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Circadian rhythms in glucocorticoids are the product of interactions between the hypothalamicpituitary- adrenal (HPA) axis and the mammalian clock gene system. The adrenal clock can generate the glucocorticoid rhythm that in turn synchronizes other peripheral clocks to maintain homeostasis. Stress acutely activates and chronically upregulates the HPA axis, suggesting that the adrenal clock could be modulated by stress. However, there is no direct evidence that stress affects the adrenal clock rhythm. We tested the hypothesis that a model of chronic subordination stress (CSS) that has a major impact on HPA axis regulation, metabolism, and emotional behavior alters adrenal and pituitary clock gene rhythms. Clock gene rhythms were assessed using mPER2::Luciferase (PER2Luc) knockin mice in which in vitro bioluminescence rhythms reflect the Per2 clock gene expression. PER2Luc mice that experienced CSS for 2 wk showed positive energy balance reflected by increased body weight and food intake. Additionally, CSS phase advanced the adrenal (~2h) and the pituitary (~1h) PER2Luc rhythm compared with control mice. The activity rhythm was not affected. The adrenal clock phase shift was associated with increased feed conversion efficiency, suggesting that the metabolic phenotype in CSS mice may be related to altered adrenal clock rhythmicity. Interestingly, a single subordination experience followed by 8 h sensory housing also phase advanced the adrenal, but not the pituitary, PER2Luc rhythm. Overall, these data demonstrate a stress-induced phase shift in a peripheral clock gene rhythm and differential stress sensitivity of two peripheral clocks within the HPA axis, suggesting a link between clock desynchrony and individual vulnerability to stress. [ABSTRACT FROM AUTHOR]

Alterations in the circadian blood pressure pattern are frequently observed in hypertension and lead to increased cardiovascular morbidity. However, there are no studies that have investigated a possible implication of the Period2 gene, a key component of the molecular circadian clock, on the circadian rhythms of blood pressure and heart rate. To address this question, we monitored blood pressure, heart rate, and locomotor activity 24 h a day by telemetry in mice carrying a mutation in the Period2 gene and in wild-type control mice. Under a standard 12:12-h light-dark cycle, mutant mice showed a mild cardiovascular phenotype with an elevated 24-h heart rate, a decreased 24-h diastolic blood pressure, and an attenuation of the dark-light difference in blood pressure and heart rate. Locomotor activity was similar in both groups and did not appear to explain the observed hemodynamic differences. When mice were placed under constant darkness during eight consecutive days, wildtype mice maintained 24-h rhythms, whereas there was an apparent progressive loss of 24-h rhythm of blood pressure, heart rate, and locomotor activity in mutant mice. However, a chi square periodogram revealed that circadian rhythms were preserved under complete absence of any light cue, but with shorter periods by ∼40 mm, leading to a cumulative phase shift toward earlier times of ∼5 h and 20 mm by the end of the 8th day. When heart rate, mean arterial pressure, and activity were recalculated according to the endogenous circadian periods of each individual mouse, the amplitudes of the circadian rhythms ("subjective night"-"subjective day" differences) were maintained for all variables studied. Our data show that mutation of the Period2 gene results in an attenuated dipping of blood pressure and heart rate during both light-dark cycles and constant darkness, and in shorter circadian periods during constant darkness. [ABSTRACT FROM AUTHOR]

Continuous disruption of circadian rhythms, as seen in human shift workers, has been associated with the development of a number of adverse mental and physiological conditions. However, scientific evidence linking circadian disruption to overall health, particularly in animal models, is not well documented. In this study, we have demonstrated that exposing C57BL/6J mice to 12-h phase shifts every 5 days for 3 mo had no effect on body weight or intestinal physiology. However, when animals were further challenged with dextran sodium sulfate to induce colitis, chronic shifting of the light-dark cycle led to a dramatic increase in the progression of the colitis as indicated by reduced body weight, abnormal intestinal histopathology, and an exacerbated inflammatory response. These data indicate that circadian disruption is an important predisposing factor that may provoke the onset or worsening of various disease states such as inflammatory disorders. This study provides further evidence for continued investigations using animal models of circadian disruption to examine the consequences of circadian disruption on health when organisms are faced with a "challenging" environment. [ABSTRACT FROM AUTHOR]

