The temporal structure of behaviour and sleep homeostasis.

The amount and architecture of vigilance states are governed by two distinct processes, which occur at different time scales. The first, a slow one, is related to a wake/sleep dependent homeostatic Process S, which occurs on a time scale of hours, and is reflected in the dynamics of NREM sleep EEG slow-wave activity. The second, a fast one, is manifested in a regular alternation of two sleep states--NREM and REM sleep, which occur, in rodents, on a time scale of ~5-10 minutes. Neither the mechanisms underlying the time constants of these two processes--the slow one and the fast one, nor their functional significance are understood. Notably, both processes are primarily apparent during sleep, while their potential manifestation during wakefulness is obscured by ongoing behaviour. Here, we find, in mice provided with running wheels, that the two sleep processes become clearly apparent also during waking at the level of behavior and brain activity. Specifically, the slow process was manifested in the total duration of waking periods starting from dark onset, while the fast process was apparent in a regular occurrence of running bouts during the waking periods. The dynamics of both processes were stable within individual animals, but showed large interindividual variability. Importantly, the two processes were not independent: the periodic structure of waking behaviour (fast process) appeared to be a strong predictor of the capacity to sustain continuous wakefulness (slow process). The data indicate that the temporal organization of vigilance states on both the fast and the slow time scales may arise from a common neurophysiologic mechanism.

TNFR1 is essential for CD40, but not for lipopolysaccharide-induced sickness behavior and clock gene dysregulation.

Autoimmune and infectious diseases are associated with behavioral changes referred to as sickness behavior syndrome (SBS). In autoimmunity, the generation of anti-self T lymphocytes and autoantibodies critically involves binding of CD40 ligand on T-cells to its receptor CD40 on B-cells, dendritic cells and macrophages. Activation of CD40 leads to production of proinflammatory cytokines and, as shown here, induces SBS. Here we report that these behavioral changes depend on the expression of tumor necrosis factor alpha receptor 1 (TNFR1), but not on interleukin-1 receptor 1 or interleukin-6. Moreover, the intensity of SBS correlates with suppression of E-box controlled clock genes, including Dbp, and upregulation of Bmal1. However, the absence of TNFR1 does not interfere with the development of SBS and dysregulation of clock genes in mice treated with lipopolysaccharide. Thus, our results suggest that TNFR1 mediates SBS and dysregulation of clock genes in autoimmune diseases.

Manipulation of adenosine kinase affects sleep regulation in mice.

Sleep and sleep intensity are enhanced by adenosine and its receptor agonists, whereas adenosine receptor antagonists induce wakefulness. Adenosine kinase (ADK) is the primary enzyme metabolizing adenosine in adult brain. To investigate whether adenosine metabolism or clearance affects sleep, we recorded sleep in mice with engineered mutations in Adk. Adk-tg mice overexpress a transgene encoding the cytoplasmic isoform of ADK in the brain but lack the nuclear isoform of the enzyme. Wild-type mice and Adk(+/-) mice that have a 50% reduction of the cytoplasmic and the nuclear isoforms of ADK served as controls. Adk-tg mice showed a remarkable reduction of EEG power in low frequencies in all vigilance states and in theta activity (6.25-11 Hz) in rapid eye movement (REM) sleep and waking. Adk-tg mice were awake 58 min more per day than wild-type mice and spent significantly less time in REM sleep (102 ± 3 vs 128 ± 3 min in wild type). After sleep deprivation, slow-wave activity (0.75-4 Hz), the intensity component of non-rapid eye movement sleep, increased significantly less in Adk-tg mice and their slow-wave energy was reduced. In contrast, the vigilance states and EEG spectra of Adk(+/-) and wild-type mice did not differ. Our data suggest that overexpression of the cytoplasmic isoform of ADK is sufficient to alter sleep physiology. ADK might orchestrate neurotransmitter pathways involved in the generation of EEG oscillations and regulation of sleep.

Metabolic response of the cerebral cortex following gentle sleep deprivation and modafinil administration.

