A role of the circadian system and circadian proteins in aging

Circadian rhythms are genetically determined biological rhythms that are considered an important adaptive mechanism to the cyclical light/dark alterations in the Earth environment. Age-related changes in the circadian time-keeping mechanism are well known, and seemingly contribute to various pathologies of aging. Recent findings demonstrate that the circadian system and circadian proteins play direct roles in many physiological processes, including those associated with aging. The core circadian proteins BMAL1 and PERIODs, in addition to their known functions in the circadian oscillator, play essential non-redundant roles in the control of tissue homeostasis and aging. Although the exact mechanisms are unknown, the involvement of circadian proteins in the regulation of metabolism, genotoxic stress response and reactive oxygen species (ROS) homeostasis can be responsible for the premature aging, observed in some circadian mutants. The understanding of the molecular mechanisms of these non-circadian activities of the circadian proteins will ultimately lead to the improvement in prevention and treatment of age-related pathologies.     

Relations between muricide, circadian rhythm and consummatory behavior

Three forms of behavior--muricide, eating, and drinking--have been studied at six photic periods during a 12/12 hr light/dark circadian cycle to which the subjects have been habituated. One hundred and eight rats served as subjects, 18 per photic period. The frequency of muricide was recorded for each period and subsequent food and water intakes were measured during a 1 hr test period. Results show a significantly higher frequency of muricide during the dark than during periods of light. Food intake covaried significantly with the incidence of muricide rs = 0.89, p less than 0.05), while no such relationship was found between muricide and water intake (rs = 0.17, p less than 0.05). The findings are consistent with reports of circadian changes in other rodent behaviors, including rhythmicity in home-cage and in shock-induced aggression. Covariation of muricide and eating does not establish a causal relation between the two. Three models of physiological mechanisms which might provide substrates for the covariance are discussed.     

Food and light as entrainers of circadian running activity in the rat

The purpose of this experiment was to determine the extent to which circadian running activity could be controlled by two different environmental cues: periodic access to food and ambient light cycles. Seven male rats were successively exposed to the following four conditions: (1) With light cycles (LD 12:12) and continuous access to food, the animals displayed a basically nocturnal pattern of running. (2) With access to food for two hours during the illuminated portion of the LD cycle, all of the animals showed a burst of running preceding food presentation. Three of these seven animals concurrently showed diminished running associated with the light cycle. (3) The animals continued to run before the periodic presentation of food when constant light replaced the LD cycle. (4) When allowed continuous access to food, and still exposed to constant light, the animals continued to show bursts of running around the time that food had been delivered. Rats' circadian activity cycles were therefore influenced by periodic access to food. Moreover, when periodic food was offered during the illuminated portion of the LD cycle (when rats are normally inactive) food presentation was a more potent entrainer than photic cues in controlling running activity.     

Melatonin secretion in the Mashona mole-rat, Cryptomys darlingi--influence of light on rhythmicity

The hormone melatonin is synthesised and secreted from the pineal gland in darkness and triggers the daily and seasonal timing of various physiological and behavioural processes. The Mashona mole-rat, Cryptomys darlingi, lives in subterranean burrows that are completely sealed and is therefore rarely, if ever, exposed to light under natural conditions. Hence, this species is of particular interest for studies on rhythms of melatonin secretion. We investigated how plasma melatonin concentrations of the Mashona mole-rat responded to exposure to a long-term standard photoperiod of 12 h light, 12 h dark (12:12 LD), constant light (LL) and constant dark (DD). In addition, we examined whether plasma melatonin concentration was coupled to locomotor activity. Mashona mole-rats displayed rhythms of plasma melatonin concentration that appeared entrained to the standard LD photoperiod, suggesting that the mole-rat is capable of perceiving and entraining to this photic zeitgeber. Furthermore, under chronic constant lighting conditions (DD, LL), circadian rhythms in plasma melatonin concentration were observed, suggesting the possible existence of an endogenous rhythm. Light suppressed melatonin secretion, but constant light did not abolish the rhythm of plasma melatonin concentration. Between active and non-active animals, no difference in plasma melatonin concentration was found for any of the sequential photoperiods (LD1 DD, LD2, LL), tentatively suggesting that the rhythm of melatonin secretion is uncoupled from that of locomotor activity.     

Effect of pinealectomy and circadian rhythm on avoidance behavior in the male rat

Male adult albino rats were divided into six groups: two pinealectomized (Px); two sham-operated (Sh) and two serving as controls (C). Half of these groups were studied in daylight and the other half at night. The animals were open-field tested and then conditioned by the avoidance behavior test in the appropriate light period. No differences were observed among the groups when they were conditioned in the dark; however, the Px were conditioned significantly more rapidly than Sh or C in daylight. Intragroup comparisons between night/day conditioning showed them to be similar in Px but more rapid at night in both Sh and C. The Sh group is unique and not comparable to controls.     

