Excess Neonatal Testosterone Causes Male-Specific Social and Fear Memory Deficits in Wild-Type Mice

Neurodevelopmental disorders disproportionately affect males compared with females. The biological mechanisms of this male susceptibility or female protection have not been identified. There is evidence that fetal/neonatal gonadal hormones, which play a pivotal role in many aspects of development, may contribute. Here, we investigate the effects of excess testosterone (T) during a critical period of sex-specific brain organization on social approach and fear learning behaviors in C57BL/6J wild-type mice. Male, but not female, mice treated with T on the day of birth (Postnatal Day 0; PN0) exhibited decreased social approach as juveniles and decreased contextual fear memory as adults, compared with vehicle (veh)-treated controls. These deficits were not driven by anxiety-like behavior or changes in locomotion or body weight. Mice treated with the same dose of T on PN18, which is outside of the critical period of brain masculinization, did not demonstrate impairments compared with the veh group. These findings indicate that excess T during a critical period of early development, but not shortly after, induces long-term deficits relevant to the male sex bias in neurodevelopmental disorders.