STUDY OBJECTIVES: The main energy reserve of the brain is glycogen, which is almost exclusively localized in astrocytes. We previously reported that cerebral expression of certain genes related to glycogen metabolism changed following instrumental sleep deprivation in mice. Here, we extended our investigations to another set of genes related to glycogen and glucose metabolism. We also compared the effect of instrumentally and pharmacologically induced prolonged wakefulness, followed (or not) by 3 hours of sleep recovery, on the expression of genes related to brain energy metabolism. DESIGN: Sleep deprivation for 6-7 hours. SETTING: Animal sleep research laboratory. PARTICIPANTS: Adults OF1 mice. INTERVENTIONS: Wakefulness was maintained by "gentle sleep deprivation" method (GSD) or by administration of the wakefulness-promoting drug modafinil (MOD) (200 mg/kg i.p.). MEASUREMENTS AND RESULTS: Levels of mRNAs encoding proteins related to energy metabolism were measured by quantitative real-time PCR in the cerebral cortex. The mRNAs encoding protein targeting to glycogen (PTG) and the glial glucose transporter were significantly increased following both procedures used to prolong wakefulness. Glycogenin mRNA levels were increased only after GSD, while neuronal glucose transporter mRNA only after MOD. These effects were reversed after sleep recovery. A significant enhancement of glycogen synthase activity without any changes in glycogen levels was observed in both conditions. CONCLUSIONS: These results indicate the existence of a metabolic adaptation of astrocytes aimed at maintaining brain energy homeostasis during the sleep-wake cycle.

Sleep deprivation in the dark period does not impair memory in OF1 mice.

There is increasing evidence that sleep facilitates memory acquisition and consolidation. Moreover, the sleep-wake history preceding memory acquisition and retention as well as circadian timing may be important. We showed previously that sleep deprivation (SD) following learning in OF1 mice impaired their performance on an object recognition task. The learning task was scheduled at the end of the 12 h dark period and the test 24 h later. To investigate the influence of the prominent circadian sleep-wake distribution typical for rodents, we now scheduled the learning task at the beginning of the dark period. Wakefulness following immediately after the learning task was attained either by gentle interference (SD; n = 20) or by spontaneous wheel running (RW; n = 20). Two control groups were used: one had no RW throughout the experiment (n = 23), while the other group's wheel was blocked immediately after acquisition (n = 16), thereby preventing its use until testing. Recognition memory, defined as the difference in exploration of a novel and of familiar objects, was assessed 24 h later during the test phase. Motor activity and RW use were continuously recorded. Remarkably, performance on the object recognition task was not influenced by the protocols; the waking period following acquisition did not impair memory, independent of the method inducing wakefulness (i.e., sleep deprivation or spontaneous running). Thus, all groups explored the novel object significantly longer than the familiar ones during the test phase. Interestingly, neither the amount of rest lost during the SD interventions nor the amount of rest preceding acquisition influenced performance. However, the total amount of rest obtained by the control and SD mice subjected to acquisition at "dark offset" correlated positively (r = 0.66) with memory at test, while no such relationship occurred in the corresponding groups tested at dark onset. Neither the amount of running nor intermediate rest correlated with performance at test in the RW group. We conclude that interfering with sleep during the dark period does not affect object recognition memory consolidation.

European guidelines for the certification of professionals in sleep medicine: report of the task force of the European Sleep Research Society.

In recent years, sleep medicine has evolved into a full-grown discipline, featuring a multidisciplinary approach to diagnosis and treatment of patients with sleep disorders. Sleep medicine cuts across the boundaries of different conventional disciplines and is therefore open to medical and non-medical professionals with different specialty backgrounds. The aim of the current paper is to introduce a qualification for those professionals whose main occupation is to practice sleep medicine in the setting of a sleep medicine centre. The drafting of guidelines dealing with requirements for such qualification was entrusted to a task force by the European Sleep Research Society. The guidelines are the result of a progressive consensus procedure in which standards were defined for education, training, and evaluation. The final step along this pathway is a theoretical and practical examination, providing proof of proficiency in the field of sleep medicine. This paper describes the object of specific competences, the scope of sleep medicine, and the qualification procedures that pertain to three professional categories: medical specialists, non-medical professionals with a university master degree (such as psychologists and biologists), and nurses and technologists. Indices of preceding practical experience and theoretical knowledge are presented in Appendices 1 and 2. These guidelines are a European standard. They may be adapted in the future according to new scientific insights. National certification programs that comply with these guidelines may be subject to homologation by the ESRS.

