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PubMed2004

Dexras1 potentiates photic and suppresses nonphotic responses of the circadian clock.

Circadian rhythms of physiology and behavior are generated by biological clocks that are synchronized to the cyclic environment by photic or nonphotic cues. The interactions and integration of various entrainment pathways to the clock are poorly understood. Here, we show that the Ras-like G protein Dexras1 is a critical modulator of the responsiveness of the master clock to photic and nonphotic inputs. Genetic deletion of Dexras1 reduces photic entrainment by eliminating a pertussis-sensitive circadian response to NMDA. Mechanistically, Dexras1 couples NMDA and light input to Gi/o and ERK activation. In addition, the mutation greatly potentiates nonphotic responses to neuropeptide Y and unmasks a nonphotic response to arousal. Thus, Dexras1 modulates the responses of the master clock to photic and nonphotic stimuli in opposite directions. These results identify a signaling molecule that serves as a differential modulator of the gated photic and nonphotic input pathways to the circadian timekeeping system.

Animals↗
PubMed1979

Stickiness to Glass: Circadian Changes in the Cell Surface of Chlamydomonas reinhardi.

Conditions were found in which Chlamydomonas reinhardi exhibits a circadian alteration of its cell surface, measured as ability to stick to glass. Under these same conditions the cells also show circadian rhythms of cell division and release of daughter cells. The three rhythmic phenomena were shown to have typical properties of rhythms controlled by the biological clock. The rhythm of stickiness was used to demonstrate that in a mixed culture containing two cell populations with natural periods differing by 2 to 3 hours, the cells did not mutally entrain each other and that this rhythm could be successfully applied in an enrichment procedure for mutants of the biological clock. Stickiness was shown to be independent of growth and motility of the cells and unaffected by red or far red illimination. Minimally sticking cells did not affect the sticking of maximally sticking cells in a mixed culture; nor was there a progressive increase in stickiness shown at the minimum from one cycle to the next in a pure culture. These results indicate that sticking probably is not mediated by long lived adhesive material or enzymes excreted into the medium. Several tests of the sensitivity of stickiness to replacement of the growth medium by distilled water or water containing various compounds suggest that ions might play an important role in the sticking reaction.

Journal Article↗
PubMed2004

Temporal precision in the mammalian circadian system: a reliable clock from less reliable neurons.

The mammalian SCN contains a biological clock that drives remarkably precise circadian rhythms in vivo and in vitro. This study asks whether the cycle-to-cycle variability of behavioral rhythms in mice can be attributed to precision of individual circadian pacemakers within the SCN or their interactions. The authors measured the standard deviation of the cycle-to-cycle period from 7-day recordings of running wheel activity, Period1 gene expression in cultured SCN explants, and firing rate patterns of dispersed SCN neurons. Period variability of the intact tissue and animal was lower than single neurons. The median variability of running wheel and Period1 rhythms was less than 40 min per cycle compared to 2.1 h in firing rate rhythms of dispersed SCN neurons. The most precise SCN neuron, with a period deviation of 1.1 h, was 10 times noisier than the most accurate SCN explant (0.1 h) or mouse (0.1 h) but comparable to the least stable explant (2.1 h) and mouse (1.1 h). This variability correlated with intrinsic period in mice and SCN explants but not with single cells. Precision was unrelated to the amplitude of rhythms and did not change significantly with age up to 1 year after birth. Analysis of the serial correlation of cycle-to-cycle period revealed that approximately half of this variability is attributable to noise outside the pacemaker. These results indicate that cell-cell interactions within the SCN reduce pacemaker noise to determine the precision of circadian rhythms in the tissue and in behavior.

Aging↗
PubMed2000

Dimerization and nuclear entry of mPER proteins in mammalian cells.

