Adolescent Parvalbumin Expression in the Left Orbitofrontal Cortex Shapes Sociability in Female Mice

Abstract

The adolescent social experience is essential for the maturation of the prefrontal cortex in mammalian species. However, it still needs to be determined which cortical circuits mature with such experience and how it shapes adult social behaviors in a sex-specific manner. Here, we examined social-approaching behaviors in male and female mice after postweaning social isolation (PWSI), which deprives social experience during adolescence. We found that the PWSI, particularly isolation during late adolescence, caused an abnormal increase in social approaches (hypersociability) only in female mice. We further found that the PWSI female mice showed reduced parvalbumin (PV) expression in the left orbitofrontal cortex (OFC_L). When we measured neural activity in the female OFC_L, a substantial number of neurons showed higher activity when mice sniffed other mice (social sniffing) than when they sniffed an object (object sniffing). Interestingly, the PWSI significantly reduced both the number of activated neurons and the activity level during social sniffing in female mice. Similarly, the CRISPR/Cas9-mediated knockdown of PV in the OFC_L during late adolescence enhanced sociability and reduced the social sniffing-induced activity in adult female mice via decreased excitability of PV⁺ neurons and reduced synaptic inhibition in the OFC_L. Moreover, optogenetic activation of excitatory neurons or optogenetic inhibition of PV⁺ neurons in the OFC_L enhanced sociability in female mice. Our data demonstrate that the adolescent social experience is critical for the maturation of PV⁺ inhibitory circuits in the OFC_L; this maturation shapes female social behavior via enhancing social representation in the OFC_L.

SIGNIFICANCE STATEMENT Adolescent social isolation often changes adult social behaviors in mammals. Yet, we do not fully understand the sex-specific effects of social isolation and the brain areas and circuits that mediate such changes. Here, we found that adolescent social isolation causes three abnormal phenotypes in female but not male mice: hypersociability, decreased PV⁺ neurons in the left orbitofrontal cortex (OFC_L), and decreased socially evoked activity in the OFC_L. Moreover, parvalbumin (PV) deletion in the OFC_L in vivo caused the same phenotypes in female mice by increasing excitation compared with inhibition within the OFC_L. Our data suggest that adolescent social experience is required for PV maturation in the OFC_L, which is critical for evoking OFC_L activity that shapes social behaviors in female mice.