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PubMed2005

In vivo evidence for a controlled offset of melatonin synthesis at dawn by the suprachiasmatic nucleus in the rat.

The daily rhythm of melatonin synthesis in the rat pineal gland is controlled by the central biological clock, located in the suprachiasmatic nucleus (SCN), via a multi-synaptic pathway involving, successively, neurones of the paraventricular nucleus of the hypothalamus (PVN), sympathetic preganglionic neurones of the intermediolateral cell column of the spinal cord, and norepinephrine containing sympathetic neurones of the superior cervical ganglion. Recently, we showed that, in the rat, the SCN uses a combination of daytime inhibitory and nighttime stimulatory signals toward the PVN-pineal pathway in order to control the daily rhythm of melatonin synthesis, GABA being responsible for the daytime inhibitory message and glutamate for the nighttime stimulation. The present study was initiated to further check this concept, and to investigate the involvement of the inhibitory SCN output in the early morning circadian decline of melatonin release, with the hypothesis that, at dawn, the increased release of GABA onto pre-autonomic PVN neurones results in a diminished norepinephrine stimulation of the pineal, and ultimately an arrest of melatonin release. First, we established that prolonged norepinephrine stimulation of the pineal gland was indeed sufficient to prevent the early morning decline of melatonin release. Blockade of GABA-ergic signaling in the PVN at dawn could not prevent the early morning decline of melatonin completely. Therefore, these results show that an increased GABAergic inhibition of the PVN neurones that control the sympathetic innervation of the pineal gland, at dawn, is not sufficient to explain the early morning decline of melatonin release.

Adrenergic alpha-Agonists↗
PubMed2005

Environmental light and suprachiasmatic nucleus interact in the regulation of body temperature.

The mammalian biological clock, located in the suprachiasmatic nucleus (SCN), is crucial for circadian rhythms in physiology and behavior. However, equivocal findings have been reported on its role in the circadian regulation of body temperature. The goal of the present studies was to investigate the interaction between the SCN and environmental light in the regulation of body temperature. All recordings were performed by telemetry in free moving male Wistar rats. Firstly, we demonstrated an endogenous circadian rhythm in body temperature independent of locomotor activity. This rhythm was abolished by stereotactic lesioning of the SCN. Secondly, we demonstrated a circadian phase-dependent suppressive effect of light ('negative masking') on body temperature. Light suppressed body temperature more at the end of the subjective night (circadian time [CT] 22) than in the middle (CT 6) and at the end (CT 10) of the subjective day. This circadian-phase dependent suppression was not demonstrated in SCN-lesioned animals. Surprisingly, after half a year of recovery from lesioning of the SCN, light regained its suppressing action on body temperature, resulting in a daily body temperature rhythm only under light-dark conditions. In contrast to body temperature, light could not substantially mimic a daytime inhibitory SCN-output in the regulation of heart rate and locomotor activity. The present results suggest that, after lesioning of the SCN as main relay station for the immediate body temperature-inhibition by light, secondary relay nuclei can fully take over this function of the SCN. These findings provide a possible explanation for the controversy in literature over the question whether the SCN is required for the diurnal rhythm in body temperature. Furthermore, they show that light may have an acute effect on behavior and physiology of the organism via the SCN, which extends beyond the generally acknowledged effect on melatonin secretion.

Analysis of Variance↗
PubMed2006

The importance of circadian rhythms on drug response in hypertension and coronary heart disease--from mice and man.

