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PubMed2004

Pharmacological modulation of circadian rhythms: a new drug target in psychotherapeutics.

Daily variation in an organism's physiology and behaviour is regulated by the synchrony that is achieved between the internal timing mechanisms - the circadian rhythms of the biological clock - and the prevailing environmental cues. Proper synchrony constitutes an adaptive response; improper or lost synchrony may well yield maladaptation and, in the case of humans, a psychiatric disorder. On a basic level, the circadian system is comprised of three parts: a central oscillator, its various neuronal inputs and its outputs. For all three of these parts, the dissemination of new information is moving at an unprecedented pace, and the number of molecular targets for the opportunistic pharmacologist is growing in step. Monoamines, neuropeptides, kinases - sorting through all these, much less developing one into a drug discovery programme, may be the biggest challenge. However, the potential benefits in targeting a basic flaw in a fundamental biological system may be enormous.

Animals↗

PubMed1987

Repetition as the essence of life on this earth: music and genes.

In prebiotic nucleic acid replication, templates appear to have been in short supply. A single round of tandem duplication of existing oligomers assured progressive extension of templates to the length adequate for encoding of polypeptide chains. Thus, the first set of coding sequences had to be repeats of base oligomers encoding polypeptide chains of various periodicities. On one hand, the readiness of these periodical polypeptide chains to assume alpha-helical and/or beta-sheet secondary structures contributed to the extremely rapid initial functional diversification of these polypeptide chains. It would be recalled that most, if not all, of the sugar-metabolizing enzymes had already achieved the inviolable functional competence before the division of prokaryotes from eukaryotes. On the other hand, a certain (dipeptidic?) of the peptidic periodicities was apparently chosen as the timekeeping unit by the biological clock. Musical compositions too apparently evolved originally as a timekeeping device. Accordingly, repetitiousness is evident in all musical compositions. Evolution of musical compositions from the early Baroque to the late Romantic parallels that of coding sequences from rather exact repeats of base oligomers to more complex modern coding sequences in which repetitious elements are less conspicuous and more varied. Inasmuch as the earth is governed by the hierarchy of periodicities (days, months and years), such reliance on periodicities is rather expected.

Amino Acid Sequence↗

PubMed1995

Definition of the developmental transition from dopaminergic to photic regulation of c-fos gene expression in the rat suprachiasmatic nucleus.

D1-dopamine receptor stimulation induces c-fos gene expression in the fetal suprachiasmatic nucleus (SCN), but not in the adult rat SCN. Light exposure at night induces c-fos gene expression in the adult SCN. The present experiments were designed to define the developmental transition from dopaminergic to photic regulation of c-fos gene expression in the SCN. Treatment with the D1-dopamine receptor agonist SKF 38393 (10 mg/kg) increased SCN c-fos gene expression during both day and night on postnatal day (PD) 0, 1, and at night on PD 2, but the c-fos response disappeared by PD 4. Photic induction of c-fos gene expression was apparent during both day and night at each age examined, from PD 0 through PD 6. The magnitude and distribution of c-fos expression following light during the daytime was distinguishable from the response to light at night beginning on PD 2, indicating that the circadian clock regulates (gates) the c-fos response by PD 2. Orbital enucleation prevents the induction of c-fos by light at night on PD 2, indicating retinal mediation. Developmental loss of the c-fos response to SKF is not precipitated by the arrival of the retinohypothalamic tract; animals enucleated on PD 0 were insensitive to SKF on PD 6, as were visually intact controls. The results demonstrate that both dopaminergic and photic inputs can regulate SCN c-fos gene expression early in the neonatal period, and that the developmental loss of sensitivity to SKF is not due to the arrival of photic input to the SCN. The developmental transition from dopaminergic to photic regulation of c-fos gene expression roughly parallels the developmental transition from maternal to photic entrainment of the developing biological clock.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1984

The suprachiasmatic nuclei of the fetal rat: characterization of a functional circadian clock using 14C-labeled deoxyglucose.

The circadian clock located in the suprachiasmatic nuclei (SCN) was characterized in the fetal rat by using 14C-labeled deoxyglucose to monitor glucose utilization (metabolic activity) of the nuclei. A clear day-night oscillation of metabolic activity was detectable in the fetal SCN from the 19th through the 21st days of gestation; the nuclei were metabolically active during the subjective day and metabolically inactive during the subjective night. During the subjective day on gestational day 21, the fetal SCN were found to manifest high metabolic activity for most of the subjective day. We were able to acutely dissociate SCN metabolic activity in the mother rat from that in the fetus by exposing the pregnant animals to light during the normal dark period of diurnal lighting on gestational day 20. The results show the utility of the deoxyglucose method for directly investigating prenatally the function of the biological clock located in the SCN.

