Adolescent social isolation induces sex-specific behavioral and neural alterations

Adversities associated to isolation during adolescence, including the lack ofappropriate emotional and social experiences, can jeopardize the individualdevelopment leading to the onset of mental illnesses such as major depressivedisorder. Girls are more vulnerable than boys to isolation. However, the relativecontribution of biological and cultural factors to a such gender-dependent differenceremains unclear. To identify the role of biological factors in this distinct vulnerability, weexposed adolescent C57BL/6 male and female mice (n=12-14) to social isolation andwe evaluated their behavioral responses, investigating both emotional and cognitivecompetencies. In addition, we assessed alterations in immune activation and brainplasticity by measuring the expression levels of several pro- and anti-inflammatorycytokines and neural plasticity markers. Finally, we investigated the hormonal stressresponse by evaluating the hypothalamic–pituitary–adrenal (HPA) axis reactivity. Ourfindings indicate that adolescent social isolation leads to the development ofdepressive- and anxiety-like traits, although it impacts distinct behavioral domains withvarying degrees in males and females. Both genders exhibited deficiencies in theemotional realm, displaying enhanced anhedonia and anxiety compared to theirrespective control groups. Moreover, males exhibited cognitive impairments linked toan altered HPA axis activity. Remarkably, social isolation influenced immune activationin both sexes, resulting in decreased pro-inflammatory markers and diminished neuralplasticity. Overall, these results affirm the significant impact of social experiencesduring adolescence on neurodevelopment. Notably, our study reveals that both malesand females are equally susceptible to the effects of isolation, although sex-specificdifferences become apparent in the alterations observed at both behavioral andphysiological levels.