The circadian system in mammals is a hierarchy of oscillators throughout the organism that are coordinated by the circadian clock in the hypothalamic suprachiasmatic nucleus. Peripheral clocks act to integrate time-of-day information from neural or hormonal signals, regulating gene expression, and, subsequently, organ physiology. However, the mechanisms by which the central clock communicates with peripheral oscillators are not understood and are likely tissue specific. In this study, we establish a mouse vascular cell model suitable for investigations of these mechanisms at a molecular level. Using the immortalized vascular smooth muscle cell line Movas-1, we determined that these cells express the circadian clock machinery with robust rhythms in mRNA expression over a 36-h period after serum shock synchronization. Furthermore, norepinephrine and forskolin were able to synchronize circadian rhythms in bmal1. With synchronization, we observed cycling of specific genes, including the tissue inhibitor of metalloproteinase 1 and 3 (timp1, timp3), collagen 3a1 (col3a1), transgelin 1 (sm22α), and calponin 1 (cnn1). Diurnal expression of these genes was also found in vivo in mouse aortic tissue, using microarray and real-time RT-PCR analysis. Both of these revealed ultradian rhythms in genes similar to the cycling observed in Movas-1 in vitro. These findings highlight the cyclical nature of structurally important genes in the vasculature that is similar both in vivo and in vitro. This study establishes the Movas-1 cells as a novel cell model from which to further investigate the molecular mechanisms of clock regulation in the vasculature. [ABSTRACT FROM AUTHOR]

Circadian rhythms of animals are reset by exposure to light as well as dark; however, although the parameters of photic entrainment are well characterized, the phase-shifting actions of dark pulses are poorly understood. Here, we determined the tonic and phasic effects of short (0.25 h), moderate (3 h), and long (6–9 h) duration dark pulses on the wheel-running rhythms of hamsters in constant light. Moderate- and long-duration dark pulses phase dependently reset behavioral rhythms, and the magnitude of these phase shifts increased as a function of the duration of the dark pulse. In contrast, the 0.25-h dark pulses failed to evoke consistent effects at any circadian phase tested. Interestingly, moderate- and long-dark pulses elevated locomotor activity (wheel-running) on the day of treatment. This induced wheel-running was highly correlated with phase shift magnitude when the pulse was given during the subjective day. This, together with the finding that animals pulsed during the subjective day are behaviorally active throughout the pulse, suggests that both locomotor activity and behavioral activation play an important role in the phase-resetting actions of dark pulses. We also found that the robustness of the wheel-running rhythm was weakened, and the amount of wheel-running decreased on the days after exposure to dark pulses; these effects were dependent on pulse duration. In summary, similarly to light, the resetting actions of dark pulses are dependent on both circadian phase and stimulus duration. However, dark pulses appear more complex stimuli, with both photic and nonphotic resetting properties. [ABSTRACT FROM AUTHOR]

The light-dark cycle is the primary synchronizing factor that keeps the internal circadian pacemaker appropriately aligned with the environmental 24-h day. Although it is known that ocular light exposure can effectively shift the human circadian pacemaker and do so in an intensity-dependent manner, the curve that describes the relationship between light intensity and pacemaker response has not been fully characterized for light exposure in the late biological night. We exposed subjects to 3 consecutive days of 5 h of experimental light, centered 1.5 h after the timing of the fitted minimum of core body temperature, and show that such light can phase advance shift the human circadian pacemaker in an intensity-dependent manner, with a logistic model best describing the relationship between light intensity and phase shift, A similar sigmoidal relationship is also observed between light intensity and the suppression of plasma melatonin concentrations that occurs during the experimental light exposure. As with a simpler, 1-day light exposure during the early biological night, our data indicate that the human circadian pacemaker is highly sensitive even to typical room light intensities during the late biological night, with ∼100 lux evoking half of the effects observed with light 10 times as bright. [ABSTRACT FROM AUTHOR]

