Sleep Deprivation alters the influence of biological sex on active-phase sleep behavior

Abstract

Poor sleep is a hazard of daily life that oftentimes cannot be avoided. Gender differences in daily sleep and wake patterns are widely reported; however, it remains unclear how biological sex, which is comprised of genetic and endocrine components, directly influences sleep regulatory processes. In the majority of model systems studied thus far, sex differences in daily sleep amount are predominant during the active (wake) phase of the sleep-wake cycle. The pervasiveness of sex differences in sleep amount throughout phylogeny suggests a strong underlying genetic component. The goal of the current study is to determine if sex differences in active-phase sleep amount are dependent on sex chromosomes in mice.Sleep was examined in the four-core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of sex phenotype (male or female). In this line, sex phenotype is determined by the presence or absence of the Sry gene, which is dissociated from the Y chromosome. Polysomnographic sleep recordings were obtained from gonadectomized (GDX) FCG mice to examine spontaneous sleep states and the ability to recover from sleep loss. We report that during the active-phase, the presence of the Sry gene accounts for most sex differences during spontaneous sleep; however, during recovery from sleep loss, sex differences in sleep amount are partially driven by sex chromosome complement. These results suggest that genetic factors on the sex chromosomes encode the homeostatic response to sleep loss.

A review of the current state of knowledge on sex differences in sleep and circadian phenotypes in rodents

“…Males with XX or XY chromosomes spent more time in NREMS than XX or XY females, confirming that gonadal phenotype/hormones regulate NREMS ( Ehlen et al, 2013 ; Nichols et al, 2020 ). However, although GDX greatly reduced this difference in the first study ( Ehlen et al, 2013 ), the difference persists in the latter ( Nichols et al, 2020 ). Therefore, these results seem to indicate that male rodents have more NREMS than females, and that this sex difference is influenced by circulating gonadal hormones and Sry expression, and not by sex chromosomes.…”

“…An absence of sex difference in time spent in NREMS in mice was reported by one study using a piezoelectric assessment of sleep (no EEG quantification; Wang et al, 2020 ), two studies underpowered to assess sex differences (e.g., n = 3 males) ( Brankack et al, 2010 ; Hellman et al, 2010 ), and two other studies not designed to primarily investigate sex differences ( Grønli et al, 2016 ; Huitron-Resendiz et al, 2018 ). In contrast, we found seven studies having shown that male mice and rats spend more time in NREMS than females ( Ehlen et al, 2013 ; Franken et al, 2006 ; Koehl et al, 2006 ; Nichols et al, 2020 ; Paul et al, 2006 ; Saré et al, 2020 ; Swift et al, 2020 ). In particular, compared to females, C57BL/6 male mice spend more time in NREMS during the dark period, which also brings their daily percentage of NREMS to a greater level ( Paul et al, 2006 ).…”

“…1 Summary of the main sex differences observed in the time spent in wakefulness, NREMS and REMS in mice (A) and rats (B). (A) Sex differences in mice have been compiled from light, dark and/or 24-h periods datasets of Franken et al (2006) , Koehl et al (2006) Paul et al (2006) , Ehlen et al (2013) , Nichols et al (2020) , and Saré et al (2020) . Of note is that an absence of sex difference have been reported for wakefulness and NREMS by Grønli et al (2016) and Huitron-Resendiz et al (2018) .…”

“…First, animals submitted to GDX show no sex difference in time spent in NREMS ( Cusmano et al, 2014 ; Paul et al, 2006 ), which was proposed, similar to time spent awake, to be mostly driven by ovarian hormones rather than by androgens ( Cusmano et al, 2014 ; Paul et al, 2006 ). To tease apart the effects of sex chromosomes (XY vs XX) from that of gonadal phenotype (testes vs. ovaries), the four core genotype (FCG) model, whose sex chromosomes (XY/XX) are independent of the gonadal phenotype (testes/ovaries; driven by a Sry gene dissociated from the Y chromosome), has been used ( Ehlen et al, 2013 ; Nichols et al, 2020 ). Males with XX or XY chromosomes spent more time in NREMS than XX or XY females, confirming that gonadal phenotype/hormones regulate NREMS ( Ehlen et al, 2013 ; Nichols et al, 2020 ).…”

“…To tease apart the effects of sex chromosomes (XY vs XX) from that of gonadal phenotype (testes vs. ovaries), the four core genotype (FCG) model, whose sex chromosomes (XY/XX) are independent of the gonadal phenotype (testes/ovaries; driven by a Sry gene dissociated from the Y chromosome), has been used ( Ehlen et al, 2013 ; Nichols et al, 2020 ). Males with XX or XY chromosomes spent more time in NREMS than XX or XY females, confirming that gonadal phenotype/hormones regulate NREMS ( Ehlen et al, 2013 ; Nichols et al, 2020 ). However, although GDX greatly reduced this difference in the first study ( Ehlen et al, 2013 ), the difference persists in the latter ( Nichols et al, 2020 ).…”