophrenia and autism spectrum disorder. The key links in the mechanism of MIA are the maternal cytokines produced in response to stressors, specifically interleukin (IL)-6. This cytokine penetrates the placenta and the fetal brain, where it binds to microglia, the innate immune cells of the central nervous system, to upregulate pro-inflammatory immune responses. In this thesis, I investigated the potential of vagus nerve stimulation (VNS), a non-pharmaceutical treatment strategy shown to downregulate peripheral immune responses, as a maternal treatment to prevent excessive pro-inflammatory immune responses and alter MIA-related changes to offspring neurodevelopment. Pregnant C57BL/6J mice were treated with VNS from embryonic day (E)15 to E19, while MIA was modelled by intraperitoneal injection of the viral mimetic polyinosinic-polycytidylic acid (polyI:C) on E17. The consequences on maternal cytokines were characterized 3 hours after injection. Offspring were tested for behavioural alterations across development at stages corresponding to juvenile, adolescence, and adulthood, using the open field test, novel object recognition test, and pre-pulse inhibition test, to measure alterations to anxiety and locomotion, recognition memory, and sensorimotor gating, respectively. The hippocampus, a key region of dysregulation in both neurodevelopmental disorders and in MIA models, was chosen in adult offspring for cellular analysis focused on microglia. Varying facets of the behavioural developmental trajectory were altered in male offspring by VNS and MIA. These behavioural changes were accompanied by pronounced changes in microglial morphology in the hippocampus, indicating MIA significantly reduced microglial size and complexity, which maternal VNS exposure could not prevent. Additionally, VNS in healthy dams seemed to increase microglial phagocytic activity in offspring compared to the offspring untreated healthy dams, while VNS in MIA-challenged prenatal development decreased phagocytosis. By contrast, in females we saw minimal behavioural alterations and no significant alterations to offspring adult microglial populations, indicating an important sexual dimorphism linked to the effects of both MIA and VNS. Overall, I characterized maternal immune responses and the resulting influence this had on offspring behavioural and neurodevelopmental outcomes, which were shaped by maternal VNS treatment in health and immune challenge, indicating the importance of further analyzing the mechanisms of both and their unique interaction in offspring neurodevelopment.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalmicrogliavagus nerve stimulation (VNS)maternal immune activation (MIA)autism spectrum disorder (ASD)ThesisGargus, M., Ben-Azu, B., Landwehr, A., Dunn, J., Errico, J.P., Tremblay, M-È., 2025. Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation. Front. Neuroschi. 18. https://doi.org/10.3389/fnins.2024.1527842Gargus, M., Poyhia, L., Errico, J.P., Rogers, M.K.N., Tremblay, M.È., 2026. Vagus nerve stimulation as an anti-inflammatory therapy for maternal immune activation-induced alterations in offspring microglia and neurodevelopment. Front. Neuroschi. 20. https://doi.org/10.3389/fnins.2026.1827714