The cardiovascular system is highly organised in time; blood pressure (BP), heart rate (HR), peripheral resistance, pressure and the release/activity of vasodilating hormones all display pronounced circadian variations. Pathophysiological events within the cardiovascular system are also not random, as shown for instance by sudden cardiac death (SCD), stroke, ventricular arrhythmias (VA), arterial embolism, and symptoms of coronary heart disease (CHD) such as myocardial infarction (MI) and ischemia, angina attacks (AA) in stable angina (stA) or variant angina (varA) or silent ischemia. In hypertensive patients various anti-hypertensive drugs were investigated in crossover studies (morning vs. evening dosing); however consistent data were only obtained for angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Whereas in dippers ACE inhibitors had a super-dipping effect when dosed at night, no consistent difference in BP lowering effect on the 24-hr BP profile was found with calcium channel blockers after morning and evening dosing. In non-dippers the calcium channel blockers isradipine and amlodipine consistently transformed non-dippers into dippers, after evening dosing. Diuretics are also able to normalize a non-dipping behaviour. Moreover, a circadian phase-dependency in pharmacokinetics has been demonstrated for various cardiovascular active drugs such as beta-blockers, calcium channel blockers, oral nitrates and ACE inhibitors, modified by the pharmaceutical formulation. There is evidence that in hypertensive dippers anti-hypertensive drugs should be given in the early morning, whereas in non-dippers it may be necessary to add an evening dose or even to use a single evening dose in order to not only reduce high BP but also to normalize a disturbed non-dipping 24 hr BP profile. In CHD, calcium channel blockers-mainly short acting and non-retarded preparations-seem to be less effective than beta-adrenoceptor antagonists in reducing ischemic events during the night and early morning. However, the role of formulation and/or subclasses of the calcium channel blockers remains to be elucidated. In order to get more insight into the circadian regulation of the cardiovascular system animal models of primary and secondary hypertension have been studied in various strains of normotensive and hypertensive rats and mice. At least in rodents there is ample evidence that the 24-hr rhythms in BP and HR are under the control of biological clock(s) as they persist under constant darkness (i.e. in free-run conditions) with a period deviating from 24 hr; these rhythms are abolished by lesioning of the "master clock" located in the suprachiasmatic nuclei (SCN). In conclusion, chronobiological and chronopharmacological studies are important experimental and clinical approaches to get a better insight into the physiological and pathophysiological regulation of the cardiovascular system including their rhythmic organisation. Circadian time-dependent clinical studies also have implications for drug therapy in hypertension and CHD.

Adrenergic beta-Antagonists↗
PubMed1999

Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer's type.

BACKGROUND: Several studies have suggested that patients with dementia experience a deterioration of biological rhythms. We investigated the daily profile of serum melatonin levels in patients with dementia of the Alzheimer's type (AD), since daily melatonin rhythm is thought to reflect the functioning of the biological clock. METHODS: Seventeen inpatients with AD, 10 psychiatric inpatients without dementia, and 11 elderly healthy volunteers participated in this study. Serum melatonin was assessed every 3 hours by radioimmunoassay. RESULTS: A daily fluctuation of melatonin levels with a significant nocturnal increase was observed in all three subject groups. However, both the AD patients and psychiatric patients without dementia showed significantly higher levels of melatonin in the daytime compared with the healthy subjects. When the effect of bright light exposure on melatonin secretion was investigated in six AD patients and five psychiatric patients without dementia, the daytime levels were markedly decreased in the patients without dementia, while no change was observed in the AD patients. CONCLUSIONS: The high levels of melatonin in the daytime associated with a lack of response to light exposure in AD patients may be due to the neurodegenerative process of this disease.

Aged↗
PubMed2000

Gap junctions in the chicken pineal gland.

The chicken pineal gland, which contains a heterogeneous cell population, sustains a circadian rhythm of activity. Synchronization of cellular activity of heterogeneous cells might be facilitated by gap junctional intercellular channels which are permeable to ions and second messengers. To test this possibility, we looked for morphologically identifiable gap junctions between the different pineal cells, used antibodies and cDNA probes to screen for the presence of connexins, and tested for functional intercellular coupling. By transmission electron microscopy and immunocytochemistry, gap junctions and connexins were observed between pinealocyte cell bodies, stromal cells, astrocytes, and astrocyte and pinealocyte processes. Two gap junctional proteins, connexin43 and connexin45, were detected by immunocytochemistry, immunoblotting and RNA blot analysis. Functional intercellular coupling was observed in the gland by transfer of low molecular weight dyes. Dye transferred between homologous and heterologous cells. These data suggest that homologous and heterologous gap junctions may provide a mechanism for coordination of the cellular responses of the elements of the biological clock which are induced by lighting cues to produce the circadian rhythm of pineal activity.

