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bioRxiv · 10.64898/2026.10.23.761383

Live-cell imaging of fetal microglia reveals time-dependent sex differences in their responsiveness to prenatal maternal stress

Lawson, A.·Rosin, M.·Rosin, J. M.
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Abstract

Prenatal maternal stress is increasingly being linked to neurodevelopmental disorders (NDDs), and across diverse maternal stressors, immune dysregulation is emerging as a common feature. This suggests that fetal microglia may influence neurodevelopment by detecting changes in signaling from the intrauterine environment. Using a mouse model of prenatal maternal stress, where pregnant mice were exposed to cold from embryonic day 11.5 (E11.5) to E15.5, we previously demonstrated that fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress using static analyses. Here, we extend these analyses by conducting live-cell imaging on the E15.5 hypothalamic paraventricular nucleus (PVN) to assess microglial morphology, motility, and phagocytic behavior in real-time under homeostatic conditions and in response to prenatal maternal cold stress exposure. Prenatal maternal cold stress induced sex- and time-specific changes in microglial morphology in the PVN, where female microglia showed increased branch complexity across the entire live-cell video recording, while male microglia only showed this response at early time-points. Interestingly, PVN microglia also showed baseline sex differences in phagocytic behavior, with male microglia showing higher phagocytic activity as compared to female microglia. In response to prenatal maternal cold stress, male microglia showed a decrease in completed phagocytic events in the PVN, whereas female microglia showed increased engagement in phagocytic activity with no change in completed phagocytic events. Microglial motility was also altered in the PVN of female embryos at early time-points in response to prenatal maternal cold stress, but no such changes were observed in males. Together, these data demonstrate that fetal microglia show sex differences in key physiologies both at baseline and in response to prenatal maternal cold stress. Through time-resolved assessment of microglial dynamics, our findings also suggest that microglial responsiveness to prenatal maternal cold stress differs between males and females, which may help to provide a cellular basis for sex differences observed across many NDDs.

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Lawson, A., Rosin, M., Rosin, J. M.. 2026-10-24. Live-cell imaging of fetal microglia reveals time-dependent sex differences in their responsiveness to prenatal maternal stress. https://doi.org/10.64898/2026.10.23.761383

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