👤 Ashlyn Swift-Gallant

Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633-0.773; juvenile USVs, d = 1.103-1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36% reduction in overall brain volume (FDR 10%). Placentas from both groups showed reduced LIX (CXCL5), but distinct immune shifts also emerged: MIA placentas exhibited elevated IL-4 and IL-1β, whereas hyperandrogenized placentas showed increased TNFα. In neonatal brains, both conditions were associated with reduced IL-2, with MIA additionally decreasing IL-17A and IL-12p70, suggesting suppression of Th1/Th17-type cytokine signaling that normally supports proinflammatory and immune-neural interactions. DRD2 and BDNF protein were upregulated in hyperandrogenized fetal brains but downregulated with MIA. These results suggest that hyperandrogenization and MIA act through distinct mechanisms, producing subtle neurodevelopmental and behavioral differences consistent with human ASD subtypes. Show less

The physical environment modulates the maternal brain and affects maternal-offspring dynamics, with downstream effects on neonatal development. In this study, we examined whether environmental enrichment (EE) influences maternal approach, neonatal ultrasonic vocalizations (USVs), and early neuroendocrine development in mice, focusing on hormonal pathways associated with maternity, stress responsivity, and gonadal hormones. Nulliparous female C57BL/6 mice were housed in EE or standard (ST) conditions prior to mating. EE cages were larger and contained extra bedding and enrichment items. Litters were culled to four pups (2/sex), and maternal approach and pup USVs were recorded on postnatal days (PND) 6 and 8 using a modified three-chamber protocol. EE dams made fewer entries into female interaction zones than ST counterparts. EE also increased USV call numbers and decreased call frequencies among pups. These effects were not sex-dependent, and despite higher emission rates, USV parameters did not correlate with maternal response in the EE group. Gene expression analyses revealed that EE altered stress- and care-related genes in the maternal brain, downregulating Prlr (prolactin receptor) and Nr3c2 (mineralocorticoid receptor) in the cortex and upregulating Prlr while downregulating Nr3c2 and Oxtr (oxytocin receptor) in the diencephalon. Further, EE housing changed neuroendocrine profiles in male pups, but not females, suggesting benefits to neurodevelopment (increased brain-derived neurotrophic factor) and alterations to sexual differentiation (Ar [androgen receptor] and Esr1 [estrogen receptor alpha]) and stress reactivity (Nr3c1 [glucocorticoid receptor] and Nr3c2). These findings highlight how environmental context can shape maternal brain and behaviour and imprint on offspring neuroendocrine development in a sex-dependent manner. Show less