模拟微重力对NIH3T3细胞近日节律基因的影响

目的:研究模拟微重力对NIH3T3细胞近日节律基因表达水平的影响。方法:NIH3T3细胞按照模拟微重力的天数分为5组,RT-PCR检测节律基因mRNA的相对表达水平。结果:实验结果显示五组样品Per1、Per2、Cry1、Bmal1、Clock的相对表达水平存在显著性差异。Per1和Per2基因mRNA的相对表达水平在模拟微重力的第2天、第3天较0天显著升高(P0.05),Per2、Cry1和Clock基因mRNA的相对表达水平在模拟微重力的第4天较其他四组显著降低(P0.05)。结论:近日节律基因的相对表达水平在模拟微重力第2、3天升高,第4天后降低。模拟微重力影响近日节律基因的表达且具有时间依赖性。     

Partial isolation of the suprachiasmatic nuclei: Effects on circadian rhythms of rat drinking behavior

The rat's daily pattern of contact with a drinking tube was observed in a light-dark cycle (LD 12:12) and in constant light (LL) after partial isolation of the suprachiasmatic nuclei (SCN) with a wire microknife that transected their lateral, dorsal, and caudal connections or the passage of a wire microknife through the SCN. Animals whose SCN had been partially isolated remained entrained to an LD cycle and phase shifted drinking behavior when the LD cycle was delayed 4 hr. Disintegration of circadian rhytmicity was observed when these rats were exposed to LL. Passage of the knife through the SCN resulted in immediate and persistent disruption of circadian rhythmicity as severe as that seen after electrolytic lesions of the SCN. These data confirm the necessity of the SCN in regulating circadian behavior and suggest that the SCN may mediate entrainment and freerunning rhythms via different neural systems.     

Splitting of the circadian rhythm of body temperature in the golden hamster

The circadian rhythm of hamster locomotor activity “splits” into two distinct circadian components during conditions of constant illumination. To determine if the circadian rhythm of body temperature also splits under these conditions, body temperature and locomotor activity were monitored concurrently in animals housed in constant illumination. Splitting of the body temperature rhythm into two circadian components was observed in animals manifesting split activity rhythms. Concurrent splitting of both rhythms suggests a common mechanism either for the generation or coupling of these rhythms.     

The multiplicity of biological oscillators in the control of circadian running activity in the rat

The purpose of this experiment was to determine the degree to which a circadian running activity could be controlled by multiple biological oscillators within a single organism. Twelve male rats, housed in running wheels, had access to food from noon to 1 p.m. daily. In addition to this noon or fixed feeding, the rats received a moving feeding during which they had access to food for 1 hr every 25 hr. These two circadian feedings had a continually shifting phase relationship to each other. The animals responded to this regime by displaying separate bursts of running activity which were in relative coordination. Each animal's behavior shifted between the three following general patterns: (1) one cycle of activity, either before the fixed or the moving feed; (2) two bursts of activity, one before the fixed feeding and one preceding the moving feeding or (3) a burst of activity not entrained to either one of the feedings but rather free running between the two. When the animals were subsequently offered continuous access to food, 10 of the 12 rats maintained two bursts of activity.     

Short-wavelength light reduces circadian elevation of intraocular pressure in rabbits

In light-dark entrained rabbits, the intraocular pressure (IOP) increases around the onset of dark due to the increased activities of ocular sympathetic nerves. This circadian elevation of IOP can be eliminated by exposing the rabbits to constant white light in the early subjective dark phase. The spectral effectiveness of light causing the reduction in IOP was studied using lights selectively filtered through various optic filters. Light which passed through a long-pass filter, with a cut-on wavelength at 570 nm or 530 nm, caused no change of the circadian IOP elevation. A significant reduction of the IOP elevation was observed with filtered light via the 495 nm long-pass filter and, to a larger extent, with light via the 475 nm long-pass filter. Short-wavelength light (380–480 nm, peak at 432 nm) passed through a band-pass filter completely eliminated the circadian IOP elevation. The aqueous humor concentration of norepinephrine (NE) under the short-wavelength light was significantly lower than the NE concentration under the filtered light via the 530 nm long-pass filter. Sensation of the short-wavelength light plays an important role in synchronizing the circadian elevation of IOP in rabbits.     

Responsiveness of the aging circadian clock to light

The present study assessed whether advances in sleep times and circadian phase in older adults might be due to decreased responsiveness of the aging circadian clock to light. Sixteen young (29.3 ± 5.6 years) and 14 older adults (67.1 ± 7.4 years) were exposed to 4 h of control dim (10 lux) or bright light (3500 lux) during the night. Phase shifts of the melatonin rhythm were assessed from the nights before and after the light exposure. Bright light delayed the melatonin midpoint in both young and older adults (p < 0.001). Phase delays for the older subjects were not significantly different from those of the young subjects for either the bright or dim light conditions. The magnitude of phase delays was correlated with both sleep offset and phase angle in the older, but not the younger subjects. The present results indicate that at light intensities commonly used in research as well as clinical practice older adults are able to phase delay to the same extent as younger subjects.     