Nuclear entry of circadian oscillatory gene products is a key step for the generation of a 24-hr cycle of the biological clock. We have examined nuclear import of clock proteins of the mammalian period gene family and the effect of serum shock, which induces a synchronous clock in cultured cells. Previously, mCRY1 and mCRY2 have been found to complex with PER proteins leading to nuclear import. Here we report that nuclear translocation of mPER1 and mPER2 (1) involves physical interactions with mPER3, (2) is accelerated by serum treatment, and (3) still occurs in mCry1/mCry2 double-deficient cells lacking a functional biological clock. Moreover, nuclear localization of endogenous mPER1 was observed in cultured mCry1/mCry2 double-deficient cells as well as in the liver and the suprachiasmatic nuclei (SCN) of mCry1/mCry2 double-mutant mice. This indicates that nuclear translocation of at least mPER1 also can occur under physiological conditions (i.e., in the intact mouse) in the absence of any CRY protein. The mPER3 amino acid sequence predicts the presence of a cytoplasmic localization domain (CLD) and a nuclear localization signal (NLS). Deletion analysis suggests that the interplay of the CLD and NLS proposed to regulate nuclear entry of PER in Drosophila is conserved in mammals, but with the novel twist that mPER3 can act as the dimerizing partner.

Animals↗
PubMed1996

The effect of light on the biosynthesis of beta-carotene and superoxide dismutase activity in the photosynthetic alga Gonyaulax polyedra.

Daily oscillations of both beta-carotene and superoxide dismutase (SOD) activity are related to the intracellular control of reactive oxygen species (ROS). It is well established that ROS are present in all aerobic cells. We studied the marine dinoflagellate Gonyaulax polyedra which has been extensively used as a model to understand the biological clock at the molecular level. beta-Carotene, besides suppressing singlet molecular oxygen (1O2), may act as a photoreceptor pigment in many photosynthetic cells. The levels of beta-carotene during the day phase were shown to be twice as high as during the night phase. The dose-response curve for light-induced carotenoid synthesis was linear for up to 45 min of light exposure, after which night phase cells contained the same levels of beta-carotene as day phase cells. Cells exposed to light pulses at different times during the dark period displayed the highest beta-carotene induction in the middle of the night. SOD activity of cell-free extracts of G. polyedra was three to four times higher during the day. This rhythm continued in cells kept in constant light, indicating that the regulation can be attributed to the cellular circadian clock. No-denaturing polyacrylamide gels revealed the presence of several SOD isoenzymes in G. polyedra, including CuZnSOD and MnSOD. Furthermore, G. polyedra SOD cross-reacts with a polyclonal antibody raised against SOD. In addition to being gene regulated by ROS concentration, G. polyedra SOD expression seems also to be under the control of the biological clock.

Animals↗
PubMed1992

Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and Alzheimer's disease.

Circadian rhythms are already present in the fetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the fetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the fetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of maternal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the fetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin.

Aging↗
PubMed2005

[Sleep and circadian rhythms in ageing].

With age, the consolidation of nocturnal sleep decreases, daytime napping increases, and sleep occurs earlier. Sleep regulation is dependent on the interaction between a circadian pacemaker (biological clock) and the sleep homeostat (sleep pressure increasing with duration of time awake). We have shown that in the healthy elderly, the amplitude of circadian rhythms (e. g. melatonin secretion) declines, as does slow wave sleep, parallel with an increase in afternoon sleepiness and a tendency to fall asleep in the early evening when younger subjects do not. Light is the major zeitgeber to stabilise the biological clock: older subjects require sufficient light exposure during daytime and in the evening, and should take no or only brief naps during the day to improve sleep.

Aged, 80 and over↗
PubMed2000

Is histamine the final neurotransmitter in the entrainment of circadian rhythms in mammals?

Adaptation of circadian rhythms to the environmental light-dark cycle is necessary for the survival of organisms. This synchronization or entrainment is only caused by light (photic input) during the dark period, according to the internal biological clock of an organism. During the light period, internal factors (non-photic input), rather than light, are able to entrain circadian rhythms. In this article, the data that implicate the neurotransmitter system for histamine in circadian entrainment are reviewed. Furthermore, we speculate that histamine receptors are the final gate at which both photic and non-photic entrainment mechanisms converge before sending a resetting signal to the intracellular biological clock.

