Fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress
- 1The University of British Columbia
Abstract
The prevalence of neurodevelopmental disorders (NDDs) has increased dramatically, with growing evidence linking prenatal maternal stress exposure to NDDs. Across diverse maternal stressors, immune dysregulation emerges as a common feature, suggesting that fetal microglia may detect changes in the intrauterine environment and influence neurodevelopment. Accordingly, we utilized a mouse model of prenatal maternal cold stress to investigate the impact of maternal stress during pregnancy on fetal microglia morphology, cellular interactions, and phagocytic behaviors. Pregnant mice were exposed to cold stress from embryonic day 11.5 (E11.5) to E15.5 and fetal hypothalamic tissue was assessed from both male and female embryos. By adapting the morphology analysis toolset MicrogliaMorphology to assess fetal microglia, we demonstrate regional differences in microglial morphology in the fetal hypothalamus at baseline, with hypothalamic nuclei such as the paraventricular nucleus (PVN) containing fewer rod-like microglia compared to the broader hypothalamus. Interestingly, prenatal maternal cold stress induced a male-specific shift in microglial morphology from ameboid to ramified within the E15.5 PVN. Male embryos also displayed increased microglial-arginine vasopressin (AVP) neuronal interactions and microglial phagocytosis within the E15.5 PVN, but these changes were unique to microglia with a ramified morphology and were not observed when microglia with an ameboid or rod-like morphology were assessed. Using pHrodo bioparticles and flow cytometry, we further illustrate that prenatal maternal cold stress drives increased phagocytic activity in the E15.5 hypothalamus of male embryos, but not females. Together, these data demonstrate that prenatal maternal cold stress alters microglia morphology and drives morphology-dependent microglial interactions and phagocytic behaviors in male embryos which are unique to the hypothalamic PVN--a nuclei critical for social behaviors. Our findings also suggest that specific hypothalamic nuclei such as the PVN may be more sensitive to prenatal maternal stress, which has the potential to provide a cellular basis underlying the sex differences in microglia-dependent social deficits that were previously reported for this model.
Versions
Related
- Live-cell imaging of fetal microglia reveals time-dependent sex differences in their responsiveness to prenatal maternal stress
- Reelin doses normalizing behavioural alterations induced by repeated corticosterone avoid eliciting neuroinflammation-associated morphology in hippocampal microglia
- A Diet Rich in Docosahexaenoic Acid Enhances Reactive Astrogliosis and Ramified Microglia Morphology in Apolipoprotein E Epsilon 4-Targeted Replacement Mice
- Statistical Parametric Mapping reveals sex-specific, phase-dependent differences in bilateral three-dimensional ground reaction force during Wushu Changbing PiJi in high-level athletes
- EcoHIV Treated Primary Microglia Exhibit a Highly Specialized and Sex-Dependent Transcriptional State
BibTeX
@misc{lawson2026fetal,
title = {{Fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress}},
author = {A. Lawson and M. Rosin and J. M. Rosin},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.14.744921},
url = {https://www.biorxiv.org/content/10.64898/2026.08.14.744921v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Fetal microglia show region-specific and morphology-dependent sex differences in their responsiveness to prenatal maternal stress
AU - A. Lawson
AU - M. Rosin
AU - J. M. Rosin
PY - 2026
DA - 2026/08/14
PB - bioRxiv
DO - 10.64898/2026.08.14.744921
UR - https://www.biorxiv.org/content/10.64898/2026.08.14.744921v2
AB - The prevalence of neurodevelopmental disorders (NDDs) has increased dramatically, with growing evidence linking prenatal maternal stress exposure to NDDs. Across diverse maternal stressors, immune dysregulation emerges as a common feature, suggesting that fetal microglia may detect changes in the intrauterine environment and influence neurodevelopment. Accordingly, we utilized a mouse model of prenatal maternal cold stress to investigate the impact of maternal stress during pregnancy on fetal microglia morphology, cellular interactions, and phagocytic behaviors. Pregnant mice were exposed to cold stress from embryonic day 11.5 (E11.5) to E15.5 and fetal hypothalamic tissue was assessed from both male and female embryos. By adapting the morphology analysis toolset MicrogliaMorphology to assess fetal microglia, we demonstrate regional differences in microglial morphology in the fetal hypothalamus at baseline, with hypothalamic nuclei such as the paraventricular nucleus (PVN) containing fewer rod-like microglia compared to the broader hypothalamus. Interestingly, prenatal maternal cold stress induced a male-specific shift in microglial morphology from ameboid to ramified within the E15.5 PVN. Male embryos also displayed increased microglial-arginine vasopressin (AVP) neuronal interactions and microglial phagocytosis within the E15.5 PVN, but these changes were unique to microglia with a ramified morphology and were not observed when microglia with an ameboid or rod-like morphology were assessed. Using pHrodo bioparticles and flow cytometry, we further illustrate that prenatal maternal cold stress drives increased phagocytic activity in the E15.5 hypothalamus of male embryos, but not females. Together, these data demonstrate that prenatal maternal cold stress alters microglia morphology and drives morphology-dependent microglial interactions and phagocytic behaviors in male embryos which are unique to the hypothalamic PVN--a nuclei critical for social behaviors. Our findings also suggest that specific hypothalamic nuclei such as the PVN may be more sensitive to prenatal maternal stress, which has the potential to provide a cellular basis underlying the sex differences in microglia-dependent social deficits that were previously reported for this model.
ER -