Sleep and the sleep electroencephalogram in C57BL/6 and C3H/HeN mice.

Different mouse strains used in biomedical research show different phenotypes associated with their genotypes. Two mouse strains commonly used in biomedical sleep research are C57Bl/6 and C3H/He, the strains differ in numerous aspects, including their ability to secrete melatonin as well as the expression of several sleep-related genes. However, sleep regulation has only limitedly been compared between C3H/HeN and C57Bl/6 mice. We therefore compared sleep-wake behaviour and EEG-measured spectral brain activity for C57bl/6 and C3H/HeN mice during a 12:12 h light: dark baseline and during and after a 6 h sleep deprivation. The C3H mice spent more time in NREM sleep around the light-dark transition and more time in REM sleep during the dark phase compared with C57bl/6 mice. The C3H mice also showed more EEG activity in the 4.5-7.5 Hz range during all stages and a stronger 24 h modulation of EEG power density in almost all EEG frequencies during NREM sleep. After the sleep deprivation, C3H mice showed a stronger recovery response, which was expressed in both a larger increase in EEG slow wave activity (SWA) and more time spent in NREM sleep. We show large differences regarding sleep architecture and EEG activity between C3H and C57bl/6 mice. These differences include the amount of waking during the late dark phase, the 24 h amplitude in EEG power density, and the amount of REM sleep during the dark phase. We conclude that differences between mouse strains should be considered when selecting a model strain to improve the generalisability of studies investigating biomedical parameters related to sleep and circadian rhythms.

Hypnotic effects of melatonin depend on the environmental lighting conditions in the rat.

Acute effects of exogenous melatonin have been widely reported to promote sleep or induce drowsiness in human. However, testing of the hypnotic effects of melatonin in nocturnal rodents has yielded contradictory results. The latter may be associated with differences in concentration, lighting conditions, time of administration of melatonin, and possibly the type of analysis. In this study, electroencephalogram (EEG) and electromyogram were recorded in pigmented male Brown Norway rats under both light-dark (LD) and constant dark (DD) conditions. Melatonin was administered intraperitoneally at a moderate dose of 3 mg/kg, at either 1 h after lights on under LD condition or 1 h after the activity offset under DD condition. The dosage is known to be able to entrain nocturnal rodents in DD conditions, but does not change sleep in rodents in LD. Only the rats under DD conditions showed a significant reduction in nonrapid eye movement (NREM) sleep latency, while the NREM sleep power spectrum remained unaffected. Under LD condition, melatonin did not alter NREM and rapid eye movement (REM) sleep latency, and had only minor effects on the NREM sleep EEG. Regardless of lighting conditions, melatonin administration resulted in less, but longer episodes for all vigilance states suggesting increased vigilance state consolidation. In the discussion, we compare our results with a summary of previously published data concerning the hypnotic effects of melatonin in polysomnographic/EEG-confirmed sleep in humans and nocturnal rodents. In conclusion, the hypnotic effect of exogenous melatonin in nocturnal rodents not only depends on the time of day, and concentration, but is also influenced by the lighting conditions. Regardless of inducing sleep or not, melatonin may consolidate sleep and through that enhance sleep quality.

Internal circadian misallignment in a mouse model of chemotherapy induced fatigue.