Mice heterozygous for both A1 and A(2A) adenosine receptor genes show similarities to mice given long-term caffeine.

Caffeine is believed to exert its stimulant effects by blocking A(2A) and A(1) adenosine receptors (A(2A)R and A(1)R). Although a genetic knockout of A(2A)R eliminates effects of caffeine, the phenotype of the knockout animal does not resemble that of caffeine treatment. In this study we explored the possibility that a mere reduction of the number of A(1)Rs and A(2A)Rs, achieved by deleting one of the two copies of the A(1)R and A(2A)R genes, would mimic some aspects of long-term caffeine ingestion. The A(1)R and A(2A)R double heterozygous (A(1)R-A(2A)R dHz) mice indeed had approximately one-half the number of A(1)R and A(2A)R, and there were little compensatory changes in A(2B) or A(3) adenosine receptor (A(2B)R or A(3)R) expression. The ability of a stable adenosine analog to activate receptors was shifted to the right by caffeine and in A(1)R-A(2A)R dHz tissue. Caffeine (0.3 g/l in drinking water for 7-10 days) and A(1)R-A(2A)R dHz genotype increased locomotor activity (LA) and decreased heart rate without significantly influencing body temperature. The acute stimulatory effect of a single injection of caffeine was reduced in A(1)R-A(2A)R dHz mice and in mice treated long term with oral caffeine. Thus at least some aspects of long-term caffeine use can be mimicked by genetic manipulation of the A(1)R and A(2A)R.

TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription.

Production of TNF-alpha and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-alpha and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-alpha on the circadian timing system. TNF-alpha is shown here to suppress the expression of the PAR bZip clock-controlled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-alpha on clock genes is shared by IL-1beta, but not by IFN-alpha, and IL-6. Furthermore, TNF-alpha interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-alpha is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-alpha and IL-1beta, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.

The EEG effects of THIP (Gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors.

THIP (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol, Gaboxadol) is a selective gamma-aminobutyric acid (GABA)(A) agonist, acting in vitro with high potency and efficacy at the extrasynaptic GABA(A)delta-containing receptors. THIP was suggested to be a potential hypnotic to treat insomnia, and it is currently in clinical trial. Here we assessed whether the GABA(A)delta-containing receptors mediate in vivo the effect of THIP on sleep and the sleep electroencephalogram (EEG). We performed EEG recordings in a mouse model deficient in the GABA(A)delta-subunit gene (delta(-/-) mice) and in wild-type littermate controls. THIP (4 and 6 mg/kg intraperitoneally) induced an abnormal EEG pattern, resulting in dramatic changes in the waking and non-rapid eye movement (NREM) sleep EEG spectra in wild-type mice. Indeed, a massive increase in EEG power lasting 2-3 h occurred in both the frontal and parietal derivation, especially in frequencies below 6 Hz. All effects were more prominent in the frontal EEG. Furthermore, the highest dose of THIP lengthened REM sleep latency and suppressed REM sleep. In contrast, vigilance states and sleep latencies were not affected in delta(-/-) mice. Moreover, only minor changes were observed in the NREM sleep EEG spectrum after THIP injection in the delta-subunit-deficient mice. The present findings do not indicate a sleep-promoting effect of THIP in mice, which is in accordance with a previous report in this species. Moreover, our results in vivo demonstrate that THIP acts preferentially at GABA(A) receptors containing the delta-subunit.

Mice convert melatonin to 6-sulphatoxymelatonin.

