Altered dorsal functional connectivity after post-weaning social isolation and resocialization in mice

Abstract

Background: Social isolation (SI) leads to various mental health disorders. Despite abundant studies on behavioral and neurobiological changes induced by post-weaning SI, the characterization of its imaging correlates, such as resting-state functional connectivity (RSFC), is critically lacking. In addition, the effects of resocialization after isolation remain unclear. Therefore, this study aimed to explore the effects of 1) SI on cortical functional connectivity and 2) subsequent resocialization on behavior and functional connectivity. Methods: Behavioral tests were conducted to validate the post-weaning SI mouse model, which is isolated during the juvenile period. Wide-field optical mapping was performed to observe both neuronal and hemodynamic signals in the cortex under anesthesia. Using seed-based and graph theoretical analyses, RSFC was analyzed. SI mice were then resocialized and the array of behavior and imaging tests was conducted. Results: 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 resocialization, mice exhibited recovered anxiogenic and aggressive behavior, but RSFC data did not show significant changes. Conclusions: We observed an overall decrease in functional connectivity in SI mice. Moreover, resocialization restored the disruptions in behavioral patterns but functional connectivity was not recovered. To our knowledge, this is the first study to report that, despite the recovering tendencies of behavior in resocialized mice, similar changes in RSFC were not observed. This suggests that disruptions in functional connectivity caused by social isolation remain as long-term sequelae.