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Continuous social isolation (SI) from an early developmental stage may have different effects in youth and adulthood. Moreover, SI is reported to impair neuronal plasticity. In this study, we used post-weaning rats to compare the impact of continuous SI on depressive-like, anxiety-related, and fear-related behaviors and neuronal plasticity in puberty and adulthood. Furthermore, we assessed the effect of lithium on behavioral changes and neuronal plasticity. Continuous SI after weaning induced depressive-like behaviors in puberty; however, in adulthood, depressive-like and anxiety-related behaviors did not increase, but-paradoxically-decreased in comparison with the controls. The decreased expression of neuronal plasticity-related proteins in the hippocampus in puberty was more prominent in the prefrontal cortex and hippocampus in adulthood. In contrast, SI after weaning tended to decrease fear-related behaviors in puberty, a decrease which was more prominent in adulthood with increased neuronal plasticity-related protein expression in the amygdala. Lithium administration over the last 14 days of the SI-induced period removed the behavioral and expression changes of neuronal plasticity-related proteins observed in puberty and adulthood. Our findings suggest that the extension of the duration of SI from an early developmental stage does not simply worsen depressive-like behaviors; rather, it induces a behavior linked to neuronal plasticity damage. Lithium may improve behavioral changes in puberty and adulthood by reversing damage to neuronal plasticity. The mechanisms underlying the depressive-like and anxiety-related behaviors may differ from those underlying fear-related behaviors.

Paradoxical changes in mood-related behaviors on continuous social isolation after weaning