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the routine circadian dock, in vitro and in vivo, at clinically relevant concentrations (EC50 = 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-D-aspartate (NMDA) receptor [D-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase (NG-nitro-L-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 μM), tetanus toxin (1 μM), P/Q/N type-calcium channel blockers (1 μM ω-agatoxin IVA and 1 μM ω-conotoxin GIVA) and bafilomycin A1 (1 μM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission. [ABSTRACT FROM AUTHOR]

Although light is considered the primary entrainer of circadian rhythms in humans, nonphotic stimuli, including exercise and melatonin also phase shift the biological clock. Furthermore, in birds and nonhuman mammals, auditory stimuli are effective zeitgebers. This study investigated whether a nonphotic auditory stimulus phase shifts human circadian rhythms. Ten subjects (5 men and 5 women, ages 18–72, mean age ± SD, 44.7 ± 21.4 yr) completed two 4-day laboratory sessions in constant dim light (<20 lux). They received two consecutive presentations of either a 2-h auditory or control stimulus from 0100 to 0300 on the second and third nights (presentation order of the stimulus and control was counterbalanced). Core body temperature (CBT) was collected and stored in 2-rain bins throughout the study and salivary melatonin was obtained every 30 min from 1900 to 2330 on the baseline and poststimulus/postcontrol nights. Circadian phase of dim light melatonin onset (DLMO) and of CBT minimum, before and after auditory or control presentation was assessed. The auditory stimulus produced significantly larger phase delays of the circadian melatonin (mean ± SD, -0.89 ± 0.40 h vs. -0.27 ± 0.16 h) and CBT (-1.16 ± 0.69 h vs. -0.44 ± 0.27 h) rhythms than the control. Phase changes for the two circadian rhythms also positively correlated, indicating direct effects on the biological clock. In addition, the auditory stimulus significantly decreased fatigue compared with the control. This study is the first demonstration of an auditory stimulus phase-shifting circadian rhythms in humans, with shifts similar in size and direction to those of other nonphotic stimuli presented during the early subjective night. This novel stimulus may be a useful countermeasure to facilitate circadian adaptation after transmeridian travel or shift work. [ABSTRACT FROM AUTHOR]

Sleep occurs in close relation to changes in body temperature. Both the monophasic sleep period in humans and the polyphasic sleep periods in rodents tend to be initiated when core body temperature is declining. This decline is mainly due to an increase in skin blood flow and consequently skin warming and heat loss. We have proposed that these intrinsically occurring changes in core and skin temperatures could modulate neuronal activity in sleep-regulating brain areas (Van Someren EJW, Chronobiol Int 17:313-54, 2000). We here provide results compatible with this hypothesis. We obtained 144 sleep-onset latencies while directly manipulating core and skin temperatures within the comfortable range in eight healthy subjects under controlled conditions. The induction of a proximal skin temperature difference of only 0.78 ± 0.03°C (mean ± SE) around a mean of 35.13 ± 0.11°C changed sleep-onset latency by 26%, i.e., by 3.09 minutes [95% confidence interval (CI), 1.91 to 4.28] around a mean of 11.85 mm (CI, 9.74 to 14.41), with faster sleep onsets when the proximal skin was warmed. The reduction in sleep-onset latency occurred despite a small but significant decrease in subjective comfort during proximal skin warming. The induction of changes in core temperature (δ = 0.20 ± 0.02°C) and distal skin temperature (δ = 0.74 ± 0.05°C) were ineffective. Previous studies have demonstrated correlations between skin temperature and sleep-onset latency. Also, sleep disruption by ambient temperatures that activate thermoregulatory defense mechanisms has been shown. The present study is the first to experimentally demonstrate a causal contribution to sleep-onset latency of skin temperature manipulations within the normal nocturnal fluctuation range. Circadian and sleep-appetitive behavior-induced variations in skin temperature might act as an input signal to sleep-regulating systems. [ABSTRACT FROM AUTHOR]