Animals↗
PubMed2000

Polysynaptic neural pathways between the hypothalamus, including the suprachiasmatic nucleus, and the liver.

The suprachiasmatic nucleus of the hypothalamus is responsible for a 24-h rhythm in basal glucose levels in the rat. The neural pathways used by the suprachiasmatic nucleus to mediate this rhythm in plasma glucose have not yet been identified. In the present study we examined whether there are any connections between hypothalamic centers, including the suprachiasmatic nucleus, and the liver, which is the main site for glucose production and storage. Transneuronal virus tracing from the liver showed that after injection of pseudorabies virus, specific neuronal cell populations in the central nervous system were labeled retrogradely, suggesting that specific sites in the central nervous system may control liver metabolism. First-order neurons belonged to the sympathetic and parasympathetic system, while second-order and third-order neurons were present in both the brainstem and hypothalamus. The presence of third-order neurons in the suprachiasmatic nucleus suggests an involvement of the biological clock in the neural control of the liver.

Animals↗
PubMed1998

Circadian rhythm of Arg-vasopressin contents in the suprachiasmatic nucleus in relation to corticosterone.

Circadian rhythms of locomotor activity and adrenal glucocorticoid are controlled by the suprachiasmatic nucleus (SCN), the center of a biological clock, in mammals. Arg-vasopressin (AVP) contents in the SCN play a role in endogenous circadian rhythm during the absence of time cues. The AVP-containing neurons in the SCN are considered to transmit a circadian signal to the other parts of the brain. The circadian rhythms of AVP in the SCN in relation to the plasma corticosterone and locomotor activity were investigated. Under the light-dark cycle, plasma corticosterone levels were reciprocally correlated with the AVP content in the SCN. Under free-running conditions with constant dim light, AVP rhythms were reciprocally synchronized with the locomotor activity. The correlation of AVP with plasma corticosterone is different at different times of the day both under the LD cycle and constant dim light. Dexamethasone (i. p., 0.1 mg/100) increased the AVP contents, and this tendency was significantly greater during the dark period. These results indicate that corticosterone in the blood may regulate the circadian rhythm through AVP variation in the SCN.

Animals↗
PubMed1999

Distribution of Ca2+-dependent protein kinase C isoforms in the suprachiasmatic nucleus of the diurnal murid rodent, Arvicanthis niloticus.

The suprachiasmatic nuclei (SCN) contain the major 'biological clock' in mammals that controls most circadian rhythms expressed by these animals. The functional importance of protein phosphorylation and intracellular Ca2+ in the mammalian circadian pacemaker is becoming increasingly apparent. Here we report the immunocytochemical localization of the four Ca2+-dependent protein kinase C (PKC) isoforms (alpha, betaI, betaII, gamma) within the SCN of the diurnal murid rodent, Arvicanthis niloticus, and the nocturnal golden hamster. In the SCN of A. niloticus, PKCalpha was the most abundant of the four isoforms. Cells containing PKCalpha were homogeneously distributed throughout the SCN. PKCbetaI cells were sparsely distributed in the perimeter of the SCN and were absent in its central area. PKCbetaII and -gamma were not found in the SCN of A. niloticus. In the SCN of the golden hamster, PKCalpha cells were most heavily concentrated in the dorsomedial region, though some were also present laterally and ventrally. The distribution of arginine-vasopressin (AVP) cells in the SCN overlapped with that of PKC in both species. Species differences in the location of the Ca2+-dependent PKC isoforms suggest differences in function such as the relaying of photic or non-photic information to the clock mechanism, or the synchronization of AVP neurons and their subsequent output signals.