BACKGROUND: Cancer survivors can experience long lasting fatigue resulting in a lower quality of life. How chemotherapy treatment contributes to this fatigue is poorly understood. Previously we have shown in a mouse model of cancer related fatigue that doxorubicin treatment induces fatigue-like symptoms related to disturbed circadian rhythms. However, the specific components of the circadian regulatory circuitry affected by doxorubicin treatment remained unclear. Therefore we investigated the role of the central circadian clock, the suprachiasmatic nucleus (SCN), in chemotherapy-induced fatigue. METHODS: We measured circadian controlled behavior and multiunit neuronal activity in the SCN in freely moving mice exhibiting fatigue-like behavior after doxorubicin treatment under both light-dark (LD) and constant dark (DD) conditions. Additionally, we assessed the expression of inflammation related genes in spleen and kidney as potential inducers of CRF. RESULTS: Doxorubicin treatment significantly reduced both the running wheel activity and time spent using the running wheel for over five weeks after treatment. In contrast to the pronounced effects on behavior and neuronal activity of doxorubicin on circadian rhythms, peripheral inflammation markers only showed minor differences, five weeks after the last treatment. Surprisingly, the circadian SCN neuronal activity under both LD and DD conditions was not affected. However, the circadian timing of neuronal activity in peri-SCN areas (the brain areas surrounding SCN) and circadian rest-activity behavior was strongly affected by doxorubicin, suggesting that the output of the SCN was altered. The reduced correlation between the SCN neuronal activity and behavioral activity after doxorubicin treatment, suggests that the information flow from the SCN to the periphery was disturbed. CONCLUSION: Our preclinical study suggests that chemotherapy-induced fatigue disrupts the circadian rhythms in peripheral brain areas and behavior downstream from the SCN, potentially leading to fatigue like symptoms. Our data suggest that peripheral inflammation responses are less important for the maintenance of fatigue. Chronotherapy that realigns circadian rhythms could represent a non-invasive way to improve patient outcomes following chemotherapy.

Comparison of sleep deprivation and a low dose of ketamine on sleep and the electroencephalogram in Brown Norway rats.

Ketamine is known for its antidepressant effects, but the mechanism underlying this effect remains largely unclear. In contrast to most antidepressant drugs, the action of ketamine is rapid, suggesting a different mode of action. A rapid antidepressant effect is also observed following sleep deprivation (SD). In the present study, we aimed to evaluate the effect of a 6-h SD and acute ketamine treatment on vigilance states, locomotor activity, and electroencephalogram (EEG) power density spectra in Brown Norway rats under constant condition over 2 recording days. After SD and after the initial waking period induced by ketamine, both treatments induced a similar increase in non-rapid eye movement (NREM) sleep and EEG slow-wave activity (SWA) in NREM sleep. Rapid eye movement (REM) sleep was reduced immediately after both treatments but was recovered later only after the SD. The effects on the waking EEG differed between the treatments, with a faster theta peak during and after SD, and no change in the waking spectrum after ketamine. In conclusion, SD and ketamine both lead to an acute increment in NREM sleep SWA as well as in a reduction in REM sleep. The results suggest that selective suppression of REM sleep, combined with enhancement of SWA during NREM may be effective in the treatment of depression.

Mechanisms of Sleep/Wake Regulation under Hypodopaminergic State: Insights from MitoPark Mouse Model of Parkinson's Disease.

Sleep/wake alterations are predominant in neurological and neuropsychiatric disorders involving dopamine dysfunction. Unfortunately, specific, mechanisms-based therapies for these debilitating sleep problems are currently lacking. The pathophysiological mechanisms of sleep/wake alterations within a hypodopaminergic MitoPark mouse model of Parkinson's disease (PD) are investigated. MitoPark mice replicate most PD-related sleep alterations, including sleep fragmentation, hypersomnia, and daytime sleepiness. Surprisingly, these alterations are not accounted for by a dysfunction in the circadian or homeostatic regulatory processes of sleep, nor by acute masking effects of light or darkness. Rather, the sleep phenotype is linked with the impairment of instrumental arousal and sleep modulation by behavioral valence. These alterations correlate with changes in high-theta (8-11.5 Hz) electroencephalogram power density during motivationally-charged wakefulness. These results demonstrate that sleep/wake alterations induced by dopamine dysfunction are mediated by impaired modulation of sleep by motivational valence and provide translational insights into sleep problems associated with disorders linked to dopamine dysfunction.

10-year anniversary of the European Somnologist examination - A historic overview and critical appraisal.

