Adversities associated with isolation during adolescence, including the lack of appropriate emotional and social experiences, can jeopardize the individual development leading to the onset of mental illnesses such as major depressive disorder. Girls have higher rates of depression compared to boys
however, the relative contribution of biological and cultural factors to such a gender-dependent difference remains unclear. To identify the role of biological factors in this distinct susceptibility, we exposed adolescent C57BL/6 male and female mice (n = 12-14) to social isolation and we evaluated their behavioral responses, investigating both emotional and cognitive competencies during adolescence. In addition, we assessed alterations in immune activation and brain plasticity by measuring the expression levels of several pro- and anti-inflammatory cytokines and neural plasticity markers. Finally, we investigated the hormonal stress response by evaluating the hypothalamic-pituitary-adrenal (HPA) axis reactivity. Our findings indicate that adolescent social isolation leads to the development of depressive- and anxiety-like traits, although it impacts distinct behavioral domains with varying degrees in males and females. Both genders exhibited deficiencies in the emotional realm, displaying enhanced anhedonia and anxiety compared to their respective control groups. Moreover, males exhibited cognitive impairments linked to an altered HPA axis activity. Remarkably, social isolation influenced immune activation in both sexes, resulting in decreased pro-inflammatory markers. Overall, these results affirm the significant impact of social experiences during adolescence on neurodevelopment. Notably, our study reveals that both males and females are equally susceptible to the effects of isolation, although sex-specific differences become apparent in the alterations observed at both behavioral and physiological levels.