Modification of female and male social behaviors in estrogen receptor beta knockout mice by neonatal maternal separation

Maternal separation (MS) is an animal model mimicking the effects of early life stress on the development of emotional and social behaviors. Recent studies revealed that MS stress increased social anxiety levels in female mice and reduced pen-pubertal aggression in male mice. Estrogen receptor (ER) beta plays a pivotal role in the regulation of stress responses and anxiety-related and social behaviors. Behavioral studies using EF beta knockout (beta ERKO) mice reported increased social investigation and decreased social anxiety in beta ERKO females, and elevated aggression levels in beta ERKO males compared to wild-type (WT) mice. In the present study, using beta ERKO and WT mice, we examined whether ER beta contributes to MS effects on anxiety and social behaviors. beta ERKO and WT mice were separated from their dam daily (4 h) from postnatal day 1-14 and control groups were left undisturbed. First, MS and ER beta gene deletion individually increased anxiety-related behaviors in the open field test, but only in female mice. Anxiety levels were not further modified in beta ERKO female mice subjected to MS stress. Second, beta ERKO female mice showed higher levels of social investigation compared with WT in the social investigation test and long-term social preference test. However, MS greatly reduced social investigation duration and elevated number of stretched approaches in WT and beta ERKO females in the social investigation test, suggesting elevated levels of social anxiety in both genotypes. Third, pen-pubertal and adult beta ERKO male mice were more aggressive than WT mice as indicated by heightened aggression duration. On the other hand, MS significantly decreased aggression duration in both genotypes, but only in pen-pubertal male mice. Altogether, these results suggest that beta ERKO mice are sensitive to the adverse effects of MS stress on subsequent female and male social behaviors, which could then have overrode the ER beta effects on female social anxiety and male aggression.