The European Somnologist certification programme was developed by the European Sleep Research Society to improve patient care in sleep medicine by providing an independent evaluation of theoretical and practical knowledge. The examination of eligible experts plays a key role in this procedure. A process was started more than 15 years ago to create the European sleep medicine curriculum, eligibility criteria for certification, and sleep centre accreditation criteria. The process was characterised by interdisciplinary collaboration, consensus, and achieving new solutions. During the past 10 years, experience has been gained by the examination and certification of more than 1000 sleep medicine experts from more than 50 countries. The process has continuously been improved. However, as the programme was designed and administered mainly by medical experts in the field, systematic influence from teaching and pedagogic experts was partially underrepresented. The current critical appraisal pinpoints several missing links in the process - mainly as a missing constructive alignment between learning objectives, learning and teaching activities, and the final assessment. A series of suggestions has been made to further improve the ESRS certification programme.

Long-Term Effect of a Single Dose of Caffeine on Sleep, the Sleep EEG and Neuronal Activity in the Peduncular Part of the Lateral Hypothalamus under Constant Dark Conditions.

BACKGROUND: Caffeine is a central nervous system stimulant that influences both the sleep-wake cycle and the circadian clock and is known to influence neuronal activity in the lateral hypothalamus, an important area involved in sleep-wake regulation. Light is a strong zeitgeber and it is known to interact with the effect of caffeine on the sleep-wake cycle. We therefore wanted to investigate the long-term effects of a single dose of caffeine under constant dark conditions. METHODS: We performed long-term (2 days) electroencephalogram (EEG)/electromyogram recordings combined with multi-unit neuronal activity recordings in the peduncular part of the lateral hypothalamus (PLH) under constant darkness in Brown Norway rats, and investigated the effect of a single caffeine treatment (15 mg/kg) or saline control given 1 h after the onset of the endogenous rest phase. RESULTS: After a reduction in sleep and an increase in waking and activity in the first hours after administration, also on the second recording day after caffeine administration, rapid eye movement (REM) sleep was still reduced. Analysis of the EEG showed that power density in the theta range during waking and REM sleep was increased for at least two days. Neuronal activity in PLH was also increased for two days after the treatment, particularly during non-rapid eye movement sleep. CONCLUSION: Surprisingly, the data reveal long-term effects of a single dose of caffeine on vigilance states, EEG, and neuronal activity in the PLH. The absence of a light-dark cycle may have enabled the expression of these long-term changes. It therefore may be that caffeine, or its metabolites, have a stronger and longer lasting influence, particularly on the expression of REM sleep, than acknowledged until now.

Adenosine, caffeine, and sleep-wake regulation: state of the science and perspectives.

For hundreds of years, mankind has been influencing its sleep and waking state through the adenosinergic system. For ~100 years now, systematic research has been performed, first started by testing the effects of different dosages of caffeine on sleep and waking behaviour. About 70 years ago, adenosine itself entered the picture as a possible ligand of the receptors where caffeine hooks on as an antagonist to reduce sleepiness. Since the scientific demonstration that this is indeed the case, progress has been fast. Today, adenosine is widely accepted as an endogenous sleep-regulatory substance. In this review, we discuss the current state of the science in model organisms and humans on the working mechanisms of adenosine and caffeine on sleep. We critically investigate the evidence for a direct involvement in sleep homeostatic mechanisms and whether the effects of caffeine on sleep differ between acute intake and chronic consumption. In addition, we review the more recent evidence that adenosine levels may also influence the functioning of the circadian clock and address the question of whether sleep homeostasis and the circadian clock may interact through adenosinergic signalling. In the final section, we discuss the perspectives of possible clinical applications of the accumulated knowledge over the last century that may improve sleep-related disorders. We conclude our review by highlighting some open questions that need to be answered, to better understand how adenosine and caffeine exactly regulate and influence sleep.

Induction of Fatigue by Specific Anthracycline Cancer Drugs through Disruption of the Circadian Pacemaker.