When food is restricted to a few hours daily, animals increase their locomotor activity 2-3 h before food access, which has been termed food anticipatory activity. Food entrainment has been linked to the expression of a circadian food-entrained oscillator (FEO) and the anatomic substrate of this oscillator seems to depend on diverse neural systems and peripheral organs. Previously, we have described a differential involvement of hypothalamic nuclei in the food-entrained process. For the food entrainment pathway, the communication between the gastrointestinal system and central nervous system is essential. The visceral synaptic input to the brain stem arrives at the dorsal vagal complex and is transmitted directly from the nucleus of the solitary tract (NST) or via the parabrachial nucleus (PBN) to hypothalamic nuclei and other areas of the forebrain. The present study aims to characterize the response of brain stem structures in food entrainment. The expression of c-Fos immunoreactivity (c-Fos-IR) was used to identify neuronal activation. Present data show an increased c-Fos-IR following meal time in all brain stem nuclei studied. Food-entrained temporal patterns did not persist under fasting conditions, indicating a direct dependence on feeding-elicited signals for this activation. Because NST and PBN exhibited a different and increased response from that expected after a regular meal, we suggest that food entrainment promotes ingestive adaptations that lead to a modified activation in these brain stem nuclei, e.g., stomach distension. Neural information provided by these nuclei to the brain may provide the essential entraining signal for FEO. [ABSTRACT FROM AUTHOR]

The criptochrome genes (Cry1 and Cry2) are involved in the molecular mechanism that controls the circadian clock, and mice lacking these genes (Cry1-/-/Cry2-/-) are behaviorally arrhythmic. It has been speculated that the circadian clock modulates the characteristics of thermoregulation, resulting in body temperature (Tb) rhythm. However, there is no direct evidence proving this speculation. We show here that Tb and heat production in Cry1-/-/Cry2-/- mice are arrhythmic under constant darkness. In contrast, both rhythms occur under a light-dark cycle and/or periodical food restriction linked with spontaneous activity and/or eating, although they are not robust as those in wild-type mice. The relationship between heat production and Tb in Cry1-/-/Cry2-/- mice is linear and identical under any conditions, indicating that their Tb rhythm is determined by heat production rhythm associated with activity and eating. However, Tb in wild-type mice is maintained at a relatively higher level in the active phase than the inactive phase regardless of the heat production level. These results indicate that the thermoregulatory responses are modulated according to the circadian phase, and the Cry genes are involved in this mechanism. [ABSTRACT FROM AUTHOR]

Jetlag results when a temporary loss of circadian entrainment alters phase relationships among internal rhythms and between an organism and the outside world. After a large shift in the light-dark (LD) cycle, rapid recovery of entrainment minimizes the negative effects of internal circadian disorganization. There is evidence in the existing literature for an activation of the hypothalamic-pituitary-adrenal (HPA) axis after a photic phase shift, and it is possible that the degree of HPA-axis response is a determining factor of reentrainment time. This study utilized a diurnal rodent, Octodon degus, to test the prediction that the alteration of cortisol levels would affect the reentrainment rate of circadian locomotor rhythms. In experiment 1, we examined the effects of decreased cortisol (using metyrapone, an 11β-hydroxylase inhibitor) on the rate of running-wheel rhythm recovery after a 6-h photic phase advance. Metyrapone treatment significantly shortened the length of time it took animals to entrain to the new LD cycle (11.5% acceleration). In experiment 2, we examined the effects of increased cortisol on the rate of reentrainment after a 6-h photic phase advance. Increasing plasma cortisol levels increased the number of days (8%) animals took to reentrain running-wheel activity rhythms, but this effect did not reach significance. A third experiment replicated the results of experiment 1 and also demonstrated that suppression of HPA activity via dexamethasone injection is capable of accelerating reentrainment rates by ∼33%. These studies provide support for an interaction between the stress axis and circadian rhythms in determining the rate of recovery from a phase shift of the LD cycle. [ABSTRACT FROM AUTHOR]

Investigates the role of stress and activity on the circadian rhythm of Syrian hamsters. Phase advance shifts of circadian activity rhythms when animal is subjected to locomotor activity during usual rest periods; Effect of sleep deprivation on phase shifts; Phase shifts resulting from resident-intruder interactions.