Shaping the light/dark pattern for circadian adaptation to night shift work

This is the second in a series of simulated night shift studies designed to achieve and subsequently maintain a compromise circadian phase position between complete entrainment to the daytime sleep period and no phase shift at all. We predict that this compromise will yield improved night shift alertness and daytime sleep, while still permitting adequate late night sleep and daytime wakefulness on days off. Our goal is to delay the dim light melatonin onset (DLMO) from its baseline phase of ∼ 21:00 to our target of ∼ 3:00. Healthy young subjects (n = 31) underwent three night shifts followed by two days off. Two experimental groups received intermittent bright light pulses during night shifts (total durations of 75 and 120 min per night shift), wore dark sunglasses when outside, slept in dark bedrooms at scheduled times after night shifts and on days off, and received outdoor light exposure upon awakening from sleep. A control group remained in dim room light during night shifts, wore lighter sunglasses, and had unrestricted sleep and outdoor light exposure. After the days off, the DLMO of the experimental groups was ∼ 00:00-1:00, not quite at the target of 3:00, but in a good position to reach the target after subsequent night shifts with bright light. The DLMO of the control group changed little from baseline. Experimental subjects performed better than control subjects during night shifts on a reaction time task. Subsequent studies will reveal whether the target phase is achieved and maintained through more alternations of night shifts and days off.     

An hour of bright white light in the early morning improves performance and advances sleep and circadian phase during the Antarctic winter

Previous work has demonstrated that exposure to an hour of bright light in the morning and the evening during the Polar winter has beneficial effects on circadian phase. This study investigated the effect of a single hour of bright white morning light on circadian phase, sleep, alertness and cognitive performance. Nine individuals (eight male, one female, median age 30years), wintering at Halley Research Station (75°S), Antarctica from 7th May until 6th August 2007, were exposed to bright white light for a fortnight from 08:30 to 09:30h, with two fortnight control periods on either side. This sequence was performed twice, before and following Midwinter. Light exposure, sleep and alertness were assessed daily by actigraphy, sleep diaries and subjective visual analogue scales. Circadian phase (assessed by urinary 6-sulphatoxymelatonin rhythm) and cognitive performance were evaluated at the end of each fortnight. During light exposure circadian phase was advanced from 4.97±0.96 decimal hours (dh) (mean±SD) to 4.08±0.68dh (p=0.003). Wake-up time was shifted by a similar margin from 8.45±1.83dh to 7.59±0.78dh (p<0.001). Sleep start time was also advanced (p=0.047) but by a lesser amount, consequently, actual sleep time was slightly reduced. There was no change in objective or subjective measures of sleep quality or subjective measures of alertness. An improvement in cognitive performance was found with both the Single Letter Cancellation Test (p<0.001) and the Digit Symbol Substitution Test (p=0.026) with preserved circadian variation. These beneficial effects of a single short duration light treatment may have implications not only for the Antarctic but other remote environments where access to natural light and delayed circadian phase, is problematic. These results require validation in larger studies at varying locations.     

The influence of day and night work on the circadian variations of cardiovascular performance

Summary Circadian variations of the pre-ejection period, Q-T interval, heart rate and oral temperature at rest and in day and night shift work were investigated. At rest, pronounced circadian variation was found in heart rate, pre-ejection period and Q-T interval. The ratio between Q-T interval and heart rate also shows a distinct circadian variation. When working, the rest rhythms of the variables were obscured. The physiological implications for shift work are discussed.Supported by the National Swedish Board for Technical Development, Grants No. 76-7096 I and 78-4307     

The development of infants' circadian rest-activity rhythm and mothers' rhythm

In order to know when and how infants obtain their circadian sleep-wake rhythm, infants' developing circadian rest-activity rhythm and mothers' circadian rhythm in the postpartum period were examined using actigraph monitoring. The subjects were 11 primipara and their infants. Actigraphic recordings for the infants and their mothers were made over 3-5 continuous days during the 3rd, 6th, 9th and 12th weeks after birth. A 24-h peak on a mean autocorrelogram of the infants' movements was detected at the 3rd week. The infants' circadian rest-activity rhythm already existed in the 3rd week. The amplitude of this 24-h peak gradually increased from the 6th to 12th week. This may be useful as an index of the development of infants' circadian rest-activity rhythm. An 11-h peak was also observed at the 3rd week. This 11-h peak was thought to be a semi-circadian rhythm. Regarding the mothers, the amplitude of the 24-h peak on the mean autocorrelogram at the 3rd week was the smallest of all other weeks, and it became larger from the 3rd to 12th week. This meant that the mothers' circadian rhythm at the 3rd week was influenced by their interrupted sleep at night to take care of their infants. The mother-infant synchronization is probably the 1st factor in the entrainment of infants' circadian sleep-wake rhythm. In this study, we also propose a novel method for compensating for missing data in autocorrelogram analysis.     