Cancer-related fatigue (CRF) is the most devastating long-term side effect of many cancer survivors that confounds the quality of life for months to years after treatment. However, the cause of CRF is poorly understood. As a result, cancer survivors, at best, receive psychological support. Chemotherapy has been shown to increase the risk of CRF. Here, we study therapy-induced fatigue in a non-tumor-bearing mouse model with three different topoisomerase II-poisoning cancer drugs. These drugs either induce DNA damage and/or chromatin damage. Shortly before and several weeks after treatment, running wheel activity and electroencephalographic sleep were recorded. We show that doxorubicin, combining DNA damage with chromatin damage, unlike aclarubicin or etoposide, induces sustained CRF in this model. Surprisingly, this was not related to changes in sleep. In contrast, our data indicate that the therapy-induced CRF is associated with a disrupted circadian clock. The data suggest that CRF is probably a circadian clock disorder that influences the quality of waking and that the development of CRF depends on the type of chemotherapy provided. These findings could have implications for selecting and improving chemotherapy for the treatment of cancer in order to prevent the development of CRF.

The European Sleep Research Society - past, present and future.

It is 50 years ago, in 1972, that the founding conference of the European Sleep Research Society (ESRS) was organised in Basel. Since then the Society has had 13 presidents and a multitude of board members and has organised, among other things, another 24 congresses. At this 50th anniversary, as the 26th ESRS congress is approaching, we have summarised the history of the ESRS. In this review, we provide a background to show why the foundation of a European society was a logical step, and show how, in the course of the past 50 years, the Society changed and grew. We give special attention to some developments that occurred over the years and discuss where the ESRS stands now, and how we foresee its future.

Sleep Deprivation Does not Change the Flash Electroretinogram in Wild-type and Opn4-/-Gnat1-/- Mice.

Sleep deprivation reduces the response of neuronal activity in the suprachiasmatic nucleus (SCN) and the phase shift in circadian behaviour to phase shifting light pulses, and thus seems to impair the adaptation of the circadian clock to the external light-dark cycle. The question remains where in the pathway of light input to the SCN the response is reduced. We therefore investigated whether the electroretinogram (ERG) changes after sleep deprivation in wild-type mice and in Opn4-/-Gnat1-/- mutant male mice. We found that the ERG is clearly affected by the Opn4-/-Gnat1-/- mutations, but that the ERG after sleep deprivation does not differ from the baseline response. The difference between wild-type and mutant is in accordance with the lack of functional rod and melanopsin in the retina of the mutant mice. We conclude that the decrease in light responsiveness of the SCN after sleep deprivation is probably not caused by changes at the retinal level, but rather at the postsynaptic site within the SCN, reflecting affected neurotransmitter signalling.

Heterogenous electrophysiological responses of functionally distinct striatal subregions to circadian and sleep-related homeostatic processes.

Basal ganglia (BG) are a set of subcortical nuclei that are involved in the control of a wide variety of motor, cognitive, and affective behaviors. Although many behavioral abnormalities associated with BG dysfunction overlap with the clinical picture precipitated by the lack of sleep, the impact of sleep alterations on neuronal activity in BG is unknown. Using wild-type C57BI mice, we investigated the circadian and sleep-related homeostatic modulation of neuronal activity in the three functional subdivisions of the striatum (i.e. sensorimotor, associative, and limbic striatum). We found no circadian modulation of activity in both ventral and dorsomedial striatum while the dorsolateral striatum displayed a significant circadian rhythm with increased firing rates during the subjective dark, active phase. By combining neuronal activity recordings with electroencephalogram (EEG) recordings, we found a strong modulation of neuronal activity by the nature of vigilance states with increased activity during wakefulness and rapid eye movement sleep relative to nonrapid eye movement sleep in all striatal subregions. Depriving animals of sleep for 6 h induced significant, but heterogenous alterations in the neuronal activity across striatal subregions. Notably, these alterations lasted for up to 48 h in the sensorimotor striatum and persisted even after the normalization of cortical EEG power densities. Our results show that vigilance and sleep states as well as their disturbances significantly affect neuronal activity within the striatum. We propose that these changes in neuronal activity underlie both the well-established links between sleep alterations and several disorders involving BG dysfunction as well as the maladaptive changes in behavior induced in healthy participants following sleep loss.