Determines if augmenting the amplitude of the rhythm of the endogenous molecule melatonin would augment the response of the circadian timing system of the hamster to a nonphotic phase-shifting agent, triazolam. Composition of the circadian timing system; Determination if the feeding regimen delivered a physiological or pharmacological dose of melatonin; Influence of melatonin on the activity of suprachiasmatic nuclei neurons.

Tests whether melatonin can facilitate phase shifts in a simulated night-work protocol. Information on the use of the pineal hormone melatonin to produce phase shifts in circadian rhythms; Comparison of phase advances produced by melatonin and by placebo pills; Role of melatonin in promoting adaptation to night work and jet travel.

Presents a study that examined the effect of prolonged exercise on modulation of phase-shifting effects of late night/early morning bright light. Correlation between baseline phase markers and phase shifts; Analysis of six-sulphatoxymelatonin phase shifts; Evaluation of phase shifts in the rhythm of temperature.

Presents a study which tested the hypothesis that the Wistar Kyoto rat, a proposed animal model of depression, would exhibit hormonal and activity rhythm alterations similar to the circadian rhythm alterations in humans. Materials and methods; Results; Discussion.

Presents information on a study which examined the effects of melatonin agonist on age-related changes in circadian response to environmental stimulus. Methodology; Results of the study; Discussion.

Provides information on a study which examined the effect of light in the development of the circadian system of rats during critical periods in the lactation stage. Materials and methods; Results; Discussion.

Focuses on a study which characterized the role of the suprachiasmatic nuclei in the circadian organization of Ruin lizards. Materials and methods of the study; Results of the study; Discussion of the results.

Focuses on a study which discussed the behavioral feedback regulation of circadian rhythm phase angle in light-dark entrained mice. Information on the circadian timekeeping system in mammals; Methodology; Result of the study.

Presents information on a study which investigated the sensitivity of young and old hamsters to the phase advancing effect of a dark pulse on the locomotor activity rhythm. Background of the effects of aging on the functional aspects of circadian rhythms; Materials and methodology used; Results and its implications.

Deals with a study which examined the relationship of circadian rhythms and pineal melatonin in the rest-activity cycle of nocturnally active rodents. Methodology of the study; Discussion on the results of the study; Perspectives.

Investigates the effects of pinealectomy (Pin-X) and melatonin implantation (Mel) on electroretinogram (ERG) rhythms in chicks. Feeding activity of representative Sham, Pin-X and Mel chicks; Raw ERG data from an intact chick; Intensity-response amplitude and intensity-response implicit time of Sham and Pin-X chicks in light-dark.

Presents information on a study which examined the interaction of homeostatic and circadian processes in the regulation of waking behavioral functions and sleep in young individuals. Methods; Results.

Presents information on a study which explored the human circadian rhythms in sleep, activity, plasma melatonin and rectal temperature under time cues in Antartica. Materials and methods; Results; Perspectives.

Focuses on a study on the effects of periodic infusions of melatonin or the melatonin agonist S20098 of variable duration or pattern on the circadian rhythms of rats. Methodology of the study; Results and discussion; Conclusion.

Discusses a study which investigated the presence of diurnal rhythms of transcription factor nuclear factor-KB (NF-KB) activation in the brain and changes in the activation after sleep deprivation. Materials and methods of the study; Result of the experiments; Discussion of the results.

Presents a study which tested the hypothesis that the free-running circadian rhythm in body temperature results from coordinated rhythms of heat production and loss in thermoneutrality. Methodology of the study; Results and discussion; Conclusion.

Presents a study on the necessary meal size to induce circadian ensuing activity (CEA) and examines the role of oral-pharyngeal factors and afferent vagal activity in CEA. Method of study; Results and discussion; Conclusion.

Presents information on a study which investigated the possibility that interstrain differences in the diurinal pattern of wheel running activity rhythms are reflected in the melatonin profiles of rats. Urine collection; Collection of plasma and pineal glands; Discussion of results.

Presents information on a study which tested whether circadian responses to light are modulated by decreased glucose availability in mice. Methods used; Design of the experiments; Discussion of results.

