Early life stress produces distinct, disease-relevant alterations in brain and behavior in males and females

Stress during early life influences brain development and can affect social, motor, and emotional processes. Here, using mice as a model system, we show that deprivation during the first week of life leads to dysregulated repetitive behaviors and social deficits in adolescence in male but not female mice, and to anxiety- and depression-like behaviors in females but not males, a novel double dissociation. Mechanistic analysis identifies dissociable, sex-specific abnormalities in cortico-striatal and cortico-septal circuits in association with these behaviors and reveals that susceptibility to dysregulated repetitive behaviors and social deficits in males is associated with XY karyotype irrespective of gonadal sex, while susceptibility to depression-like behaviors in females is associated with female gonadal sex, irrespective of chromosomal complement. These observations reveal a striking double dissociation in the effects of developmental stress.