Effects of sleep disruption and high fat intake on glucose metabolism in mice.

Poor sleep quality or quantity impairs glycemic control and increases risk of disease under chronic conditions. Recovery sleep may offset adverse metabolic outcomes of accumulated sleep debt, but the extent to which this occurs is unclear. We examined whether recovery sleep improves glucose metabolism in mice subjected to prolonged sleep disruption, and whether high fat intake during sleep disruption exacerbates glycemic control. Adult male C57BL/6J mice were subjected to 18-h sleep fragmentation daily for 9 days, followed by 1 day of recovery. During sleep disruption, one group of mice was fed a high-fat diet (HFD) while another group was fed standard laboratory chow. Insulin sensitivity and glucose tolerance were assessed by insulin and glucose tolerance testing at baseline, after 3 and 7 days of sleep disruption, and at the end of the protocol after 24h of undisturbed sleep opportunity (recovery). To characterize changes in sleep architecture that are associated with sleep debt and recovery, we quantified electroencephalogram (EEG) recordings during sleep fragmentation and recovery periods from an additional group of mice. We now report that 9 days of 18-h daily sleep fragmentation significantly reduces rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Mice respond with increases in REMS, but not NREMS, during the daily 6-h undisturbed sleep opportunity. However, both REMS and NREMS increase significantly during the 24-h recovery period. Although sleep disruption alone has no effect in this protocol, high fat feeding in combination with sleep disruption impairs glucose tolerance, effects that are reversed by recovery sleep. Insulin sensitivity modestly improves after 3 days of sleep fragmentation and after 24h of recovery, with significantly greater improvements in mice exposed to HFD during sleep disruption. Improvements in both glucose tolerance and insulin sensitivity are associated with NREMS rebound, raising the possibility that this sleep phase contributes to restorative effects of recovery sleep on glycemic control.

Prolonged sleep fragmentation of mice exacerbates febrile responses to lipopolysaccharide.

BACKGROUND: Sleep disruption is a frequent occurrence in modern society. Whereas many studies have focused on the consequences of total sleep deprivation, few have investigated the condition of sleep disruption. NEW METHOD: We disrupted sleep of mice during the light period for 9 consecutive days using an intermittently rotating disc. RESULTS: Electroencephalogram (EEG) data demonstrated that non-rapid eye movement (NREM) sleep was severely fragmented and REM sleep was essentially abolished during the 12h light period. During the dark period, when sleep was not disrupted, neither NREM sleep nor REM sleep times differed from control values. Analysis of the EEG revealed a trend for increased power in the peak frequency of the NREM EEG spectra during the dark period. The fragmentation protocol was not overly stressful as body weights and water consumption remained unchanged, and plasma corticosterone did not differ between mice subjected to 3 or 9 days of sleep disruption and home cage controls. However, mice subjected to 9 days of sleep disruption by this method responded to lipopolysaccharide with an exacerbated febrile response. COMPARISON WITH EXISTING METHODS: Existing methods to disrupt sleep of laboratory rodents often subject the animal to excessive locomotion, vibration, or sudden movements. This method does not suffer from any of these confounds. CONCLUSIONS: This study demonstrates that prolonged sleep disruption of mice exacerbates febrile responses to lipopolysaccharide. This device provides a method to determine mechanisms by which chronic insufficient sleep contributes to the etiology of many pathologies, particularly those with an inflammatory component.

Telemetric study of sleep architecture and sleep homeostasis in the day-active tree shrew Tupaia belangeri.

STUDY OBJECTIVES: In this study the authors characterized sleep architecture and sleep homeostasis in the tree shrew, Tupaia belangeri, a small, omnivorous, day-active mammal that is closely related to primates. DESIGN: Adult tree shrews were individually housed under a 12-hr light/12-hr dark cycle in large cages containing tree branches and a nest box. The animals were equipped with radio transmitters to allow continuous recording of electroencephalogram (EEG), electromyogram (EMG), and body temperature without restricting their movements. Recordings were performed under baseline conditions and after sleep deprivation (SD) for 6 hr or 12 hr during the dark phase. MEASUREMENTS AND RESULTS: Under baseline conditions, the tree shrews spent a total of 62.4 ± 1.4% of the 24-hr cycle asleep, with 91.2 ± 0.7% of sleep during the dark phase and 33.7 ± 2.8% sleep during the light phase. During the dark phase, all sleep occurred in the nest box; 79.6% of it was non-rapid eye movement (NREM) sleep and 20.4% was rapid eye movement (REM) sleep. In contrast, during the light phase, sleep occurred almost exclusively on the top branches of the cage and only consisted of NREM sleep. SD was followed by an immediate increase in NREM sleep time and an increase in NREM sleep EEG slow-wave activity (SWA), indicating increased sleep intensity. The cumulative increase in NREM sleep time and intensity almost made up for the NREM sleep that had been lost during 6-hr SD, but did not fully make up for the NREM sleep lost during 12-hr SD. Also, only a small fraction of the REM sleep that was lost was recovered, which mainly occurred on the second recovery night. CONCLUSIONS: The day-active tree shrew shares most of the characteristics of sleep structure and sleep homeostasis that have been reported for other mammalian species, with some peculiarities. Because the tree shrew is an established laboratory animal in neurobiological research, it may be a valuable model species for studies of sleep regulation and sleep function, with the added advantage that it is a day-active species closely related to primates.

Forced and voluntary exercise counteract insulin resistance in rats: the role of coping style.

