Time-Dynamic Analysis of Sex-Specific NREM Sleep Disturbance Induced by Social Isolation Among Adolescent Mice

Sleep disturbances are more prevalent in women than in men during adulthood. However, since age-related changes in sleep and the consequences of sleep disturbances can occur as early as adolescence, it remains poorly understood whether these disturbances exhibit a similar sex-specific pattern during adolescence and what the underlying molecular mechanisms may be. Male and female mice were subjected to social isolation stress starting at postnatal day 21 (P21), and electroencephalogram (EEG) was monitored during isolation period. We then employed whole-brain transcriptomic analysis and Mfuzz enrichment analyses to identify temporal and sex-specific molecular responses, dynamic gene expression patterns, and key pathways during isolation period. Male mice exhibited decreased non-rapid eye movement (NREM) sleep duration after 2, 3, and 4 weeks of isolation, while female mice did not show these disturbances after 2 and 3 weeks, but did after 4 weeks of isolation. This suggested a sex-specific pattern of sleep disturbances during adolescence, distinct from those observed in adulthood. Moreover, the decreased NREM sleep in isolated male mice was related to sensory, metabolic, and immune systems after 2-, 3-, and 4-week of isolation, respectively. While the reduction in NREM duration in female mice after 4 weeks of isolation was associated with their energy metabolism and amino acid metabolism disruptions. We found a sex-specific pattern of sleep disturbances during adolescence, with male mice being more susceptible to social isolation stress, which may be linked to early sensory system responses in isolated male mice and later-stage amino acid metabolism and energy imbalance in isolated female mice. Our findings provide insights into gender-specific interventions for sleep disorders during adolescence and underscore the importance of considering both temporal and sex differences in stress-related sleep research.