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At least 757 records · Page 42Linked to original sources
PubMed2003

The mouse VPAC2 receptor confers suprachiasmatic nuclei cellular rhythmicity and responsiveness to vasoactive intestinal polypeptide in vitro.

Expression of coherent and rhythmic circadian (approximately 24 h) variation of behaviour, metabolism and other physiological processes in mammals is governed by a dominant biological clock located in the hypothalamic suprachiasmatic nuclei (SCN). Photic entrainment of the SCN circadian clock is mediated, in part, by vasoactive intestinal polypeptide (VIP) acting through the VPAC2 receptor. Here we used mice lacking the VPAC2 receptor (Vipr2-/-) to examine the contribution of this receptor to the electrophysiological actions of VIP on SCN neurons, and to the generation of SCN electrical firing rate rhythms SCN in vitro. Compared with wild-type controls, fewer SCN cells from Vipr2-/- mice responded to VIP and the VPAC2 receptor-selective agonist Ro 25-1553. By contrast, similar proportions of Vipr2-/- and wild-type SCN cells responded to gastrin-releasing peptide, arginine vasopressin or N-methyl-D-aspartate. Moreover, VIP-evoked responses from control SCN neurons were attenuated by the selective VPAC2 receptor antagonist PG 99-465. In firing rate rhythm experiments, the midday peak in activity observed in control SCN cells was lost in Vipr2-/- mice. The loss of electrical activity rhythm in Vipr2-/- mice was mimicked in control SCN slices by chronic treatment with PG 99-465. These results demonstrate that the VPAC2 receptor is necessary for the major part of the electrophysiological actions of VIP on SCN cells in vitro, and is of fundamental importance for the rhythmic and coherent expression of circadian rhythms governed by the SCN clock. These findings suggest a novel role of VPAC2 receptor signalling, and of cell-to-cell communication in general, in the maintenance of core clock function in mammals, impacting on the cellular physiology of SCN neurons.

Animals↗
PubMed2003

Serotonin inhibits glutamate- but not PACAP-induced per gene expression in the rat suprachiasmatic nucleus at night.

Circadian rhythms of physiology and behaviour generated by the brain's biological clock located in the suprachiasmatic nucleus are entrained by light via the retinohypothalamic tract. Two neurotransmitters, glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP), found in this monosynaptic pathway mediate the effects of light to the clock. It is well known that not only light entrains the clock. Nonphotic cues mediated by neurotransmitters such as serotonin reaching the suprachiasmatic nucleus from the midbrain raphe nucleus modulate light-induced phase shifts at night. Two clock genes, per1 and per2, have been attributed a role in light-induced phase shift. In the present study, using an in vitro brain slice model and quantitative in situ hybridization for per1 and per2, we have shown that serotonin induces per1 gene expression at late subjective night but not at early night. Furthermore, serotonin application before glutamate or PACAP blocked glutamate-induced per1 expression at early night and per2 gene expression at late night. In contrast, serotonin did not influence PACAP-induced per gene expression at late night. Triple antigen immunohistochemistry and confocal microscopy supported both a pre- and post-synaptic interaction of retinohypothalamic tract (PACAP-immunoreactive) and serotonin projections on vasoactive intestinal peptide- and gastrin-releasing peptide-containing cell bodies in the ventro-lateral suprachiasmatic nucleus. Our findings suggest that the per genes could be the molecular target for the modulatory effects of serotonin on light signalling to the clock.

Animals↗
PubMed2000

An integrated theory of ageing in the nematode Caenorhabditis elegans.

Numerous theories of ageing have been proposed, and many have been tested experimentally, particularly using nematode models such as Caenorhabditis elegans. By combining those theories of ageing that remain plausible with recent findings from studies of C. elegans life span mutants, an integrated theory of ageing has been devised. This is formed from 3 interconnected elements: the evolutionary theory of ageing, the oxidative damage theory of ageing, and a nonadaptive programmed ageing theory. This tripartite theory of ageing gives rise to a number of predictions that may be tested experimentally.

Aging↗
PubMed2002

Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study.