There are large individual differences in the success rates of exercise intervention programs aimed at the prevention and treatment of obesity-related disorders. In the present study, we tested the hypothesis that differences in coping style may impact the success rates of these intervention programs. We tested insulin responses before and after voluntary wheel running in both passive (insulin resistant) Roman Low Avoidance (RLA) and proactive (insulin sensitive) Roman High Avoidance (RHA) rats using intravenous glucose tolerance tests (IVGTTs). To control for a potential difference between voluntary and forced exercise, we also included RLA and RHA rats that were subjected to forced running. We found the following: 1) when given the opportunity to run voluntarily in a running wheel, passive RLA rats run more than proactively than RHA rats; 2) voluntary exercise leads to a normalization of insulin responses during an IVGTTs in RLA rats; and 3) there were no behavioral and physiological differences in efficacy between voluntary and forced running. We conclude that exercise, both forced and voluntary, is a successful lifestyle intervention for the treatment of hyperinsulinemia, especially in individuals with a passive coping style.

Increased food intake and changes in metabolic hormones in response to chronic sleep restriction alternated with short periods of sleep allowance.

Rodent models for sleep restriction have good face validity when examining food intake and related regulatory metabolic hormones. However, in contrast to epidemiological studies in which sleep restriction is associated with body weight gain, sleep-restricted rats show a decrease in body weight. This difference with the human situation might be caused by the alternation between periods of sleep restriction and sleep allowance that often occur in real life. Therefore, we assessed the metabolic consequences of a chronic sleep restriction protocol that modeled working weeks with restricted sleep time alternated by weekends with sleep allowance. We hypothesized that this protocol could lead to body weight gain. Male Wistar rats were divided into three groups: sleep restriction (SR), forced activity control (FA), and home cage control (HC). SR rats were subjected to chronic sleep restriction by keeping them awake for 20 h per day in slowly rotating drums. To model the human condition, rats were subjected to a 4-wk protocol, with each week consisting of a 5-day period of sleep restriction followed by a 2-day period of sleep allowance. During the first experimental week, SR caused a clear attenuation of growth. In subsequent weeks, two important processes occurred: 1) a remarkable increase in food intake during SR days, 2) an increase in weight gain during the weekends of sleep allowance, even though food intake during those days was comparable to controls. In conclusion, our data revealed that the alternation between periods of sleep restriction and sleep allowance leads to complex changes in food intake and body weight, that prevent the weight loss normally seen in continuous sleep-restricted rats. Therefore, this "week-weekend" protocol may be a better model to study the metabolic consequences of restricted sleep.

Sleep deprivation impairs contextual fear conditioning and attenuates subsequent behavioural, endocrine and neuronal responses.

Sleep deprivation (SD) affects hippocampus-dependent memory formation. Several studies in rodents have shown that brief SD immediately following a mild foot shock impairs consolidation of contextual fear memory as reflected in a reduced behavioural freezing response during re-exposure to the shock context later. In the first part of this study, we examined whether this reduced freezing response is accompanied by an attenuated fear-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Results show that 6h of SD immediately following the initial shock results in a diminished adrenal corticosterone (CORT) response upon re-exposure to the shock context the next day. In the second part, we established whether the attenuated freezing response in SD animals is associated with reduced activation of relevant brain areas known to be involved in the retrieval and expression of fear memory. Immunohistochemical analysis of brain slices showed that the normal increase in phosphorylation of the transcription factor 3',5'-cyclic AMP response-element binding protein (CREB) upon re-exposure to the shock context was reduced in SD animals in the CA1 region of the hippocampus and in the amygdala. In conclusion, brief SD impairs the consolidation of contextual fear memory. Upon re-exposure to the context, this is reflected in a diminished behavioural freezing response, an attenuated HPA axis response and a reduction of the normal increase of phosphorylated CREB expression in the hippocampus and amygdala.

Chronic sleep disturbance impairs glucose homeostasis in rats.

Epidemiological studies have shown an association between short or disrupted sleep and an increased risk for metabolic disorders. To assess a possible causal relationship, we examined the effects of experimental sleep disturbance on glucose regulation in Wistar rats under controlled laboratory conditions. Three groups of animals were used: a sleep restriction group (RS), a group subjected to moderate sleep disturbance without restriction of sleep time (DS), and a home cage control group. To establish changes in glucose regulation, animals were subjected to intravenous glucose tolerance tests (IVGTTs) before and after 1 or 8 days of sleep restriction or disturbance. Data show that both RS and DS reduce body weight without affecting food intake and also lead to hyperglycemia and decreased insulin levels during an IVGTT. Acute sleep disturbance also caused hyperglycemia during an IVGTT, yet, without affecting the insulin response. In conclusion, both moderate and severe disturbances of sleep markedly affect glucose homeostasis and body weight control.

Circadian time-place learning in mice depends on Cry genes.

Endogenous biological clocks allow organisms to anticipate daily environmental cycles. The ability to achieve time-place associations is key to the survival and reproductive success of animals. The ability to link the location of a stimulus (usually food) with time of day has been coined time-place learning, but its circadian nature was only shown in honeybees and birds. So far, an unambiguous circadian time-place-learning paradigm for mammals is lacking. We studied whether expression of the clock gene Cryptochrome (Cry), crucial for circadian timing, is a prerequisite for time-place learning. Time-place learning in mice was achieved by developing a novel paradigm in which food reward at specific times of day was counterbalanced by the penalty of receiving a mild footshock. Mice lacking the core clock genes Cry1 and Cry2 (Cry double knockout mice; Cry1(-/-)Cry2(-/-)) learned to avoid unpleasant sensory experiences (mild footshock) and could locate a food reward in a spatial learning task (place preference). These mice failed, however, to learn time-place associations. This specific learning and memory deficit shows that a Cry-gene dependent circadian timing system underlies the utilization of time of day information. These results reveal a new functional role of the mammalian circadian timing system.