Animals↗
PubMed2002

The precise human bioclock, possibly imported.

Contrary to what has long been suggested, the biological clock is not a poor timekeeper. In fact, it has been working in precision for millions of years as a genetically set clock, independent of environmental periodicity. However, as the Earth's rotation has gradually slowed, this internal clock has gone through a relative phase shift. Extrapolating of changes backwards through time shows that the clock was set when mammals first appeared on the planet. Interestingly, primates are the only beings that have a free-running cycle longer than 24 hours. This bioclock may be set by lunar entrainment, or may be set extraterrestrially?

Animals↗
PubMed2003

Melatonin: clinical relevance.

This chapter reviews the neural connections between the retinas and the pineal gland and summarizes the role of the light:dark cycle and the biological clock, i.e. the suprachiasmatic nuclei, in regulating pineal melatonin synthesis and secretion. The cellular mechanisms governing the nocturnal production of melatonin are described together with the way in which the misuse of light interferes with the circadian melatonin cycle and the total quantity of the indole generated. The chapter describes the nature of the membrane melatonin receptors and their signal transduction mechanisms in peripheral organs. The clinical implications and potential uses of melatonin in terms of influencing the biological clock (e.g. sleep and jet lag), immune function, and cancer initiation and growth are noted. Additionally, the chapter includes a description of the newly discovered free radical scavenging and antioxidant activities of melatonin; it also includes a list of clinical situations in which melatonin has been used with beneficial effects.

Animals↗
PubMed1992

Nutrient intake as a time signal for circadian rhythm.

In considering nutrition and circadian rhythms, time-of-eating behavior is an inherited, genetically controlled pattern that can be phase-shifted by conditioning or training. In addition, there are metabolic responses to meal eating, such as entrainment of a number of enzyme levels, hormone concentrations and other metabolic and physiologic activities. To separate truly inherent rhythms from entrained responses, it is necessary to determine which oscillations continue their circadian rhythms under completely free-running conditions of no zeitgeber, such as darkness vs. light or meal eating vs. fasting. Where meal eating provides a time signal to a biological clock experiment, healthy animals-not starving but constantly receiving nutrition to avoid an eating time signal-should be used. The ability to determine which daily rhythms are not genetically inherent, but rather are responses to a particular time signal, requires the elimination of all but this time signal. By using free-running conditions that are totally without time-giving signals, entrainment by (response to) meal feeding is readily separated from inherited endogenous circadian rhythm. Both types of daily rhythm exist and both involve the biological clock mechanisms . A method by which to identify each is proposed.

Animal Nutritional Physiological Phenomena↗
PubMed1997

Neurobiology of circadian rhythms.

Adaptation in the temporal environment is key to survival. This is achieved by the manifestation of periodicity in occurrence of vital behavioural and physiological processes at regular intervals--the biological rhythms. Biological rhythms (= biological clocks) are ubiquitous, can be demonstrated persisting at any level of organization in the living world, and are generated and controlled by some central pacemaker(s), mostly located in the brain. In mammals, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the principal site of the endogenous circadian pacemaker, regulating many daily physiological and behavioural functions, although other neural structures could also be contributing to the circadian timekeeping system. In other vertebrates, the neural site(s) of the circadian pacemaker is(are) still unclear. An organism without brain can have the biological clock, as well, for fully functional 24-hour temporal organization has been identified in several invertebrates, including unicellular Paramecium and Gonyaulax as well as filamentous fungus, Neurospora. This article attempts to provide an update of the informations which have accumulated over the past decade about understanding of the neurophysiological and molecular bases of circadian rhythms in animals.

Adaptation, Physiological↗
PubMed2001

The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels.

