Grant: Travel Awards - Institute Community Support

The prevalence of neurodevelopmental disorders (NDDs) has increased substantially in Canada over the past decade, yet the cause(s) remain unclear. Emerging evidence indicates that the intrauterine environment plays a critical role in shaping fetal brain development and perturbations such as maternal stress can increase NDD risk. Immune dysregulation is a common feature of these conditions, implicating fetal microglia in altered neurodevelopment. My project investigates how prenatal maternal stress disrupts microglia-neural stem cell (NSC) signalling to reshape NSC programs in the developing brain using male and female mouse embryos. To start, I examined how maternal stress affects fetal NSC behaviours using a neurosphere assay. Differentiation of NSCs revealed that both male and female neurons had longer axons following maternal stress exposure. However, only males showed a significant increase in TUJ1+ neurons in response to maternal stress, whereas only stressed females displayed enhanced dendritic arborization. To explore the molecular basis of these changes, I performed single-cell RNA sequencing on fetal NSCs. Differential gene analysis uncovered distinct transcriptional signatures between control male and female NSCs and showed that maternal stress shifted female NSCs toward a more male-like transcriptional profile. Maternal stress upregulated pathways linked to neuronal growth, development, and inhibitory neuron differentiation, effects observed only in females. Importantly, our analysis suggests that maternal stress disrupts neurodevelopmental programs through altered NSC-NSC signalling in females, while males show changes in NSC-microglia signalling. Together, our findings reveal sex-specific effects of maternal stress on fetal neurodevelopment, offering insights into the distinct pathways underlying NDDs and identifying potential cellular mechanisms to inform sex-specific treatment and promote healthier outcomes in children.