Social Support Promotes Alternative Molecular and Dendritic Adaptations Following Prenatal Stress

Prenatal maternal stress (PMS) induces alterations in offspring neurodevelopment and behavior. We previously showed that social support to PMS-exposed dams improved offspring memory and social interaction. We investigated mechanisms underlying behavioral recovery. Pregnant mice were exposed to stressors and housed either with a familiar non-pregnant female (ESA) or alone (ES). Controls were non-stressed, socially housed dams (CTA). ES dams showed higher fecal corticosterone levels than ESA and CTA dams at delivery and PD7. RNA-seq of offspring prefrontal cortex identified 625 differentially expressed transcripts in ESvsESA, including protein-coding genes and lncRNA. Gene Ontology analysis highlighted synaptic transmission and neuronal connectivity. ESvsCTA & ESAvsCTA yielded 417 and 1,507 nominally significant genes. Of 73 shared genes, 93% changed in the same direction, with greater effects in ESAvsCTA, suggesting an alternative transcriptional program associated with recovery rather than restoration of the CTA state. Golgi-Cox/Sholl analysis revealed sex-dependent dendritic effects. In females, PMS reduced distal dendritic complexity (CTAvsES 80–150µm p<0.001), whereas social support attenuated this reduction (ESvsESA 40–130µm p<0.001). In males, PMS altered the radial pattern of dendritic complexity (ES.Radius p=0.032) without significant pairwise differences. Social support during pregnancy promotes molecular and structural adaptations linked to behavioral recovery.