Vitamin D deficiency is prevalent in many developed countries, and several studies suggest that vitamin D plays an essential role in brain function. A recent study showed that vitamin D deficiency was closely associated with daytime sleepiness and shorter sleep time. The relationshipbetween vitamin D levels and calcium levels is well established, and calcium level regulates slow-wave sleep generation. It is conceivable that the sleep disturbance in vitamin D deficiency may be due to an altered calcium level. Nonetheless, calcium levels, sleep disturbances, and activity rhythms have not been investigated directly. Therefore, we hypothesized that calcium and vitamin D levels might be important in regulating sleep and activity rhythm, and we analyzed the correlation with calcium levels by actigraphy analysis. Interestingly, a negative correlation was found between calcium level and sleep latency, total sleep time, use of sleep medicine, and daytime dysfunction among shift workers. In contrast, non-shift workers showed a negative correlation between the calcium level and the circadian phase. These findings suggest that low serum calcium levels may disrupt sleep–wake control and rest–activity rhythm, even if they are within the normal range.

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 post-weaning 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 (OFCL). When we measured neural activity in the female OFCL, 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 knock-down of PV in the OFCLduring 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 OFCL. Moreover, optogenetic activation of excitatory neurons or optogenetic inhibition of PV+neurons in the OFCLenhanced sociability in female mice. Our data demonstrate that the adolescent social experience is critical for the maturation of PV+inhibitory circuits in the OFCL; this maturation shapes female social behavior via enhancing social representation in the OFCL.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 OFCL, and decreased socially evoked activity in the OFCL. Moreover, PV deletion in the OFCLin vivocaused the same phenotypes in female mice by increasing excitation compared with inhibition within the OFCL. Our data suggest that adolescent social experience is required for PV maturation in the OFCL, which is critical for evoking OFCLactivity that shapes social behaviors in female mice.

The adolescent social experience is essential for the maturation of the prefrontal cortex (PFC) in mammalian species. However, it is still unclear which cortical circuits mature with such experience and how it shapes adult social behaviors in a sex-specific manner. Here, we found that the post-weaning social isolation during adolescence (PWSI) caused hypersociability in female mice only and impaired both the parvalbumin (PV) expression and social sniffing-induced activity in the left orbitofrontal cortex (OFCL). Similarly, the CRISPR/Cas9-mediated knock-down of PV in the OFCL enhanced sociability and reduced the social sniffing-induced activity in female mice via decreased excitability of PV+ neurons and reduced synaptic inhibition in the OFCL. Moreover, optogenetic activation of OFCL excitatory neurons enhanced sociability in female mice. Our data demonstrate that the adolescent social experience is critical for the maturation of PV+ inhibitory circuits in the OFCL; this maturation shapes female social behavior via enhancing social representation in the OFCL.