BACKGROUND: The periodicity of cluster headache suggests involvement of the suprachiasmatic nucleus of the hypothalamus, the biological clock. The secretion of melatonin, a hormone produced by the pineal gland and regulated by the suprachiasmatic nucleus, is altered in patients with cluster headache. Melatonin shifts circadian rhythms. A previous study of melatonin for primary prophylaxis of cluster headache demonstrated a 50% response rate. OBJECTIVE: To evaluate the use of melatonin as adjunctive therapy in patients with cluster headache who have incomplete relief of their headaches on conventional therapy. METHODS: Nine patients participated in the study, six with chronic cluster headache and three with episodic cluster headache. Patients with chronic cluster headache completed a baseline diary for 1 month, followed by 1 month of melatonin treatment, then 1 month of placebo. Patients with episodic cluster headache received placebo for 1 month, then melatonin for 1 month. Patients continued their usual prophylactic and abortive treatments during the study. Headache frequency, intensity, and use of analgesics were recorded. The primary endpoint of the study was the mean number of headaches per day, with mean daily analgesic consumption and percentage of mild, moderate, and severe headaches as secondary endpoints. RESULTS: There were no significant differences between means on analysis of variance and t testing for the melatonin, placebo, and baseline months for all primary and secondary endpoints. There were no side effects reported. CONCLUSIONS: Patients with chronic cluster headache or patients with episodic cluster headache whose headaches are uncontrolled on conventional therapy do not appear to gain therapeutically from the addition of melatonin to their usual treatment regimens. It is perhaps the phase-shifting properties of melatonin that mediate its effect in patients with episodic cluster headache, and it may be necessary to treat from the beginning of the cluster bout to reset the circadian pacemaker, thus producing a more positive outcome.

Adjuvants, Immunologic↗
PubMed2003

[A worm's life].

Despite its relative anatomic simplicity, the nematode Caenorhabditis elegans (C. elegans) is a complex multicellular organism. In this review, we describe studies that have contributed to a better understanding of certain aspects of the worm's physiology. We focus on the cellular and molecular basis of the interaction between C. elegans and its environment, including its sensory capacities, the intrinsic biological clock that governs the speed of its life, and on some of the factors that control its life span. We also outline very recent findings that have demonstrated the existence of an innate immune system in C. elegans. Finally, we highlight a number of novel techniques that are transforming the worm from a largely genetic model system into an attractive organism for functional genomic studies.

Animals↗
PubMed2001

Mitochondrial DNA, human evolution and the cancer genotype.

Mitochondrial DNA is a small, well characterized chromosome which is transmitted across the generations in the maternal lineage, independently of nuclear DNA. mtDNA acts in effect as a robust, species specific biological clock and tracer which can be used to follow the evolution and spread by geographic migration of populations from their origins. Mutations in mtDNA cause specific maternally hereditable diseases, and can be used for forensic purposes. They are not specifically implicated in neoplasia, but they may provide clues as to the nature and origins of cancer susceptibility in various populations.

DNA, Mitochondrial↗
PubMed2002

Circadian rhythm sleep disorders (CRSD).

Circadian Rhythm Sleep Disorders (CRSD) are a group of sleep disorders characterized by a malsynchronization between a person's biological clock and the environmental 24-h schedule. These disorders can lead to harmful psychological and functional difficulties and are often misdiagnosed and incorrectly treated due to the fact that doctors are unaware of their existence. In the following review we describe the characteristics of CRSD, diagnosis, treatment as well as their relationship to psychopathology, psychotropic drugs and head trauma.

Antipsychotic Agents↗
PubMed2001

The development of circadian rhythms in the fetus and neonate.

The circadian time-keeping system is the neural system that allows predictive adaptation of individuals to the reproducible 24-hour day/night alternations of our planet. A biological clock, the suprachiasmatic nucleus, receives environmental information and imposes a circadian pattern to physiological functions. Since the suprachiasmatic nucleus develops early in gestation and circadian rhythms are present in the fetus and newborn, the circadian system seems to be functional in fetal life and can receive circadian inputs through the mother. The neonate moves to an environment in which the main time giving signal is the light:dark cycle. Teleologically, a term newborn should be fit to face this challenge. But this may be quite different for a preterm infant that trades the circadian environment to which it was previously exposed for the timeless environment of the Neonatal Intensive Care Nursery. Scientists and physicians should seek new experimental and clinical approaches to answer the challenging questions of perinatal chronomedicine.

Animals↗
PubMed2001

Nycthemeral variations in core temperature and heart rate: continuous cycling exercise versus continuous rest.