The principal objective of this study was to establish whether mice can convert melatonin to 6-sulphatoxymelatonin (aMT6s). Precision-cut liver slices from C3H/He, C57BL/6, and BALB/c mice were incubated with melatonin, and the concentration of aMT6s in the culture media was determined using a sensitive and specific radioimmunoassay procedure. All three strains of mice generated aMT6s in a time-dependent manner; no significant strain differences were observed. When samples of the media were treated with sulphatase prior to analysis, aMT6s was not detectable. In contrast, similar treatment with beta-glucuronidase had no effect. 6-Sulphatoxymelatonin was present in the urine of both control and melatonin-treated C3H/He and C57BL6 mice. Treatment with melatonin led to a dramatic rise in the urinary levels of aMT6s in both mouse strains. Pre-treatment of the urines with sulphatase, but not beta-glucuronidase, markedly decreased the levels of aMT6s. Finally, in both strains urinary excretion of aMT6s displayed diurnal rhythmicity, peak excretion occurring during the dark hours. It may be inferred that: (a) mice can convert melatonin to aMT6s, both in vivo and in vitro, and (b) mice generate aMT6s in a rhythmic manner. Finally, the present studies confirm that determination of aMT6s rhythms in mice could provide an alternative, non-invasive, approach for assessing circadian clock function.

Sleep deprivation impairs object recognition in mice.

Many studies in animals and humans suggest that sleep facilitates learning, memory consolidation, and retrieval. Moreover, sleep deprivation (SD) incurred after learning, impaired memory in humans, mice, rats, and hamsters. We investigated the importance of sleep and its timing in an object recognition task in OF1 mice subjected to 6h SD either immediately after the acquisition phase (0-6 SD) or 6h later (7-12 SD), and in corresponding undisturbed controls. Motor activity was continuously recorded with infrared sensors. All groups explored two familiar, previously encountered objects to a similar extent, both at the end of the acquisition phase and 24h later during the test phase, indicating intact familiarity detection. During the test phase 0-6 SD mice failed to discriminate between the single novel and the two familiar objects. In contrast, the 7-12 SD group and the two control groups explored the novel object significantly longer than the two familiar objects. Plasma corticosterone levels determined after SD did not differ from time-matched undisturbed controls, but were significantly below the level measured after learning alone. ACTH did not differ between the groups. Therefore, it is unlikely that stress contributed to the memory impairment. We conclude that the loss of sleep and the activities the mice engaged in during the SD, impaired recognition memory retrieval, when they occurred immediately after acquisition. The delayed SD enabled memory consolidation during the 6h when the mice were allowed to sleep, and had no detrimental effect on memory. Neither SD schedule impaired object familiarity processing, suggesting that only specific cognitive abilities were sensitive to the intervention. Sleep may either actively promote memory formation, or alternatively, sleep may provide optimal conditions of non-interference for consolidation.

Running wheel accessibility affects the regional electroencephalogram during sleep in mice.

Regional aspects of sleep homeostasis were investigated in mice provided with a running wheel for several weeks. Electroencephalogram (EEG) spectra of the primary motor (frontal) and somatosensory cortex (parietal) were recorded for three consecutive days. On a single day (day 2) the wheel was locked to prevent running. Wheel running correlated negatively with the frontal-parietal ratio of slow-wave activity (EEG power between 0.75 and 4.0 Hz) in the first 2 h after sleep onset (r = -0.60; P < 0.01). On day 2 frontal EEG power (2.25-8.0 Hz) in non-rapid eye movement sleep exceeded the level of the previous day, indicating that the diverse behaviors replacing wheel-running elicited more pronounced regional EEG differences. The frontal-parietal power ratio of the lower frequency bin (0.75-1.0 Hz) in the first 2 h of sleep after dark onset correlated positively with the duration of the preceding waking (r = 0.64; P < 0.001), whereas the power ratio in the remaining frequencies of the delta band (1.25-4.0 Hz) was unrelated to waking. The data suggest that in mice EEG power in the lower frequency, corresponding to the slow oscillations described in cats and humans, is related to local sleep homeostasis.

Influence of estrus cycle and ageing on activity patterns in two inbred mouse strains.

