Sex Differences in Mouse Sleep Introduction Although the Maintenance of Adequate Sleep Time and Sleep Quality Are Important for Many Aspects of Overall Health and Neurocognitive

ALTHOUGH THE MAINTENANCE OF ADEQUATE SLEEP TIME AND SLEEP QUALITY ARE IMPORTANT FOR MANY ASPECTS OF OVERALL HEALTH AND NEUROCOGNITIVE performance,1-4 very little is known about how sex may affect the health and performance consequences associated with poor and inadequate sleep. A number of sex differences in sleep have, however, been reported. For instance, clinical studies using various methods of sleep analysis suggest that women experience more episodes of insomnia than men and that the concurrence of insomnia with several forms of clinical depression is more prevalent in women.5-8 Conversely, men are more susceptible to and far more likely to suffer from sleep apnea than women.8-10 Most studies of sleep-wake regulation have focused on males despite, and in large part because of, compelling evidence that fluctuations in the reproductive hormone environment influence a variety of sleep-wake parameters. Studies that have analyzed sleep-wake regulatory processes in humans and animal models have revealed important sex differences, but the underlying physiologic processes linking the sleep-wake cycle to sex and sex determinants remain poorly understood.11-16 Given the evident importance of sex differences in normal and pathophysiologic sleepwake states, there is a need to develop stronger animal models to determine the mechanisms responsible for the ability of sex to influence sleep. Although animal models for sleep are reliable for determining the role of specific behaviors and physiologic factors on sleep and wakefulness, few studies in animals have directly examined the influence of sex on sleep. Two studies in rats found that males display significantly more paradoxical sleep during the day and night than females,17,18 whereas another study in SwissWebster mice reported a slight diurnal sex differences in rapid eye movement (REM) and NREM sleep amount.19 Interestingly, recent studies have found that Drosophila display several sex dimorphisms in rest and activity patterns under baseline and restdeprivation conditions,20,21 indicating that sex and its interaction with the environment influences sleep-wake parameters across a wide range of species. Although sexual dimorphism of sleep in mice, the primary mammalian genetic model for sleep investigation, was reported in abstract form more than 15 years ago,19,22 little information about the role of sex on sleep and wakefulness in this species is available. Estrous cycle-related differences in the sleep-wake pattern of female rats and humans have made it difficult to study sex effects on sleep; however, the C57BL/6J (B6) mouse, which exhibits very little change in sleep distribution across the estrous cycle,23 represents a unique candidate model for examining sexrelated differences in sleep and wakefulness. We report here several studies that have identified sex-specific parameters of sleep and wakefulness in the B6 mouse under baseline, as well as sleepdeprivation conditions. Furthermore, we describe the impact of the removal of gonads in adult male and female mice on sex differences in sleep and wakefulness. These findings create the framework for utilizing the mouse as a model organism to study and characterize the mechanisms through which sex influences sleep and how the hormone environment influences the effect of sex on the sleep-wake cycle. Diurnal Sex Differences in the Sleep-Wake Cycle of Mice are Dependent on Gonadal Function