(The) effects of chronic social isolation on social behavior and brain network

Abstract

Social isolation (SI), the deprivation of social contact, is a global problem that can lead to a strongly aversive emotional state in humans and influences the health of individuals across the life-course. As modern society faces social problems such as a surge in single-person households and the recommendation of social isolation due to the COVID-19 pandemic, the importance of research on how chronic social isolation can affect people is being emphasized. According to the previous results, the effects of chronic social isolation are different depending on the period of experience. In this study, we mainly investigated the effects of chronic social isolation in the juvenile period and adulthood on social behavior and brain network in an animal model.Since chronic social isolation in the juvenile period disrupts normal developmental states, abundant studies on post-weaning social isolation have enlightened the behavioral deficits and neurobiological underpinnings. However, the characterization of its imaging correlates is critically lacking. Therefore, in the first part of this study, we investigated changes in the functional connectivity associated with social behavioral deficits and the effect of re-socialization, the behavioral intervention of juvenile social isolation, on the brain network using a wide-field optical imaging method. Behaviorally, SI mice showed elevated anxiety, social preference, and aggression. RSFC analyses using the seed-based approach revealed decreased cortical functional connectivity in SI mice, especially in the frontal region. Graph network analyses demonstrated significant reduction in network segregation measures. After re-socialization, mice exhibited recovered anxiogenic and aggressive behavior, but RSFC data did not show significant changes. This suggests that disruptions in functional connectivity caused by social isolation remain as long-term sequelae.Acute social isolation in adulthood leads to an increase in affiliative behaviors such as social interaction, whereas chronic social isolation results in the heterogeneous consequences of anti-social behaviors. In the second part of this study, we examined closely the behavioral consequences of chronic social isolation in adulthood, especially social withdrawal behaviors, and characterized changes in the brain networks during social behaviors using the electrophysiological recordings. We found isolation-induced social withdrawal behaviors in the chronic adult SI model during direct interaction with the juvenile conspecifics. Furthermore, chronic SI mice were divided into two groups based on the level of withdrawal behaviors: susceptible (SUS) and resilient (RES) SI mice exhibited high and low social withdrawal behaviors, respectively. We found increased social interactions in RES mice and identified a network between the anterior insular cortex (AIC) and the medial prefrontal cortex (mPFC) associated with these behaviors. In addition, we identified a network between the AIC and the nucleus accumbens core (NAcc) associated with increased withdrawal behaviors in SUS mice. Furthermore, SUS mice exhibited disrupted sociability with the changes in the AIC-NAcc network. These results may not only facilitate an understanding of specific brain network for social behavioral changes in chronic individual housing in adulthood but may also uncover the important role of AIC in representing the susceptibility to negative social experiences.