Animals↗
PubMed2000

Cloning and characterization of rat casein kinase 1epsilon.

Genes differentially expressed in the subjective day and night in the rat suprachiasmatic nucleus (SCN) were surveyed by differential display. A gene homologous to human casein kinase 1epsilon (CK1epsilon) was isolated, which initially appeared to be expressed in the suprachiasmatic nucleus (SCN) in a circadian manner. We here describe the cDNA cloning of the rat CK1epsilon and characterization of the protein products. The rCK1epsilon is predominantly expressed in the brain including the SCN, binds and phosphorylates mPer1, mPer2, and mPer3 in vitro, and translocates mPer1 and mPer3, but not mPer2, to the cell nucleus depending on its kinase activity when coexpressed with these Per proteins in COS-7 cells.

Alternative Splicing↗
PubMed1987

Towards a general theory of adaptive walks on rugged landscapes.

Adaptive evolution, to a large extent, is a complex combinatorial optimization process. In this article we take beginning steps towards developing a general theory of adaptive "walks" via fitter variants in such optimization processes. We introduce the basic idea of a space of entities, each a 1-mutant neighbor of many other entities in the space, and the idea of a fitness ascribed to each entity. Adaptive walks proceed from an initial entity, via fitter neighbors, to locally or globally optimal entities that are fitter than their neighbors. We develop a general theory for the number of local optima, lengths of adaptive walks, and the number of alternative local optima accessible from any given initial entity, for the baseline case of an uncorrelated fitness landscape. Most fitness landscapes are correlated, however. Therefore we develop parts of a universal theory of adaptation on correlated landscapes by adaptive processes that have sufficient numbers of mutations per individual to "jump beyond" the correlation lengths in the underlying landscape. In addition, we explore the statistical character of adaptive walks in two independent complex combinatorial optimization problems, that of evolving a specific cell type in model genetic networks, and that of finding good solutions to the traveling salesman problem. Surprisingly, both show similar statistical features, encouraging the hope that a general theory for adaptive walks on correlated and uncorrelated landscapes can be found. In the final section we explore two limits to the efficacy of selection. The first is new, and surprising: for a wide class of systems, as the complexity of the entities under selection increases, the local optima that are attainable fall progressively closer to the mean properties of the underlying space of entities. This may imply that complex biological systems, such as genetic regulatory systems, are "close" to the mean properties of the ensemble of genomic regulatory systems explored by evolution. The second limit shows that with increasing complexity and a fixed mutation rate, selection often becomes unable to pull an adapting population to those local optima to which connected adaptive walks via fitter variants exist. These beginning steps in theory development are applied to maturation of the immune response, and to the problem of radiation and stasis. Despite the limitations of the adaptive landscape metaphor, we believe that further development along the lines begun here will prove useful.

Adaptation, Biological↗
PubMed1997

Tone duration discrimination in Parkinson's disease.

Patients with Parkinson's disease (PD) and healthy controls took a computerized test of tone duration discrimination (TDD) using pairs of tones of 0.4-1.6 sec duration, presented at intervals of 0.5-4 sec. In PD patients as well as controls, TDD was impaired by even slight degrees of cognitive deterioration. PD yielded impaired TDD in females, but not in males. This suggests that the dopamine-powered biological clock, which is vulnerable to PD, is more important for the processing of durations in the 1-sec range in women than in men.

Adult↗
PubMed2002

Metallothioneins (I+II) and thyroid-thymus axis efficiency in old mice: role of corticosterone and zinc supply.

