Effects of social stimuli on sleep in mice: non-rapid-eye-movement (NREM) sleep is promoted by aggressive interaction but not by sexual interaction

Sleep is generally considered to be a process of recovery from prior wakefulness. In addition to being affected by the duration of the waking period, sleep architecture and sleep EEG also depend on the quality of wakefulness. In the present experiment, we examined how sleep is affected by different social stimuli (social conflict and sexual interaction). Male C57BL/6J mice were placed in the cage of an aggressive dominant male or an estrous female for 1 h in the middle of the light phase. The conflict with an aggressive male had a pronounced NREM sleep-promoting effect. EEG slow wave activity, a measure of NREM sleep intensity, was increased for about 6 h and NREM sleep time was significantly increased for 12 h. REM sleep was strongly suppressed during the remainder of the light phase after the conflict, followed by a rebound later in the recovery phase. The sexual interaction, in contrast, had only mild effects. Both NREM sleep and REM sleep were somewhat suppressed shortly after the interaction. In a separate group of mice, blood samples were taken to measure prolactin and corticosterone. The results suggest that the temporary suppression of REM sleep following the social stimuli may be partly due to elevated corticosterone. The different effects of the social stimuli on NREM sleep are not easily explained by differences in the hormone responses. In conclusion, although both social conflict and sexual interaction induce a strong physiological activation, only social conflict has a strong stimulatory effect on NREM sleep mechanisms.

Use of KC-135 parabolic flights to determine if brief changes in the gravity field can influence the phase and/or period of the circadian clock

In February 1994 a total of 10 hampsters flew on two separate KC-135 flights. On one flight, 25 animals experienced 31 parabolas, thus going through 31 cycles of hypergravity (up to about 1.8 G). On the other flight, the animals were exposed to 43 parabolas. fifty additional animals served as ground based controls and were treated in the same fashion as the experimental animals. The profiles of plasma GH, corisol and coricosterone from representative parabolic flight and ground control animals during pre-flight, in-flight, and post-flight conditions are depicted

Rhythmic Leptin Is Required for Weight Gain from Circadian Desynchronized Feeding in the Mouse

The neuroendocrine and metabolic effects of leptin have been extensively researched since the discovery, and the later identification, of the leptin gene mutated within the ob/ob mouse. Leptin is required for optimal health in a number of physiological systems (e.g. fertility, bone density, body weight regulation). Despite the extensive leptin literature and many observations of leptin’s cyclical pattern over the 24-hour day, few studies have specifically examined how the circadian rhythm of leptin may be essential to leptin signaling and health. Here we present data indicating that a rhythmic leptin profile (e.g. 1 peak every 24 hours) leads to excessive weight gain during desynchronized feeding whereas non-rhythmic leptin provided in a continuous manner does not lead to excessive body weight gain under similar feeding conditions. This study suggests that feeding time can interact with leptin’s endogenous rhythm to influence metabolic signals, specifically leading to excessive body weight gains during ‘wrongly’ timed feeding

Circadian Disruption and Metabolic Disease: Findings from Animal Models

Social opportunities and work demands have caused humans to become increasingly active during the late evening hours, leading to a shift from the predominantly diurnal lifestyle of our ancestors to a more nocturnal one. This voluntarily decision to stay awake long into the evening hours leads to circadian disruption at the system, tissue, and cellular levels. These derangements are in turn associated with clinical impairments in metabolic processes and physiology. The use of animal models for circadian disruption provides an important opportunity to determine mechanisms by which disorganization in the circadian system can lead to metabolic dysfunction in response to genetic, environmental, and behavioral perturbations. Here we review recent key animal studies involving circadian disruption and discuss the possible translational implications of these studies for human health and particularly for the development of metabolic disease

Metabolic Effects of Bariatric Surgery in Mouse Models of Circadian Disruption

Background/Objectives: Mounting evidence supports a link between circadian disruption and metabolic disease. Humans with circadian disruption (for example, night-shift workers) have an increased risk of obesity and cardiometabolic diseases compared with the non-disrupted population. However, it is unclear whether the obesity and obesity-related disorders associated with circadian disruption respond to therapeutic treatments as well as individuals with other types of obesity. Subjects/Methods: Here, we test the effectiveness of the commonly used bariatric surgical procedure, Vertical Sleeve Gastrectomy (VSG), in mouse models of genetic and environmental circadian disruption. Results: VSG led to a reduction in body weight and fat mass in both ClockΔ19 mutant and constant-light mouse models (PP\u3e0.05). Within circadian-disrupted models, VSG also led to improved glucose tolerance and lipid handling (P\u3c0.05). Conclusions: Together these data demonstrate that VSG is an effective treatment for the obesity associated with circadian disruption, and that the potent effects of bariatric surgery are orthogonal to circadian biology. However, as the effects of bariatric surgery are independent of circadian disruption, VSG cannot be considered a cure for circadian disruption. These data have important implications for circadian-disrupted obese patients. Moreover, these results reveal new information about the metabolic pathways governing the effects of bariatric surgery as well as of circadian disruption

Environmental Perturbation of the Circadian Clock Disrupts Pregnancy in the Mouse

