Maternal Social Support Reshapes the Offspring Brain Transcriptome to Buffer Prenatal Stress in Mice

Early-life adversity, including prenatal stress, has lasting consequences for maternal and offspring mental health. However, the mechanisms through which social support buffers these effects remain poorly understood. Using a mouse model, we examined whether gestational social support from a familiar female protects against prenatal stress and whether this protection restores a stress-free molecular phenotype or engages a distinct compensatory program. Pregnant females exposed to unpredictable prenatal stress displayed impaired maternal care, elevated peripartum corticosterone levels, and reduced prefrontal and amygdala expression of oxytocinergic and dopaminergic genes. Their offspring showed impaired maternal-odor preference and long-term spatial memory. Strikingly, socially supported mothers and their offspring were virtually indistinguishable from unstressed controls across these behavioral and candidate-gene measures. Female companions increased affiliative interactions specifically in response to the pregnant female's distress, consistent with a targeted prosocial response. However, whole-transcriptome analysis of offspring prefrontal cortex revealed a more complex picture: differentially expressed genes associated with stress and social support converged on synaptic transmission and neuronal connectivity, yet the transcriptome of socially supported offspring did not return to the control state. Instead, it diverged further along the same trajectory as prenatal stress, indicating an amplified rather than reversed molecular shift. These findings support a two-level model in which social support normalizes stress-reactive proximal signaling while activating a distinct adaptive transcriptional program in the developing brain. Maternal social support may therefore represent a modifiable factor that mitigates the intergenerational consequences of early-life adversity and reshape resilience as an active adaptation rather than restoration of baseline state.  .