# Time-Dynamic analysis of sex-specific NREM sleep disturbance induced by social isolation among adolescent mice

## TL;DR

This study finds that adolescent male mice are more vulnerable to sleep disturbances from social isolation than females, with differences in how their bodies respond over time.

## Contribution

The study reveals a sex-specific pattern of NREM sleep disturbance during adolescence linked to distinct molecular pathways in male and female mice.

## Key findings

- Male mice showed decreased NREM sleep after 2, 3, and 4 weeks of isolation, while females showed disturbances only after 4 weeks.
- Male mice's sleep disturbances were linked to sensory, metabolic, and immune systems, while females' were tied to energy and amino acid metabolism.
- The findings suggest sex-specific interventions for adolescent sleep disorders and highlight the importance of considering temporal and sex differences in sleep research.

## Abstract

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 electroencephalography (EEG) was monitored during isolation period. We then employed whole-brain transcriptomic analysis and Mfuzz enrichment analysis 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, which differs 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 weeks 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. 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.