Doublecortin-like expressing astrocytes of the suprachiasmatic nucleus are implicated in the biosynthesis of vasopressin and influences circadian rhythms.

We have recently identified a novel plasticity protein, doublecortin-like (DCL), that is specifically expressed in the shell of the mouse suprachiasmatic nucleus (SCN). DCL is implicated in neuroplastic events, such as neurogenesis, that require structural rearrangements of the microtubule cytoskeleton, enabling dynamic movements of cell bodies and dendrites. We have inspected DCL expression in the SCN by confocal microscopy and found that DCL is expressed in GABA transporter-3 (GAT3)-positive astrocytes that envelope arginine vasopressin (AVP)-expressing cells. To investigate the role of these DCL-positive astrocytes in circadian rhythmicity, we have used transgenic mice expressing doxycycline-induced short-hairpin (sh) RNA's targeting DCL mRNA (DCL knockdown mice). Compared with littermate wild type (WT) controls, DCL-knockdown mice exhibit significant shorter circadian rest-activity periods in constant darkness and adjusted significantly faster to a jet-lag protocol. As DCL-positive astrocytes are closely associated with AVP-positive cells, we analyzed AVP expression in DCL-knockdown mice and in their WT littermates by 3D reconstructions and transmission electron microscopy (TEM). We found significantly higher numbers of AVP-positive cells with increased volume and more intensity in DCL-knockdown mice. We found alterations in the numbers of dense core vesicle-containing neurons at ZT8 and ZT20 suggesting that the peak and trough of neuropeptide biosynthesis is dampened in DCL-knockdown mice compared to WT littermates. Together, our data suggest an important role for the astrocytic plasticity in the regulation of circadian rhythms and point to the existence of a specific DCL+ astrocyte-AVP+ neuronal network located in the dorsal SCN implicated in AVP biosynthesis.

Sleep Network Deterioration as a Function of Dim-Light-At-Night Exposure Duration in a Mouse Model.

Artificial light, despite its widespread and valuable use, has been associated with deterioration of health and well-being, including altered circadian timing and sleep disturbances, particularly in nocturnal exposure. Recent findings from our lab reveal significant sleep and sleep electroencephalogram (EEG) changes owing to three months exposure to dim-light-at-night (DLAN). Aiming to further explore the detrimental effects of DLAN exposure, in the present study, we continuously recorded sleep EEG and the electromyogram for baseline 24-h and following 6-h sleep deprivation in a varied DLAN duration scheme. C57BL/6J mice were exposed to a 12:12 h light:DLAN cycle (75lux:5lux) vs. a 12:12 h light:dark cycle (75lux:0lux) for one day, one week, and one month. Our results show that sleep was already affected by a mere day of DLAN exposure with additional complications emerging with increasing DLAN exposure duration, such as the gradual delay of the daily 24-h vigilance state rhythms. We conducted detrended fluctuation analysis (DFA) on the locomotor activity data following 1-month and 3-month DLAN exposure, and a significantly less healthy rest-activity pattern, based on the decreased alpha values, was found in both conditions compared to the control light-dark. Taking into account the behavioral, sleep and the sleep EEG parameters, our data suggest that DLAN exposure, even in the shortest duration, induces deleterious effects; nevertheless, potential compensatory mechanisms render the organism partly adjustable and able to cope. We think that, for this reason, our data do not always depict linear divergence among groups, as compared with control conditions. Chronic DLAN exposure impacts the sleep regulatory system, but also brain integrity, diminishing its adaptability and reactivity, especially apparent in the sleep EEG alterations and particular low alpha values following DFA.