Animals↗

PubMed2004

Fatigue and performance models: general background and commentary on the circadian alertness simulator for fatigue risk assessment in transportation.

Mathematical models of fatigue and performance are potentially powerful tools to predict the effects of duty-rest schedules in many situations. Most current models, including the Circadian Alertness Simulator (CAS), derive from the two-process theory of sleep regulation. In these models, performance and fatigue are determined by a homeostatic process that depends solely on sleep/wake history, and a circadian process, driven by the biological clock. These models assume: 1) performance capability recovers in an exponential manner during sleep; 2) the homeostatic and circadian processes are additive. Current evidence suggests that both assumptions require modification. An attractive feature of the CAS is that it computes alertness curves for individuals, based on individual sleep/wake histories and other data. However, statistical evaluation is usually based on group data, with few performance metrics. As in other models, there is no substantive theory to connect the alertness computation with specific cognitive or psychomotor functions.

Circadian Rhythm↗

PubMed1990

Entrainment of circadian phase in developing gray short-tailed opossums: mother vs. environment.

In a marsupial species, the gray short-tailed opossum (Monodelphis domestica), the suprachiasmatic nuclei (SCN), the site of a circadian clock, are formed postnatally and begin oscillating as a circadian clock on day 20. In this study, we examined how the timing (phase) of the SCN clock in the developing opossum is coordinated to the environmental light-dark cycle. When pups were reared from birth in darkness by intact dams, the circadian phases in SCN metabolic activity (monitored by 2-deoxy-D-[14C]glucose autoradiography) in 27-day-old pups were desynchronized. When pups were reared in a light-dark cycle that was 12 h out of phase with the circadian time of blinded dams, the pattern of SCN metabolic activity on day 20 was rhythmic and in phase with the light-dark cycle but out of phase with the circadian time of the dam. On day 20, retina-mediated light activation of SCN metabolic activity was also demonstrated, and anterograde tract-tracing studies revealed the presence of the retinohypothalamic tract within the SCN. These results show there is no influence of the opossum dam on the timing of the pup's biological clock. Instead, from the inception of the daily rhythm in SCN metabolic activity, its timing is regulated by retina-mediated light-dark entrainment.

Animals↗

PubMed1994

Neuropeptide Y and behaviorally induced phase shifts.

Neuropeptide Y-containing fibers project from the intergeniculate leaflet of the lateral geniculate nucleus to the suprachiasmatic nucleus. Previous studies have indicated that this pathway may be involved in non-photic resetting of the circadian clock. Therefore, we investigated the possibility that neuropeptide Y mediates phase shifts induced by a particular non-photic stimulus, a pulse of running in a novel wheel. Confining hamsters to a small nest box failed to block phase shifts induced by neuropeptide Y given at zeitgeber time 4; this indicates that increased locomotor activity is not necessary for the observed shifts. Antiserum raised against neuropeptide Y or normal serum was administered at circadian time 5 through a cannula aimed at the suprachiasmatic nucleus. The hamsters were then removed from their cages and placed in a novel wheel for 3 h. Hamsters that received normal serum and ran > 5000 revolutions in the novel wheel advanced their rhythms (mean shift 2.55 h +/- 0.22 S.E.M.) by amounts similar to those of unoperated hamsters. Administration of neuropeptide Y antiserum attenuated the shift normally associated with running in a novel wheel (mean shift 0.21 h +/- 0.14 S.E.M.). These studies indicate that the neuropeptide Y input from the lateral geniculate nucleus to the biological clock is involved in the phase shifts seen in response to novelty-induced wheel running. It also provides another example of the ability of antisera to alter behavior. This may be a useful approach in manipulations of neurochemical activity when antagonists are not yet available or poorly defined.

Animals↗

PubMed1989

Central administration of muscimol phase-shifts the mammalian circadian clock.

The suprachiasmatic nucleus (SCN) of the hypothalamus contains a neural oscillatory system which regulates many circadian rhythms in mammals. Immunohistochemical evidence indicates that a relatively high density of GABAergic neurons exist in the suprachiasmatic region. Since intraperitoneal injections of the benzodiazepine, triazolam, have been shown to induce phase shifts in the free-running circadian rhythm of locomotor activity in the golden hamster, the extent to which microinjections of muscimol, a specific agonist for gamma-aminobutyric acid (GABA), may cause phase-shifts in hamster activity rhythms was investigated. Stereotaxically implanted guide cannulae aimed at the region of the SCN were used to deliver repeated microinjections in individual animals. A phase-response curve (PRC) generated from microinjections of muscimol revealed that the magnitude and direction of permanent phase-shifts in the activity rhythm were associated with the time of administration. The PRC generated for muscimol was characterized by maximal phase-advances induced 6 h before activity onset and by maximal phase-delays which occurred 6 h after activity onset. The PRC for muscimol had a shape similar to a PRC previously generated for the short-acting benzodiazepine, triazolam. Single microinjections of different doses of muscimol given 6 h before activity onset induced phase-advances in a dose-dependent fashion. Histological analysis revealed that phase shifts induced by the administration of muscimol were associated with the proximity of the injection site to the SCN area. These data indicate that a GABAergic system may exist within the suprachiasmatic region as part of a central biological clock responsible for the regulation of the circadian rhythm of locomotor activity in the golden hamster.