Despite the widespread use of inbred mice in research, little is known about aging of the circadian system in female mice, although interactions between female gonadal hormones and circadian rhythms have been established. We investigated the influence of the estrus cycle on circadian aspects of running-wheel activity and changes in the course of aging in female C57BL/6 and C3H/He mice recorded continuously between the ages of 3 and 19 months. In the young, cycling mice the second part of the proestrus night was often, but not consistently, characterized by increased motor activity compared to the remaining estrus cycle nights. After estrus cycling had ceased in the course of ageing, the estrus-dependent day-to-day variability in activity was reduced. The amplitude of the daily rest-activity rhythm decreased progressively after the age of 8 months in C3H/He and 10 months in C57BL/6 mice. The capacity for resynchronisation of activity onset to the LD-cycle was compared in young and old mice after an 8-h phase advance of the LD-cycle. Resynchronisation was significantly slower in old C3H/He mice and unaffected by age in C57BL/6 mice. The circadian period in constant darkness did not change with age in either strain. However, the period was shorter in 17-month old C57BL/6 mice compared to an additional group, which was recorded at the same age, after at least 1-month adaptation to the recording conditions. The results show that the reproductive state as well as ageing influence motor activity patterns of female mice in a strain- and cohort-dependent manner.

Sleep deprivation and daily torpor impair object recognition in Djungarian hamsters.

Sleep has been shown to play a facilitating role in memory consolidation, whereas sleep deprivation leads to performance impairment both in humans and rodents. The effects of 4-h sleep deprivation on recognition memory were investigated in the Djungarian hamster (Phodopus sungorus). Because sleep during the first hours after daily torpor has many similarities to recovery from sleep deprivation, the effects of spontaneous torpor on object recognition were also assessed. A 4-h sleep deprivation, starting immediately after an object learning task, diminished the ability of the hamsters to: (1) discriminate between an already encountered object (target) and a novel object presented in a novel context, (2) retrieve a target within a complex spatial scene, and (3) detect a spatial rearrangement of familiar objects in a familiar context. Plasma stress hormone levels were similar in sleep-deprived and control hamsters. The occurrence of a daily torpor episode during retention was associated with impaired old-new object discrimination performance in the more effortful complex spatial scene task only, and in a two-object choice situation in a novel context no torpor-induced deficit was found. Our results show that post learning sleep deprivation and daily torpor induce a deficit in familiar object retrieval performance in a complex spatial scene, while sparing familiarity-based recognition and novelty processing. Sleep deprivation during the first 4 h of memory consolidation hampered also recency memory for discrete objects. Stress was not a factor contributing to the sleep deprivation-induced impairment.

Regional differences in NREM sleep slow-wave activity in mice with congenital callosal dysgenesis.

Topographic differences in the sleep EEG have been repeatedly found in humans and rodents. A frontal predominance of EEG slow-wave activity (0.75-4 Hz; delta band) during non-rapid eye movement (NREM) sleep is particularly evident under conditions of increased sleep propensity. Local aspects of neuronal connectivity in the neocortex that are modified by specific neuronal stimulation may underlie these differences. To investigate the role of altered neuronal connectivity on anterior-posterior EEG topography, sleep was recorded in mice with congenital dysgenesis of the corpus callosum (B1 strain) during baseline and after 6 h sleep deprivation (SD). In these mice neuronal connections within a hemisphere are increased due to the longitudinal Probst bundle, a structure of re-routed callosal fibers. After SD the frequencies above 1.5 Hz within the delta band in NREM sleep were reduced in B1 mice compared with control C57BL/6 mice, a strain that has a normal corpus callosum, while power in the lowest frequency band (0.75-1.0 Hz) was enhanced in B1 mice. The differences between the strains subsided in the course of recovery. The redistribution of EEG power within the delta band in the frontal region in mice with a well developed Probst bundle, suggests a role of intracortical connectivity in local sleep regulation.

Theta activity in the waking EEG is a marker of sleep propensity in the rat.