Thymic atrophy or thymus absence causes depressed thyroid-thymus axis (TTA) efficiency in old, young propyl-thiouracil (PTU) (experimental hypothyroidism) and in young-adult thymectomised (Tx) mice, respectively. Altered zinc turnover may be also involved in depressed TTA efficiency. Zinc turnover is under the control of zinc-bound metallothioneins (Zn-MTs) synthesis. Thyroid hormones, corticosterone and nutritional zinc affect Zn-MT induction. Zn-MT releases zinc in young-adult age during transient oxidative stress for prompt immune response. In constant oxidative stress (ageing and liver regeneration after partial hepatectomy), high liver Zn-MTs, low zinc ion bioavailability and depressed TTA efficiency appear. This last finding suggested that MT might not release zinc during constant oxidative stress leading to impaired TTA efficiency. The aim of this work/study is to clarify the role of Zn-MTs (I+II) in TTA efficiency during development and ageing. The main results are (1) Old and PTU mice display high corticosterone, enhanced liver MTmRNA, low zinc and depressed TTA efficiency restored by zinc supply. Increased survival and no significant increments in basal liver Zn-MTs proteins occur in old and PTU mice after zinc supply. (2) Lot of zinc ions bound with MT in the liver from old mice than young (HPLC). (3) Young-adult Tx mice, evaluated at 15 days from thymectomy, display high MTmRNA and nutritional-endocrine-immune damage restored by zinc supply or by thymus grafts from old zinc-treated mice. (4) Young-adult Tx mice, but evaluated at 40 days from thymectomy, display natural normalisation in MTmRNA and nutritional-endocrine-immune profile with survival similar to normal mice. (5) Stressed (constant dark for 10 days) mice overexpressing MT display low zinc, depressed immunity, reduced thymic cortex, high corticosterone, altered thyroid hormones turnover showing a likeness with old mice. These findings, taken altogether, show that corticosterone is pivotal in MTs induction under stress. MTs bind preferentially zinc ions in constant oxidative stress, but with no release of zinc from MT leading to impaired TTA efficiency. Zinc supply restores the defect because zinc has no interference in affecting pre-existing Zn-MTs protein concentrations in old and PTU mice. Therefore, free zinc ions are available for TTA efficiency after zinc supply. Thymus from old zinc-treated mice induces the same restoring effect when transplanted in Tx recipients. However, Tx mice display natural normalisation in MTmRNA and in nutritional-endocrine-immune profile in the long run. Therefore, Zn-MTs (I+II) are crucial in zinc homeostasis for endocrine-immune efficiency during the entire life assuming a role of potential and novel 'biological clock of ageing'.

Aging↗
PubMed2004

Neuropeptides in hypothalamic neuronal disorders.

A few examples of hypothalamic, peptidergic disorders leading to clinical signs and symptoms are presented in this review. Increased activity of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) and decreased activity of the vasopressin neurons in the biological clock and of the thyroxine-releasing hormone (TRH) neurons in the PVN contribute to the signs and symptoms of depression. In men, the central nucleus of the bed nucleus of the stria terminalis (BSTc) is about twice as large and contains twice as many somatostatin neurons as in women. In transsexuals this sex difference is reversed, pointing to a role of this structure in gender. Luteinizing hormone-releasing hormone (LHRH) neurons are formed in the fetal olfactory placade and migrate along the terminal nerve fibers into the hypothalamus. In Kallmann's syndrome the migration process of the LHRH (gonadotropin-releasing hormone) neurons is aborted, which explains the joint occurrence of hypogonadotropic hypogonadism and anosmia in this syndrome. In postmenopausal women, the neurons of the infundibular nucleus hypertrophy and become hyperactive because of the disappearance of the estrogen feedback and contain hyperactive peptidergic neurons. Climacteric flushes may be caused by hyperactivity of the neurokinin-B or LHRH neurons in this nucleus. The hypocretin (orexin) neurons in the perifornical area are involved in sleep. In narcolepsy with cataplexy, a loss of these neurons, probably due to an autoimmune process, is found. Obese subjects with a mutation in the gene that encodes for leptin, the preproghrelin gene, or the alpha-melanocyte-stimulating hormone (alpha-MSH) gene have been described. Decreased numbers and activity of the oxytocin neurons in the PVN may be responsible for the absence of satiety in Prader-Willi syndrome. Moreover, a glucocorticoid receptor polymorphism is associated with obesitas and dysregulation of the hypothalamus-pituitary-adrenal axis. In contrast, two single nucleotide polymorphisms (SNPs) of the AGRP gene have been associated with anorexia nervosa.