Animals↗

PubMed2003

The diurnal modulation of hormonal responses in the rat varies with different stimuli.

The circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus not only controls the basal daily temporal organization of many neuroendocrine functions, but also its responsiveness. We studied the time-of-day influence on plasma changes in adrenocorticotropic hormone (ACTH), corticosterone, glucagon and leptin concentrations elicited by an insulin-induced hypoglycaemic event. Male Wistar rats were exposed to an insulin challenge at six different times during the light/dark cycle. The time-of-day of exposure markedly affected the responses of all four hormones studied. Generally, the magnitude of the different hormone responses correlated with their basal daily release pattern (i.e. the responses of ACTH and corticosterone were largest around lights off, and glucagon and leptin responses were most pronounced during the dark period). With regard to the hormones of the hypothalamic-pituitary-adrenal axis, the presently reported time-of-day dependent modulation is completely opposite to that previously reported for novelty or restraint. Therefore, these findings provide further support for the existence of at least two different neural pathways that are able to activate the hypothalamic-pituitary-adrenal axis, and provide different substrates for modulation by the biological clock. This observation warrants a thorough examination of possible functional explanations for the observed differences.

Adrenocorticotropic Hormone↗

PubMed2005

Tracing from fat tissue, liver, and pancreas: a neuroanatomical framework for the role of the brain in type 2 diabetes.

The hypothalamus uses hormones and the autonomic nervous system to balance energy fluxes in the body. Here we show that the autonomic nervous system has a distinct organization in different body compartments. The same neurons control intraabdominal organs (intraabdominal fat, liver, and pancreas), whereas sc adipose tissue located outside the abdominal compartment receives input from another set of autonomic neurons. This differentiation persists up to preautonomic neurons in the hypothalamus, including the biological clock, that have a distinct organization depending on the body compartment they command. Moreover, we demonstrate a neuronal feedback from adipose tissue that reaches the brainstem. We propose that this compartment-specific organization offers a neuroanatomical perspective for the regional malfunction of organs in type 2 diabetes, where increased insulin secretion by the pancreas and disturbed glucose metabolism in the liver coincide with an augmented metabolic activity of visceral compared with sc adipose tissue.

Adipose Tissue↗

PubMed2000

Influence of light in the NICU on the development of circadian rhythms in preterm infants.

The fetal biological clock is an endogenous clock capable of generating circadian rhythms and responding to maternal entraining signals. By at least the third trimester of pregnancy fetal diurnal rhythms are entrainable by maternal day-night rhythms. Maternal illness during pregnancy and premature birth are obvious clinical factors that may adversely affect circadian rhythm development. Premature birth of the fetus has a most dramatic impact on maternal fetal interactions. The effect on biorhythms appears to be temporary and is greatest on the most immature infants. The results to date support the importance of fetal circadian rhythms and the relative lack of these rhythms in the preterm infant. It is well known that growth and development in the prematurely born infant are influenced by a multitude of factors; clearly, the neonatal intensive care unit is not a surrogate for the maternal placental unit. This article reviews what is known about circadian development in the human infant with an emphasis on the unique circumstances of the preterm infant. The research on the short- and long-term effects of environmental interventions on circadian, sleep, and neurologic development is discussed. Although an earlier onset of circadian development did not result with cycled lighting in the neonatal nursery, there may still be important biological effects that have not been studied. There are sufficient data to state that there is no reason for continuing a chaotic, noncircadian environmental approach for the care of the prematurely born infant.

Body Temperature↗

PubMed1992

The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data.

Accurate estimation of the phases and amplitude of the endogenous circadian pacemaker from constant-routine core-temperature series is crucial for making inferences about the properties of the human biological clock from data collected under this protocol. This paper presents a set of statistical methods based on a harmonic-regression-plus-correlated-noise model for estimating the phases and the amplitude of the endogenous circadian pacemaker from constant-routine core-temperature data. The methods include a Bayesian Monte Carlo procedure for computing the uncertainty in these circadian functions. We illustrate the techniques with a detailed study of a single subject's core-temperature series and describe their relationship to other statistical methods for circadian data analysis. In our laboratory, these methods have been successfully used to analyze more than 300 constant routines and provide a highly reliable means of extracting phase and amplitude information from core-temperature data.