At present it is not clear which factors are responsible for the diurnal pattern of plasma leptin levels, although the timing of food intake and circulating hormones such as glucocorticoids and insulin have both been proposed as independent determinants. In this study we show that ablation of the biological clock by thermal lesions of the hypothalamic suprachiasmatic nucleus (SCN) completely eliminates the diurnal pattern of plasma leptin levels. By contrast, removal of the diurnal corticosterone signal by adrenalectomy and corticosterone replacement did not affect diurnal plasma leptin levels. More importantly, removal of the nocturnal feeding signal by submitting the animals to a regular feeding schedule of six meals per day did not abolish the diurnal plasma leptin levels. However, both SCN lesions and the regular feeding schedule did cause an increase in the 24-h mean plasma leptin levels. As neither rhythmic feeding, insulin, or corticosterone signals can completely explain the diurnal plasma leptin rhythm, we conclude that biological clock control of the sympathetic input to the adipocyte is essential for regulation of the daily rhythm in leptin release.

Adipocytes↗
PubMed2004

Melanopsin containing retinal ganglion cells are light responsive from birth.

Photoentrainment of the biological clock located in the suprachiasmatic nucleus (SCN) begins shortly after birth. Here we show using c-FOS immunoreactivity as a marker for neuronal activity that the melanopsin/PACAP containing retinal ganglion cells (RGCs) which project to the SCN as the retinohypothalamic tract (RHT) are responsive to light from birth. After postnatal day 12 where the classical photoreceptors become functional other RGCs and cells of the inner nuclear cell layer also respond to light. Light also induces c-FOS immunoreactivity in the retinorecipient SCN from the first postnatal day and accordingly PACAP immunoreactive fibres are visible in the SCN. The results indicate that the retina is light responsive before functional rods and cones and that the RHT is functional from birth supporting that photoentrainment of the biological clock begins shortly after birth.

Age Factors↗
PubMed1998

Altered neuronal activity rhythm and glutamate receptor expression in the suprachiasmatic nuclei of Trypanosoma brucei-infected rats.

The parasites Trypanosoma brucei cause African trypanosomiasis (sleeping sickness), a severe neuropsychiatric disease with marked disturbances of sleep-wake alternation. The sites of brain lesions are not well characterized. The present experimental investigation is focused on the hypothalamic suprachiasmatic nuclei, which play a role of a biological clock entraining endogenous rhythms in the mammalian brain. The electrophysiological properties of these neurons were analyzed in slice preparations from trypanosome-infected rats. The neuronal spontaneous activity, which shows a circadian oscillation, was markedly altered in the infected animals, displaying a reduced firing rate and phase advance of its circadian peak. The direct retinal fibers, which play a pivotal role in entrainment of the circadian pacemaker, displayed a normal density and distribution in the suprachiasmatic nuclei of infected animals after intraocular tracer injections in vivo. At the postsynaptic level, immunohistochemistry and Western blotting revealed in the suprachiasmatic nuclei of infected rats a selective decrease of the expression of glutamate AMPA GluR2/3 and NMDAR1 receptor subunits that gate retinal afferents. These data disclose an impairment of the neuronal functions in the biological clock in African trypanosomiasis, and may serve to unravel functional and molecular mechanisms behind endogenous rhythm disturbances.

Animals↗
PubMed1996

Daily melatonin treatments regulate the circadian melatonin rhythm in the adult Djungarian hamster.