Circadian rhythms have formed the subject of many researches in man during bed rest or usual routine, but have been little studied during continuous and sustained physical exercise. This study deals with the influence of time of day on biological markers in competitive cyclists during continuous physical exercise versus continuous rest. Ultra-distance cyclists were studied over a 24 h period (13:00 to 13:00 h the next day) in the laboratory. The subjects were requested to maintain a constant speed (set at 65% - 70% of their maximal aerobic speed obtained during a preliminary test) on their own bicycles which were equipped with home trainers. Workload, core temperature and heart rate were monitored continuously. The same measures were also recorded while the athletes were resting awake until 13:00 h the next day. Results show that in both situations, core temperature and heart rate exhibited significant circadian variations (p < 0.001). Furthermore, during exercise, an accentuation of amplitude and mean of every rhythm (p < 0.05) with a phase lag (p < 0.05) were observed. Despite a strenuous and continuous physical exercise requiring special physiological adaptations, the rhythmic variations observed at rest persisted, which highlighted the influence of biological clocks.

Adult↗
PubMed2005

Circuit topology and the evolution of robustness in two-gene circadian oscillators.

Many parameters driving the behavior of biochemical circuits vary extensively and are thus not fine-tuned. Therefore, the topology of such circuits (the who-interacts-with-whom) is key to understanding their central properties. I here explore several hundred different topologies of a simple biochemical model of circadian oscillations to ask two questions: Do different circuits differ dramatically in their robustness to parameter change? If so, can a process of gradual molecular evolution find highly robust topologies when starting from less robust topologies? I find that the distribution of robustness among different circuit topologies is highly skewed: Most show low robustness, whereas very few topologies are highly robust. To address the second evolutionary question, I define a topology graph, each of whose nodes corresponds to one circuit topology that shows circadian oscillations. Two nodes in this graph are connected if they differ by only one regulatory interaction within the circuit. For the circadian oscillator I study, most topologies are connected in this graph, making evolutionary transitions from low to high robustness easy. A similar approach has been used to study the evolution of robustness in biological macromolecules, with similar results. This suggests that the same principles govern the evolution of robustness on different levels of biological organization. The regulatory interlocking of several oscillating gene products in biological circadian oscillators may exist because it provides robustness.

Biological Clocks↗
PubMed2003

Rhythmic binding of a WHITE COLLAR-containing complex to the frequency promoter is inhibited by FREQUENCY.

The biological clock of Neurospora crassa includes interconnected transcriptional and translational feedback loops that cause both the transcript and protein encoded by the frequency gene (frq) to undergo the robust daily oscillations in abundance, which are essential for clock function. To understand better the mechanism generating rhythmic frq transcript, reporter constructs were used to show that the oscillation in frq message is transcriptionally regulated, and a single cis-acting element in the frq promoter, the Clock Box (C box), is both necessary and sufficient for this rhythmic transcription. Nuclear protein extracts used in binding assays revealed that a White Collar (WC)-1- and WC-2-containing complex (WCC) binds to the C box in a time-of-day-specific manner. Overexpression of an ectopic copy of FRQ or addition of in vitro-generated FRQ resulted in reduced WCC binding to the C box. These data suggest that oscillations in frq transcript result from WCC binding to the frq promoter and activating transcription with subsequent changes in FRQ levels having an inverse effect on WCC binding. In this way rhythmic expression and turnover of FRQ drives the rhythm in its own transcription.

Amino Acid Sequence↗
PubMed2003

Two Arabidopsis circadian oscillators can be distinguished by differential temperature sensitivity.

Circadian rhythms are widespread in nature and reflect the activity of an endogenous biological clock. In metazoans, the circadian system includes a central circadian clock in the brain as well as distinct clocks in peripheral tissues such as the retina or liver. Similarly, plants have distinct clocks in different cell layers and tissues. Here, we show that two different circadian clocks, distinguishable by their sensitivity to environmental temperature signals, regulate the transcription of genes that are expressed in the Arabidopsis thaliana cotyledon. One oscillator, which regulates CAB2 expression, responds preferentially to light-dark versus temperature cycles and fails to respond to the temperature step associated with release from stratification. The second oscillator, which regulates CAT3 expression, responds preferentially to temperature versus light-dark cycles and entrains to the release from stratification. Finally, the phase response curves of these two oscillators to cold pulses are distinct. The phase response curve of the oscillator component TOC1 to cold pulses is similar to that of CAB2, indicating that CAB2 is regulated by a TOC1-containing clock. The existence of two clocks, distinguishable on the basis of their sensitivity to temperature, provides an additional means by which plants may integrate both photoperiodic and temperature signals to respond to the changing seasons.

