Behavioral Impact of Adolescent Social Isolation Stress: A Multidimensional Assessment in Male NMRI Mice

Rearing in social isolation (SI) during adolescence compromises brain development and behavior. Most studies have used post-weaning SI that encompasses the entire adolescence period to investigate the consequences of adverse early-life experiences. However, adolescence comprises heterogeneous developmental phases, characterized by differences in the timing of maturation of brain regions and the endocrine system, during which exposure to adverse environments may exert distinct effects on behavioral outcomes. Here, we assessed the immediate effects on a broad range of emotional and cognitive behaviors of a 3-week SI period during mid to late adolescence in male NMRI mice. We employed z-score standardization across behavioral domains, followed by principal component analysis (PCA), to enhance the accuracy of the behavioral phenotyping and to identify domain-specific behavioral vulnerabilities to stress. Our findings indicate that mid to late SI increased locomotor activity and induced anxiety- and depressive-like behaviors, without impairing the cognitive domain. PCA further revealed a significant separation between socially isolated and group-housed animals, with hyperactivity and depressive-like behavior emerging as the main contributors to this differentiation. These results demonstrate that even less extreme forms of SI, when applied from mid to late adolescence, can substantially alter emotional responses. This study highlights the vulnerability of this developmental window and supports the use of the NMRI mouse strain as a relevant model for investigating variability in stress-related behavioral responses.