Annual variation in attentional response after methylphenidate treatment.

Prevalence rates of attention-deficit/hyperactivity disorder (ADHD) differ with geographical areas varying in sunlight intensity. Sun- or daylight reaching the retina establishes entrainment of the circadian clock to daylight. Changes herein, hence, alterations in clock alignment, could be reflected indirectly in inattention via sleep duration. We here studied (1) annual variation in inattention at treatment initiation; (2) annual variation in response to ADHD treatment [methylphenidate (MPH)] by day of treatment initiation; and (3) dose dependence. We predicted least baseline inattention during a period of high sunlight intensity implying more room for improvement (i.e., a better treatment response) when sunlight intensity is low. These hypotheses were not confirmed. High-dose treated patients, however, had significantly better attention after treatment than low-dosed treated patients, only when treated in the period from winter to summer solstice. Change in solar irradiance (SI) during low-dosed treatment period was negatively related to attentional improvement. The above described findings were primarily found in inattention ratings and replicated in omission errors on a continuous performance task. Daylight and inattention have been proposed to be related via mediation of the circadian system. One mechanism of MPH may be to enhance sensitivity to the diurnal entrainment to sunlight and the question can be raised whether appropriate lighting could potentiate the effects of stimulants.

Disruption of circadian rhythm by alternating light-dark cycles aggravates atherosclerosis development in APOE*3-Leiden.CETP mice.

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3-Leiden.CETP mice to either regular light-dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. We found that mice exposed to 15 weeks of alternating light-dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light-dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light-dark cycles directly aggravates atherosclerosis development.

Time-restricted feeding improves adaptation to chronically alternating light-dark cycles.

Disturbance of the circadian clock has been associated with increased risk of cardio-metabolic disorders. Previous studies showed that optimal timing of food intake can improve metabolic health. We hypothesized that time-restricted feeding could be a strategy to minimize long term adverse metabolic health effects of shift work and jetlag. In this study, we exposed female FVB mice to weekly alternating light-dark cycles (i.e. 12 h shifts) combined with ad libitum feeding, dark phase feeding or feeding at a fixed clock time, in the original dark phase. In contrast to our expectations, long-term disturbance of the circadian clock had only modest effects on metabolic parameters. Mice fed at a fixed time showed a delayed adaptation compared to ad libitum fed animals, in terms of the similarity in 24 h rhythm of core body temperature, in weeks when food was only available in the light phase. This was accompanied by increased plasma triglyceride levels and decreased energy expenditure, indicating a less favorable metabolic state. On the other hand, dark phase feeding accelerated adaptation of core body temperature and activity rhythms, however, did not improve the metabolic state of animals compared to ad libitum feeding. Taken together, restricting food intake to the active dark phase enhanced adaptation to shifts in the light-dark schedule, without significantly affecting metabolic parameters.

Effects of chronic caffeine consumption on sleep and the sleep electroencephalogram in mice.

BACKGROUND: Caffeine is one of the most widely consumed psychostimulants, and it impacts sleep and circadian physiology. AIM: Caffeine is generally used chronically on a daily basis. Therefore, in the current study, we investigated the chronic effect of caffeine on sleep in mice. METHODS: We recorded the electroencephalogram and electromyogram on a control day, on the first day of caffeine consumption (acute), and following two weeks of continuous caffeine consumption (chronic). In the latter condition, a period of six-hour sleep deprivation was conducted during the light period. Control mice, which received normal drinking water, were also recorded and sleep deprived. RESULTS: We found that caffeine induced differential effects following acute and chronic consumption. Over 24 h, waking increased following acute caffeine whereas no changes were found in the chronic condition. The daily amplitude of sleep-wake states increased in both acute and chronic conditions, with the highest amplitude in the chronic condition, showing an increase in sleep during the light and an increase in waking during the dark. Furthermore, electroencephalogram slow-wave-activity in non-rapid eye-movement sleep was increased, compared with both control conditions, during the first half of the light period in the chronic condition. It was particularly challenging to keep the animals awake during the sleep deprivation period under chronic caffeine. CONCLUSIONS: Together the data suggest an increased sleep pressure under chronic caffeine. In contrast to the traditional conception on the impact on sleep, chronic caffeine intake seems to increase the daily sleep-wake cycle amplitude and increase sleep pressure in mice.