Arabidopsis↗
PubMed1976

Circadian organization of the estrous cycle of the golden hamster.

In constant dim illumination the hamster estrous cycle free-runs with a period that is a quadruple multiple of the concurrently recorded rhythm of wheel-running activity; both activity and estrous cycles are generated by biological clocks. Maintenance of stable phase angle differences between heat onset and running onset before and after treatment with deuterium oxide suggests that a common circadian system generates periodicities in estrus and activity. An organization of the estrous cycle is proposed in which the stimulus for the ovulatory surge of luteinizing hormone is generated by a circadian system that includes the suprachiasmatic nuclei of the hypothalamus. Various possible interactions of estradiol and photoperiod with the neurogenic stimulus for the luteinizing hormone surge are described and implications of different types of circadian organization of the estrous cycle for theories of sexual differentiation are considered.

Animals↗
PubMed1982

Mechanism for shifting the phase of a circadian rhythm by serotonin: involvement of cAMP.

Serotonin (5-hydroxytryptamine, 5-HT) shifts the phase of the circadian rhythm in the eye of Aplysia. We have examined the role of cAMP in mediating the effects of 5-HT on the rhythm. The phase shifts produced by 5-HT are mimicked by treatments that should increase intracellular levels of cAMP. An analogue of cAMP-8-benzylthio-cAMP, advanced and delayed the rhythm at phases in which 5-HT had similar effects on the rhythm. In addition, two phosphodiesterase inhibitors, Ro-20-1724 and papaverine, caused advance phase shifts where 5-HT advances the rhythm. The phosphodiesterase inhibitors Ro-20-1724 and 3-isobutyl-1-methylxanthine each potentiated the effect of subthreshold doses of 5-HT on the rhythm. The effects of 5-HT and 8-benzylthio-cAMP on the rhythm were nonadditive, indicating that 5-HT and 8-benzylthio-cAMP affect the rhythm through a common pathway. Finally, 5-HT produced large changes (13-fold) in the levels of cAMP in the eye. These results indicate that cAMP mediates the effect of 5-HT on the rhythm. There are two possible roles for cAMP in the circadian system. Either the cAMP system is an intracellular step in an entrainment pathway or it is part of the biological clock. Because 5-HT, 8-benzylthio-cAMP, and three phosphodiesterase inhibitors inhibit impulses from the eye, cAMP may also mediate the inhibition produced by 5-HT, or it might be involved in regulating the frequency of spontaneous impulses throughout the day.

Action Potentials↗
PubMed1987

Involvement of a specific protein in the regulation of a circadian rhythm in Aplysia eye.

Our previous results indicated that protein synthesis was necessary for serotonin (5-hydroxytryptamine, 5-HT) to regulate the phase of the biological clock in the Aplysia eye. Also, we showed that 5-HT appeared to increase the synthesis of a 34-kDa protein with an isoelectric point of 7.2. Subsequent studies were carried out to quantitate the effect of 5-HT on the 34-kDa protein and to examine whether the 34-kDa protein was involved in the circadian timing system. The regional specificity of the effect of 5-HT on the 34-kDa protein was investigated. The proximal portion of the eye appeared to synthesize much more of the 34-kDa protein than the distal portion. Also, 5-HT had a much larger effect on the synthesis of the 34-kDa protein in the proximal portion than in the distal portion. The proximal location of synthesis and the 5-HT effect on the synthesis of the 34-kDa protein correlate with the proximal location of cells and processes that are necessary for the expression of the circadian rhythm. The relationship between the effect of 5-HT on the circadian rhythm and the effect of 5-HT on the 34-kDa protein was also examined. As 5-HT causes phase shifts in the rhythm by activating adenylate cyclase to increase cAMP, forskolin and 8-benzylthioadenosine 3',5'-cyclic monophosphate mimicked the effect of 5-HT on the 34-kDa protein. We also found that 5-HT significantly increased the synthesis of the 34-kDa protein at phases when 5-HT delays or advances the phase of the rhythm but did not increase the synthesis of the 34-kDa protein at a phase when 5-HT did not phase shift. This phase-dependent effect of 5-HT on the 34-kDa protein qualitatively accounts for the phase dependence of the effect of 5-HT on the circadian rhythm. These results, when considered together with our earlier data, suggest that the synthesis of the 34-kDa protein is directly involved in the phase shift produced by 5-HT. The 34-kDa protein is worthy of future investigation as a candidate for a component of the circadian oscillator.