Animals↗
PubMed2000

Mop3 is an essential component of the master circadian pacemaker in mammals.

Circadian oscillations in mammalian physiology and behavior are regulated by an endogenous biological clock. Here we show that loss of the PAS protein MOP3 (also known as BMAL1) in mice results in immediate and complete loss of circadian rhythmicity in constant darkness. Additionally, locomotor activity in light-dark (LD) cycles is impaired and activity levels are reduced in Mop3-/- mice. Analysis of Period gene expression in the suprachiasmatic nucleus (SCN) indicates that these behavioral phenotypes arise from loss of circadian function at the molecular level. These results provide genetic evidence that MOP3 is the bona fide heterodimeric partner of mCLOCK. Furthermore, these data demonstrate that MOP3 is a nonredundant and essential component of the circadian pacemaker in mammals.

ARNTL Transcription Factors↗
PubMed2000

The suprachiasmatic nucleus and the circadian time-keeping system revisited.

Many physiological and behavioral processes show circadian rhythms which are generated by an internal time-keeping system, the biological clock. In rodents, evidence from a variety of studies has shown the suprachiasmatic nucleus (SCN) to be the site of the master pacemaker controlling circadian rhythms. The clock of the SCN oscillates with a near 24-h period but is entrained to solar day/night rhythm by light. Much progress has been made recently in understanding the mechanisms of the circadian system of the SCN, its inputs for entrainment and its outputs for transfer of the rhythm to the rest of the brain. The present review summarizes these new developments concerning the properties of the SCN and the mechanisms of circadian time-keeping. First, we will summarize data concerning the anatomical and physiological organization of the SCN, including the roles of SCN neuropeptide/neurotransmitter systems, and our current knowledge of SCN input and output pathways. Second, we will discuss SCN transplantation studies and how they have contributed to knowledge of the intrinsic properties of the SCN, communication between the SCN and its targets, and age-related changes in the circadian system. Third, recent findings concerning the genes and molecules involved in the intrinsic pacemaker mechanisms of insect and mammalian clocks will be reviewed. Finally, we will discuss exciting new possibilities concerning the use of viral vector-mediated gene transfer as an approach to investigate mechanisms of circadian time-keeping.

Animals↗
PubMed1998

D1-dopamine receptor binding and tyrosine hydroxylase-immunoreactivity in the fetal and neonatal hamster suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the site of an endogenous biological clock that regulates mammalian circadian rhythms. Circadian rhythms, although endogenously driven, are synchronized or entrained to daily environmental cues. Developmentally, the SCN begins to oscillate before birth and is entrained to the maternal circadian rhythm by a mechanism that is still unclear. Recent evidence in rats and hamsters suggests that a fetal dopaminergic system and D1-dopamine receptors may be involved in the process of entraining the fetal clock. The present study using [3H]SCH 23390 autoradiography and tyrosine hydroxylase (TH) immunocytochemistry determined the developmental time courses of the appearance of D1 receptor in, and catecholaminergic input to, the hamster SCN. [3H]SCH 23390 binding to D1-dopamine receptors was first detected in the fetal SCN on embryonic day (E) 15, the day before birth in this species, and persisted through adulthood. The TH immunoreactive fibers were first observed on day E15 coursing just ventral to the fetal SCN but TH-immunoreactive cells and fibers were not seen within the SCN until postnatal day (P) 5. The presence of D1-dopamine receptor binding in the fetal hamster SCN is consistent with the role of these receptors in entrainment of the fetal circadian pacemaker to maternal cues. However, a receptor-transmitter mismatch exists between D1-dopamine receptors and TH-immunoreactive fibers in the fetal SCN suggesting that the role of dopamine in maternal-fetal entrainment may be as a paracrine or humoral signal.

Animals↗