Gonadal Steroid Modulation of Sleep and Wakefulness in Male and Female Rats Is Sexually Differentiated and Neonatally Organized by Steroid Exposure

Abstract

The paucity of clinical and preclinical studies investigating sex differences in sleep has resulted in mixed findings as to the exact nature of these differences. Although gonadal steroids are known to modulate sleep in females, less is known about males. Moreover, little evidence exists concerning the origin of these sex differences in sleep behavior. Thus, the goal of this study was to directly compare the sensitivity of sleep behavior in male and female Sprague Dawley rats to changes in the gonadal steroid milieu and to test whether the sex differences in sleep are the result of brain sexual differentiation or differences in circulating gonadal steroids. Here we report the magnitude of change in sleep behavior induced by either estradiol (E2) or testosterone (T) was greater in females compared with males, suggesting that sleep behavior in females is more sensitive to the suppressive effects of gonadal steroids. Furthermore, we demonstrated that the organizational effects of early gonadal steroid exposure result in male-like responsivity to gonadal steroids and directly alter the activity of the ventrolateral preoptic area (VLPO), an established sleep-promoting nucleus, in adult masculinized females. Moreover, the nonaromatizable androgen dihydrotestosterone did not suppress sleep in either males or females, suggesting that the T-mediated effect in females was due to the aromatization of T into E2. Together our data suggest that, like sex behavior, sex differences in sleep follow the classical organizational/activational effects of gonadal steroids.

Sex differences in sleep: impact of biological sex and sex steroids

“…Recent findings in adult rats support this assertion and further suggest that sleep patterns in females remain sensitive to fluctuations in oestradiol while males on the other hand seem insensitive to changes in both oestradiol and testosterone [108]. Gonadectomized male and female rats exhibit no significant differences in any vigilance state.…”

“…Thus, the effect of sex steroids on sleep might be chronotype dependent, such that oestradiol in rodents may work to consolidate sleep and wake behaviours to the appropriate phases. Indeed, oestradiol administered to ovariectomized rats increases the duration of total sleep in the light phase by a small but significant degree [108] (figure 3). Moreover, findings from SD studies further support that ovarian steroids and oestradiol in particular may facilitate recovery from sleep loss [121,122,125 -127].…”

“…Under normal sleep conditions, oestradiol administered to ovariectomized adult rats increases spontaneous total sleep (NREM and REM) in the light phase while suppressing total sleep in the dark phase, resulting in more consolidated wake bouts (not shown). Data redrawn from [108]. Following a 6-h bout of sleep deprivation (SD), oestradiol facilitated REM recovery sleep in the light phase allowing a return to baseline levels in the dark phase.…”

Multifaceted origins of sex differences in the brain

“…R. Soc. B 371: 20150106 sleep appear to have origins in development and to be sexually differentiated by hormones in the same manner as so many other traits [95]. Inappropriate attention to sleep disorders in women has compounding effects.…”

The Neurobiology of Sleep and Wakefulness

“…327, 330, 332-334 Studies exploiting genetic tools to dissociate genetic and gonadal sex, along with use of classical neuroendocrine paradigms, recently showed that sex differences in sleep appear to be developmentally determined by a combination of genetic sex and gonadal hormone exposure. 335, 336 Estradiol downregulates the synthetic enzyme for PGD 2 , 337 increases Hcrt and Hcrt receptor expression levels, 338, 339 and modulates Fos expression in the VLPO and TM. 331 …”