Action Potentials↗
PubMed1990

N-acetylaspartylglutamate: a transmitter candidate for the retinohypothalamic tract.

The retinohypothalamic tract is the neural pathway mediating the photic entrainment of circadian rhythms in mammals. Important targets for these retinal fibers are the suprachiasmatic nuclei (SCN) of the hypothalamus, which are thought to be primary sites for the biological clock. The neurotransmitters that operate in this projection system have not yet been determined. Immunohistochemistry and radioimmunoassay performed with affinity-purified antibodies to N-acetylaspartylglutamate (NAAG) demonstrate that this neuron-specific dipeptide, which may act as an excitatory neurotransmitter, is localized extensively in the retinohypothalamic tract and its target zones, including the SCN. Optic nerve transections resulted in significant reductions in NAAG immunoreactivity in the optic chiasm and SCN. Analysis of NAAG concentrations in micropunches of SCN, by means of radioimmunoassay, showed approximately 50% reductions in NAAG levels. These results suggest that this peptide may act as one of the neurotransmitters involved in retinohypothalamic communication and circadian rhythm entrainment.

Animals↗
PubMed1993

Neuronal synchronization without calcium-dependent synaptic transmission in the hypothalamus.

A critical question in understanding the mammalian brain is how populations of neurons become synchronized. This is particularly important for the neurons and neuroendocrine cells of the hypothalamus, which are activated synchronously to control endocrine glands and the autonomic nervous system. It is widely accepted that communication between neurons of the adult mammalian brain is mediated primarily by Ca(2+)-dependent synaptic transmission. Here we report that synchronous neuronal activity can occur in the hypothalamic suprachiasmatic nucleus without active Ca(2+)-dependent synaptic transmission. Simultaneous extracellular recordings of neuronal activity in the suprachiasmatic nucleus, which contains the mammalian biological clock, confirmed a circadian rhythm of synchronized activity in hypothalamic slices. Ca(2+)-free medium, which blocks chemical synaptic transmission and increases membrane excitability, produced periodic and synchronized bursts of action potentials in a large population of suprachiasmatic nucleus neurons with diverse firing patterns. N-Methyl-D-aspartic acid, non-N-methyl-D-aspartic acid, and gamma-aminobutyric acid type A receptor antagonists had no effect on burst synchrony. Whole-cell patch-clamp recordings confirmed that the Ca(2+)-free solution blocked evoked postsynaptic potentials and that the mixture of antagonists blocked the remaining spontaneous postsynaptic potentials. Therefore, mechanisms other than Ca(2+)-dependent synaptic transmission can synchronize neurons in the mammalian hypothalamus and may be important wherever neuronal networks are synchronized.

2-Amino-5-phosphonovalerate↗
PubMed1996

Diurnal variation of the adenylyl cyclase type 1 in the rat pineal gland.

Nocturnal melatonin production in the pineal gland is under the control of norepinephrine released from superior cervical ganglia afferents in a rhythmic manner, and of cyclic AMP. Cyclic AMP increases the expression of serotonin N-acetyltransferase and of inducible cAMP early repressor that undergo circadian oscillations crucial for the maintenance and regulation of the biological clock. In the present study, we demonstrate a circadian pattern of expression of the calcium/calmodulin activated adenylyl cyclase type 1 (AC1) mRNA in the rat pineal gland. In situ hybridization revealed that maximal AC1 mRNA expression occurred at midday (12:00-15:00), with a very low signal at night (0:00-3:00). We established that this rhythmic pattern was controlled by the noradrenergic innervation of the pineal gland and by the environmental light conditions. Finally, we observed a circadian responsiveness of the pineal AC activity to calcium/calmodulin, with a lag due to the processing of the protein. At midday, AC activity was inhibited by calcium (40%) either in the presence or absence of calmodulin, while at night the enzyme was markedly (3-fold) activated by the calcium-calmodulin complex. These findings suggest (i) the involvement of AC1 acting as the center of a gating mechanism, between cyclic AMP and calcium signals, important for the fine tuning of the pineal circadian rhythm; and (ii) a possible regulation of cyclic AMP on the expression of AC1 in the rat pineal gland.

Adenylyl Cyclases↗