How Old Is Your Brain? Slow-Wave Activity in Non-rapid-eye-movement Sleep as a Marker of Brain Rejuvenation After Long-Term Exercise in Mice.

Physical activity is beneficial for health. It has been shown to improve brain functioning and cognition, reduce severity of mood disorders, as well as facilitate healthy sleep and healthy aging. Sleep has been studied in healthy aged mice and absolute slow-wave-activity levels (SWA, electroencephalogram power between 0.75 and 4.0 Hz) in non-rapid-eye-movement sleep (NREM) were elevated, suggesting changes in brain connectivity. To investigate whether physical activity can diminish this aging-induced effect, mice of three age groups were provided with a running wheel (RW) for 1-3 months (6-months-old, n = 9; 18-months-old, n = 9; 24-months-old, n = 8) and were compared with control sedentary mice (n = 11, n = 8 and n = 9 respectively). Two weeks before the sleep-wake recordings the running wheels were removed. The electroencephalogram (EEG) and electromyogram were continuously recorded during undisturbed 24 h baseline (BL) and a sleep-deprivation was conducted during the first 6 h of the second day. Increased waking and decreased NREM sleep was found in the young RW mice, compared to young controls. These effects were not evident in the 18 and 24 months old mice. Unlike sleep architecture, we found that SWA was altered throughout the whole age spectrum. Notably, SWA was increased with aging and attenuated with exercise, exhibiting the lowest levels in the young RW mice. To utilize the cross-age revealing features of SWA, we applied machine learning techniques and found that characteristic information regarding age and exercise was enclosed in SWA. In addition, with cluster analysis, we could classify and accurately distinguish the different groups based solely on their SWA. Therefore, our study comprises a three-fold contribution: (a) effects of exercise on sleep are sustained following 2 weeks after removal of the wheel, (b) we show that EEG SWA can be used as a physiological marker of brain age in the mouse,

Chronic high-caloric diet modifies sleep homeostasis in mice.

Obesity prevalence and sleep habit changes are commonplace nowadays, due to modern lifestyle. A bidirectional relationship likely exists between sleep quality and metabolic disruptions, which could impact quality of life. In our study, we investigated the effects of a chronic high-caloric diet on sleep architecture and sleep regulation in mice. We studied the effect of 3 months high-caloric diet (HCD, 45% fat) on sleep and the sleep electroencephalogram (EEG) in C57BL/6J mice during 24-hr baseline (BL) recordings, and after 6-hr sleep deprivation (SD). We examined the effect of HCD on sleep homeostasis, by performing parameter estimation analysis and simulations of the sleep homeostatic Process S, a measure of sleep pressure, which is reflected in the non-rapid-eye-movement (NREM) sleep slow-wave-activity (SWA, EEG power density between 0.5 and 4.0 Hz). Compared to controls (n = 11, 30.7 ± 0.8 g), mice fed with HCD (n = 9, 47.6 ± 0.8 g) showed an increased likelihood of consecutive NREM-REM sleep cycles, increased REM sleep and decreased NREM sleep EEG SWA. After SD, these effects were more pronounced. The simulation resulted in a close fit between the time course of SWA and Process S in both groups. HCD fed mice had a slower time constant (Ti  = 15.98 hr) for the increase in homeostatic sleep pressure compared with controls (5.95 hr) indicating a reduced effect of waking on the increase in sleep pressure. Our results suggest that chronic HCD consumption impacts sleep regulation.