The circadian clock has been linked to reproduction at many levels in mammals. Epidemiological studies of female shift workers have reported increased rates of reproductive abnormalities and adverse pregnancy outcomes, although whether the cause is circadian disruption or another factor associated with shift work is unknown. Here we test whether environmental disruption of circadian rhythms, using repeated shifts of the light:dark (LD) cycle, adversely affects reproductive success in mice.Young adult female C57BL/6J (B6) mice were paired with B6 males until copulation was verified by visual identification of vaginal plug formation. Females were then randomly assigned to one of three groups: control, phase-delay or phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-delayed and phase-advanced mice were subjected to 6-hr delays or advances in the LD cycle every 5–6 days, respectively. The number of copulations resulting in term pregnancies was determined. Control females had a full-term pregnancy success rate of 90% (11/12), which fell to 50% (9/18; p<0.1) in the phase-delay group and 22% (4/18; p<0.01) in the phase-advance group.Repeated shifting of the LD cycle, which disrupts endogenous circadian timekeeping, dramatically reduces pregnancy success in mice. Advances of the LD cycle have a greater negative impact on pregnancy outcomes and, in non-pregnant female mice, require longer for circadian re-entrainment, suggesting that the magnitude or duration of circadian misalignment may be related to the severity of the adverse impact on pregnancy. These results explicitly link disruptions of circadian entrainment to adverse pregnancy outcomes in mammals, which may have important implications for the reproductive health of female shift workers, women with circadian rhythm sleep disorders and/or women with disturbed circadian rhythms for other reasons

SCN lesions abolish ultradian and circadian components of activity rhythms in LEW/Ztm rats

A trimodal locomotor activity pattern has been observed in LEW/Ztm rats. Complete and partial lesions of the suprachiasmatic nucleus (SCN) were used to determine whether the same neural substrate may underlie the circadian rhythms and the ultradian modulation of wheel-running activity in these rats. Whereas sham lesions had little or no effect on the wheel-running activity pattern, complete SCN lesions resulted in a complete loss of circadian and ultradian activity components under free-running or 12:12 h light-dark cycle (12:12 LD) conditions. Ultradian and circadian activity components were still present after partial SCN lesions. Periodogram analysis for any given animal revealed that the ultradian periods were always submultiples of the entrained or free-running circadian period. Furthermore there was a high correlation between the amplitudes of circadian and ultradian spectral estimates, but with a different slope in males and females. These results indicate that in LEW/Ztm rats the SCN contributes to the control of both the circadian wheel-running rhythm and the trimodal ultradian modulation of that behavior

Estrous correlated modulations of circadian and ultradian wheel-running activity rhythms in LEW/Ztm rats

Estrogen treatment alters the expression of ultradian activity rhythms in male and female LEW/Ztm rats. This finding raises the possibility that the expression of ultradian rhythms may vary on different days of the estrous cycle. To test this hypothesis, we recorded the circadian and ultradian wheel-running activity rhythms of entrained (LD 12:12) and free-running sexually mature LEW/Ztm females during their 4- or 5-day estrous cycle. The mean daily activity, the duration of activity, the circadian period of activity, and the occurrence of ultradian rhythms differed significantly among the days of the estrous cycle. In LD 12:12, the phase angle difference between the beginning of activity and light offset varied reliably in 5-day cycling animals. The highest daily mean of activity, the longest duration, and the shortest circadian period length were observed on the day of estrus in both entrained and free-running animals. The day of estrus was characterized by a constant high level of activity throughout the activity phase, while the days following ovulation showed a bi- or trimodal activity pattern. Power spectrum analysis revealed significant ultradian components for the days of metestrus and diestrus, but only circadian components for the days of proestrus and estrus. These results were interpreted as indicating that endogenous changes in circulating hormone levels can induce changes in the ultradian and circadian patterns of wheel-running activity in LEW/Ztm rats

Circadian Timing of Food Intake Contributes to Weight Gain

Studies of body weight regulation have focused almost entirely on caloric intake and energy expenditure. However, a number of recent studies in animals linking energy regulation and the circadian clock at the molecular, physiological, and behavioral levels raise the possibility that the timing of food intake itself may play a significant role in weight gain. The present study focused on the role of the circadian phase of food consumption in weight gain. We provide evidence that nocturnal mice fed a high‐fat diet only during the 12‐h light phase gain significantly more weight than mice fed only during the 12‐h dark phase. A better understanding of the role of the circadian system for weight gain could have important implications for developing new therapeutic strategies for combating the obesity epidemic facing the human population today

Phase shifting the circadian clock with cycloheximide : response of hamsters with an intact or a split rhythm of locomotor activity

Systematic administration of the protein synthesis inhibitor, cycloheximide, induced both phase advances and phase delays in the circadian rhythm of wheel-running activity in hamsters (Mesocricetus auratus) maintained in constant darkness or constant light. The magnitude and direction of the phase shifts were dependent on the circadian time (CT) of drug treatment. The phase response curves in constant darkness and constant light were of similar general shape, but they differed in the overall mean amplitude of the phase shifts. Maximal phase advances were observed after injections around CT 6-8, maximal delays at CT 0-2. Injections of various doses of cycloheximide at CT 0 induced a dose-dependent phase delay in the rhythm with a maximum delay induced by 10 mg cycloheximide. Injections of cycloheximide in animals with a split activity rhythm caused phase shifts of both components in the same direction (20/39) and in different directions (10/39). The results support the hypothesis that 80S ribosomal protein synthesis plays an important role in the biochemical mechanisms of circadian systems