The present study tested the hypothesis that daily melatonin treatments influence the biological clock mechanism controlling the circadian melatonin rhythm. Adult male and female Djungarian hamsters in light:dark = 16L:8D (lights on 0300-1900 h) were administered melatonin subcutaneously (s.c.) each day (5 micrograms/0.2 ml saline) in the morning at 1000 h (AM) or late afternoon at 1700 h (PM); controls received a vehicle injection (CON). After 14 days, pineal and serum melatonin concentrations were determined at various times on the last day of treatment and the next day in constant darkness (no treatment). The rhythm in pineal gland melatonin content was similar in each of the three groups on the last day of treatment (about 6 h duration). On the next day in constant dark, the rising phase was advanced and duration extended by 2 h or more in melatonin-treated hamsters compared to that in CONs (ANOVA). In circulation, the melatonin rhythm in AM and PM groups was phase advanced (onset and peak) on both days of the study. Thus duration was extended by up to 4.5 h compared to that in saline-treated controls. Moreover, amplitude of the nighttime serum melatonin rise was elevated up to fivefold relative to that in the CON group (ANOVA and Accumulated Sums analysis). The effects of repeated melatonin treatments on amplitude and phase of the serum melatonin rhythm raise the possibility that the circadian clock that controls pineal gland production of melatonin may also regulate melatonin secretion. From this and another study, the apparent half-life of melatonin in circulation was estimated to be 7.5 min; the melatonin injection initially produced pharmacological concentrations that were followed by low serum melatonin levels within 2 h. Thus, in both melatonin treatment groups, the data suggest that two distinct periods of elevated serum melatonin were present each day. The cellular mechanism for melatonin action must take into consideration how a brief interruption in elevated melatonin in circulation (about 1 h in the PM group) is recognized as a continuous duration (short daylength), whereas a more extended baseline period is transduced as an abbreviated or long daylength (about 7 h in the AM group). These data further suggest that the biological clock mechanism that generates the circadian melatonin rhythm is responsive to the influence of daily melatonin treatments and presumably to the feedback action of endogenous melatonin on its own rhythm in the Djungarian hamster in long days.

Animals↗
PubMed1999

Light intensity and age at first egg in pullets.

Layer strain pullets were reared on litter and given an 8-h photoperiod to 10 wk of age. They were then transferred to cages in which light intensity at the feed trough varied from 5 to 14 lx. Thirty birds continued on 8 h light (L):16 h dark (D) (negative controls), and another 30 birds were given 14L:10D (positive controls). Two other groups of 30 birds were given a regimen of 3 dim:8 L:3 dim:10 D with intensity during the dim phase ranging from 0.03 to 0.42 lx (very dim) or from 0.6 to 3.0 lx (marginal). Mean age at first egg (AFE) differed by 30 d between the positive and negative controls. Birds receiving very dim lighting matured 10 d earlier than the negative controls but 20 d later than positive controls. It is concluded that either the very dim light was itself nonstimulatory but had a phase shifting effect upon the biological clock that caused the 8-h normal light to fall partly in the photoinducible phase, or the first 3 h of very dim light was added to the bright phase to form an 11-h photoperiod. Birds in the top tier of the room with marginal supplementary lighting received 1.7 to 3.0 lx and matured at the same age as the positive controls, whereas those in the bottom tier received 0.6 to 0.9 lx and matured at the same age as the negative controls. Birds in the middle tier showed an intermediate AFE. It is concluded that the threshold intensity at the feed trough for white light stimulation of the photoperiodic mechanism in caged pullets lies between 0.9 and 1.7 lx. However, very dim lighting, below the threshold required for stimulation of a photoperiodic response, may shift the biological clock with unexpected consequences and, as a result, there is no known intensity of dim light that can be equated with darkness for all purposes.

Animals↗
PubMed1992

D1-dopamine receptors activate c-fos expression in the fetal suprachiasmatic nuclei.

The existence of an activatable dopamine system within the hypothalamic suprachiasmatic nuclei (SCN), the site of a biological clock, was investigated in rats during fetal life. In situ hybridization studies revealed that D1-dopamine receptor mRNA was highly expressed in the fetal SCN and not expressed in other hypothalamic regions. Cocaine injected into pregnant rats or directly into rat fetuses on day 20 of gestation selectively activated c-fos gene expression in the fetal SCN; cocaine did not induce c-fos expression elsewhere in the fetal brain or in the maternal SCN. This cocaine-induced activation of c-fos expression in fetal SCN was mediated in part through D1-dopamine receptors, as the cocaine-induced activation was partially blocked by the D1-dopamine receptor antagonist SCH 23390. In addition, the selective D1-dopamine receptor agonist SKF 38393 induced high levels of c-fos expression in the fetal SCN. The presence of an activatable dopamine system within the fetal SCN provides a mechanism through which maternal signals could entrain the fetal biological clock and through which maternally administered psychotropic drugs could alter normal development of the circadian timing system.

Animals↗