In humans, EEG power in the theta frequency band (5-8 Hz) during quiet waking increases during sleep deprivation (SD), and predicts the subsequent homeostatic increase of sleep slow-wave activity (SWA; EEG power between 0.5 and 4.0 Hz). These findings indicate that theta power in waking is an EEG variable, which reflects the rise in sleep propensity. In rodents, a number of short sleep attempts, as well as SWA in the waking EEG increase in the course of SD, but neither variable predicts the subsequent homeostatic increase of EEG SWA during recovery sleep. To investigate whether there is an EEG marker for sleep propensity also in rodents, the EEG of the rat was recorded during 6 h SD in the first half of the light period (SDL, n = 7). During SDL, power of the waking EEG showed an increase in the delta (1.5-4 Hz) and low theta (5-6.5 Hz) band. Based on the neck muscle EMG, wakefulness was subdivided into active (high EMG activity) and quiet (low EMG activity) waking. During quiet waking, the theta peak occurred at 5.5 Hz, the frequency at which the increase of EEG power during SD was most pronounced. This increase was due to higher amplitude of theta waves, while wave incidence (frequency) was unchanged. Correlation analysis showed that the rise in EEG power in the 5-7 Hz band during SD predicted the subsequent enhancement of SWA in non-rapid eye movement sleep. The analysis of data of a further batch of rats which were sleep deprived for 6 h after dark onset (SDD, n = 7) revealed a significant increase in theta-wave amplitude during the SD and a tendency for a similar, positive correlation between the increase of theta power (5-7 Hz) and subsequent SWA. The results indicate that in rats, as in humans, a specific waking EEG frequency, i.e., theta power in quiet waking is a marker of sleep propensity.

The GABAA receptor agonist THIP alters the EEG in waking and sleep of mice.

THIP is a GABA(A) agonist with hypnotic properties consisting in reducing sleep latency and prolonging and consolidating sleep. THIP has been reported to increase EEG slow-wave activity (SWA; EEG power in the 0.75-4 Hz band) in non-REM (NREM) sleep in both rats and humans. We investigated the effects of THIP on sleep in C57BL/6 mice. EEG recordings were performed after 2, 4 and 6 mg/kg THIP and saline control. The results were compared with analyses of recordings obtained after 6 h of sleep deprivation (SD) in the same strain of mice. The two higher doses of THIP induced an abnormal EEG pattern both in waking and NREM sleep. The EEG was characterized by sporadic asymmetric high-voltage potentials recurring at a low-frequency (<1 Hz) on the background of a low-amplitude EEG pattern. In contrast, after SD the typical regular synchronous high amplitude delta waves predominated. THIP at 4 and 6 mg/kg led to a prominent enhancement of spectral power in the low-frequency range of the waking and sleep EEG which was much higher than the increase attained after 6 h SD. This effect was particularly prominent in the waking EEG. In NREM sleep the increase of spectral power after THIP reflected the frequency of recurrence of the high-voltage potentials, and was restricted to a narrower frequency band than after SD. The EEG changes after 2mg/kg differed little from saline control. Sleep latency was not affected by the two lower doses of THIP, and was prolonged after 6 mg/kg. REM sleep was suppressed after the two higher doses. In contrast to previous results reported in other species, THIP did not have a hypnotic action in mice. The changes induced by THIP in the waking and sleep EEG differed from those caused by enhanced physiological sleep pressure encountered after SD. Considering the abnormal EEG pattern and the similarity of the spectral changes in the sleep and waking EEG, THIP does not seem to exert a specific effect on mechanisms involved in sleep regulation.

The wake-promoting hypocretin/orexin neurons change their response to noradrenaline after sleep deprivation.

Sleep deprivation is accompanied by the progressive development of an irresistible need to sleep, a phenomenon whose mechanism has remained elusive. Here, we identified for the first time a reflection of that phenomenon in vitro by showing that, after a short 2 h period of total sleep deprivation, the action of noradrenaline on the wake-promoting hypocretin/orexin neurons changes from an excitation to an inhibition. We propose that such a conspicuous modification of responsiveness should contribute to the growing sleepiness that accompanies sleep deprivation.

Women's sleep in health and disease.

A huge amount of knowledge about sleep has accumulated during the last 5 decades following the discovery of rapid eye movement (REM) sleep. Nevertheless, there are numerous areas of considerable ignorance. One of these concerns the particularities of sleep in women. Most basic and clinical studies have been performed in male subjects, and only very recently research groups around the world have addressed women's sleep in health and disease. In this review, we summarize the present knowledge on the influence of oestrogens on the brain and on the distinctive changes of sleep across the menstrual cycle, during pregnancy and menopause. In addition, studies in female rodents are reviewed as well as the knowledge on female peculiarities regarding the interactions between sleep regulation and age-related changes in circadian rhythms. We also address specific aspects of sleep loss and sleep disorders in women. Finally, very recent studies on the sociology of sleep are summarized and future directions in the field are discussed.