Presents information on a study which determined if C57Bl/6J mice would develop depressive-like symptoms after exposure to chronic stress. Investigation of long-term changes in the daily pattern of activity associated with chronic stress; Methodology; Data analysis; Result and discussion.

Details a study on later endogenous circadian temperature nadir that is relative to an earlier wake time in older people. Theoretical background; Materials and methods; Results.

Presents a study that showed that the circadian system of mice can integrate extremely brief and repeated photic stimuli to produce large phase shifts. Methodology used in the study; Difference between the visual system and the circadian system; What the data revealed; Practical application.

Presents a study on the influence of exercise on the organization of the timing system. Analysis of the effect of voluntary locomotor activity on the circadian feeding behavior of rats subjected to different lighting conditions; Materials and methods used in the study; Perspectives.

Presents information on a study that evaluated the usefulness of cynomolgus macaques maintained under standardized conditions as physiological models for circadian rhythms of bone and calcium metabolism. Methods of increasing bone density in women; Circadian rhythm markers; Food and water consumption; Serum calcium and phosphorus.

Presents information on a study about the entertainment limits of the circadian rhythms of feeding activity in Wistar rats. Range of entertainment of feeding rhythms to symmetrical light-dark (LD) cycles; Interaction of circadian and homeostatic processes that regulate the feeding behavior of rats kept under LD cycles; What the results indicate.

Focuses on a study which investigates the phase shifting effects of times calorie restriction in mice during exposure to 12:12-h light-dark cycle. Details on circadian rhythms; Methodology of the study; Discussion on the results of the study.

Examines whether metabolic rhythms persist during fasting and whether such rhythms could be entrained to a restricted feeding schedule. Factors which influenced the circadian rhythms; Materials and methods used in the study; Rhythmic patterns during fasting conditions; Changes in the serum concentration of free fatty acids, ketone bodies and triacylglycerides during exposure to restricted feeding schedules for three weeks.

Evaluates the simultaneous effects on sleep of prior time awake (PRW) and time of day (TOD). Details on the methods used in the experiment; Conclusion pertaining to the effect of homeostatic and circadian influences on sleep; Findings on the sensitivity of rapid eye movement sleep to the need for slow-wave sleep.

Examines the capability of daily melatonin injections to entrain circadian rhythms in different seasons. Information on the locomotor rhythms of lizards; Role of suprachiasmatic nuclei (SCN) in the mediation of summer locomotor rhythms to melatonin; Significance of the results of the study.

Examines the sensitivity to light of the human circadian pacemaker throughout subjective day and assesses possible transients after the light stimulus. Time course of stable phase resetting of core body temperature via bright light; Effects of intensity of background lighting relative to bright light.

Characterizes the effects of low-protein malnutrition on the circadian rhythm of drinking behavior and on suprachiasmatic nuclei (SCN) immunohistochemistry in rats. Behavioral aspects; SCN cytoarchitecture; Indirect effects of malnutrition on circadian rhythmicity; Evidence of a circadian oscillator entrainable to food availability independent of SCN.

Investigates the roles of the eye and the gonad in the dual-oscillator circadian system of the female Japanese quail. Dissociation of the circadian body temperature rhythm after blocking of ocular light by eye-patching; Dependence of the long free-running rhythm of continuous lighting in the presence of the ovary.

Investigates motor activity circadian rhythm in rats after exposure to LD cycles of 4-h period. Observance of a four-hour rhythm in the motor activity of rats when maintained under T4; Formation of circadian rhythm in rats by several circadian oscillators; Inhibition of internal coupling within the system by constant bright light.

Compares the entrainment of wheel-running activity rhythms in hamsters initially exposed to daily light-dark (LD) cycles with abrupt light transitions. Upper limit of entrainment to LD cycles; Total phase shift resulting from exposures.

Examines response to light and circadian rhythm of glutamate and aspartate in rat suprachiasmatic nucleus (SCN). Increase of locomotor activity during nighttime; Extracellular excitatory amino acid levels in the vicinity of the rat SCN.