Photosynchronization of the circadian clock of Schizosaccharomyces pombe: Mitochondrial cytochrome b is an essential component

Summary Visible light exerts a dual effect on Schizosaccharomyces pombe. It synchronizes its circadian clock to a diurnal light-dark cycle. At lower temperatures it slows down, and at higher intensities eventually inhibits, growth. Screening of available mutants deficient in one or two mitochondrial cytochromes indicated involvement of these cytochromes in both effects. Mutants lacking only one cytochrome were as sensitive to light inhibition as was the wild-type. Mutants deficient in both cytochrome b and cytochrome a/a ₃ showed partial resistance to a varying degree, but growth rate of the dark control was never reached. With respect to synchronization the pattern is more clearcut. Two mutants lacking only cytochrome a/a ₃ could still be syndronized. In contrast, four different mutants lacking only cytochrome b, and four different mutants lacking both cytochrome b and cytochrome a/a ₃ , all failed to entrain to a light-dark cycle. These results demonstrate that mitochondrial cytochrome b is necessary for photosynchronization either as the primary photoreceptor or as a part of the transduction chain.     

Microcomputerized measurement of the circadian locomotor rhythm in microorganisms

A computerized close-up video/photoamplifier system was implemented for the study of circadian locomotor rhythm in a population of a ciliate protozoan, Paramecium. This fully microcomputerized system facilitated automatic long-term measurement of three parameters in parallel: (1) numbers of specimens per 10 min traversing beneath a fixed point in an experimental vessel, (2) times taken by specimens to traverse the point, and (3) interval times between subsequent specimens traversing the point. Stochastic analyses using these parameters can derive the circadian fluctuation of physiological variables, such as swimming speed and the frequency of avoiding reaction (abrupt change in swimming direction). The computerized system simultaneously accomplished the acquisition of these three sets of data, their transient storage, and their graphic display according to given format. The system software was constituted so that an experimenter with little computer knowledge, could easily operate the system by answering questions displayed on the computer monitor.     

Entrainment of the circadian activity rhythm to the light cycle: Effective light intensity for a Zeitgeber in the retinal degenerate C3H mouse and the normal C57BL mouse

Effective light intensities for entrainment of activity rhythms were obtained in the retinal degenerated C3Hf/He mice and the normal C57BL/6J mice. The circadian activity rhythms of the mice were examined under LD 12:12 cycles with one of five different levels of light (L phase) and complete darkness (D phase). The thresholds of a Zeitgeber, defined as the light intensity effective for 50% entrainment, were estimated between 1 lux and 5 lux in the C3H and lower than 0.01 lux in the C57BL mice. These results suggest that at least two different kinds of photoreceptor including rods and cones participate in the photic entrainment of the circadian activity rhythms.     

Interaction of estradiol and photoperiod on activity patterns in the female hamster

The extent of the effects of estradiol on the locomotor rhythm in hamsters is unknown. This study was designed to determine the ability of estradiol alone and in combination with the photoperiod to alter activity patterns. Intact animals displayed higher levels of activity in LD 16:8 than in LD 6:18. Ovariectomy without estradiol treatment caused a sharp decline in activity in LD 16:8; estradiol treatment prevented this. In LD 6:18, activity levels were unaffected by either estradiol or ovariectomy. Estradiol altered the temporal distribution of activity only in LD 6:18, advancing peak activity towards lights-off. Estradiol decreased the variability in day to day onsets of activity in LD 6:18, but did not affect onsets in LD 16:8. The data suggest that the activity rhythm of the hamster is comprised of discrete components; the response of each component to estradiol is differentially altered by photoperiod. Furthermore, estradiol is vital for the expression of high activity levels in the LD 16:8 female.     

近日节律的改变与高血压脑出血手术治疗预后关系的研究

目的：研究近日节律的改变与高血压脑出血手术治疗预后的关系。方法：收集100例高血压基底节区脑出血的病例,每例患者均进行了标准的开颅血肿清除术。术后连续24小时监测心率,每小时记录一次。用单一余弦法进行术后24小时心率的近日节律分析。根据术后近日节律的出现和消失将患者分组,利用统计学比较两组预后的差异。结果：术后24小时心率近日节律出现组预后好的患者比例明显优于消失组（P〈0．01）。结论：近日节律的改变有可能早期预测高血压脑出血手术治疗的预后。