Adult↗

PubMed1984

Enzymatic maturation of the gastrointestinal tract and its relevance to food allergy and intolerance in infancy.

The biologic clock that determines the temporal sequence of maturation of digestive and absorptive processes in the gastrointestinal tract is genetically predetermined, but may be modified by dietary, hormonal, or other factors. In general it may be said that the gastrointestinal tract of full-term neonates is capable of digesting and absorbing a nutritionally adequate quantity of dietary protein but capacity is limited. Very low birth weight preterm infants, who are surviving the early neonatal period in increasing numbers, have immaturity of a wide range of digestive and membrane-associated absorptive processes; in addition macromolecular absorption may be increased. Whether a limited capacity to digest food protein results in increased or altered antigenic stimulation of these immature infants remains speculative with present knowledge. Immaturity of intestinal lactase may lead to problems of lactose intolerance, but there is recent evidence that lactase activity may be inducible by milk feeding.

Absorption↗

PubMed2005

A new actimetry-based test of photic sensitization in a murine photosensitive magnesium depletion model.

Photic hypersensitivity may induce various signs of nervous hypersensitivity, including diurnal cephalalgias, anxiety, dyssomnia, seizures, fatigue and/or myalgias. The patients usually present both dishabituation and generalization in response to repetitive light stimuli instead of habituation as in normal subjects. These clinical manifestations appear when light intensity is maximum (daytime; spring and summer) in magnesium-depleted patients with hypofunction of the biological clock. The best photic hypersensitivity management involves darkness therapy, either darkness per se or darkness-mimicking agents. To detect efficiently the best drugs that may be used in the treatment of disorders due to photosensitive magnesium depletion, we are proposing a simple and reproducible actimetry-based test in a murine photosensitive magnesium depletion model. Photostimulation using a stroboscope (100 J, 50 Hz) was performed on magnesium-deficient and control mice. It led to habituation with a decreased activity in response to intermittent light stimulation in control mice, whereas it induced in magnesium-deficient mice both sensitization (or potentiation), with nervous hyperexcitability, and generalization, involving sound hypersensitivity, after visual stimulation. In preclinical evaluation, this test provides a valuable animal model to study the neuroprotective effect of drugs in photosensitive syndromes, which often associate sensitization and generalization to various stimuli.

Animals↗

PubMed1997

[Changes in the 24-hour rhythm of plasma melatonin in patients with liver cirrhosis--relation to sleep architecture].

OBJECTIVE: To assess the 24 hr plasma melatonin profile as a marker of the output rhythm from the circadian clock and to study sleep diaries as reflection of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. PATIENTS: A total of 14 subjects, 7 non-alcoholic cirrhotics and 7 age-, sex-, and educationally-matched controls. Exclusion criteria were factors that could affect melatonin levels (intercontinental travel, shift work, therapy with betablockers or corticosteroids). MEASUREMENTS: Plasma melatonin was measured every 30 min for 24 hr by radioimmuno assay and sleep recordings by polysomnography. Neuropsychological testing included visual reaction time. Trailmaking test A and B and the Digit Symbol Test. Sleep diaries were kept for the week prior to admission. RESULTS: Time of onset of melatonin rise was displaced from 19:50 +/- 26 min in the controls to 21:30 +/- 13 min (p = 0.013) in patients with liver cirrhosis. The time of peak melatonin levels was consistently and significantly delayed from 00:36 +/- 33 min in controls to 5:36 +/- 29 min (p < 0.001) in patients. Cirrhotic subjects showed markedly elevated melatonin levels during daytime, when melatonin is normally absent. Polysomnographic tracings showed no differences in patients and controls, but sleep diaries indicated more frequent nocturnal awakenings (p = 0.05) and daytime naps. CONCLUSIONS: A marked alteration of plasma melatonin rhythm is found in cirrhotic patients with subclinical hepatic encephalopathy. This disruption may reflect changes in the output of the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is possible that some of the metabolic disturbances that lead to hepatic encephalopathy may also alter the function of the biological "clock".

Adult↗

PubMed1995

Alterations in growth rate associated with a normally persisting circadian rhythm during spaceflight.

BACKGROUND: Biological clocks time many physiological parameters with periodicities close to 24 h; those which persist in the absence of environmental cues are circadian. An earlier shuttle experiment (STS-9) examined circadian pacemaker function and growth rate of Neurospora crassa and demonstrated damped rhythm amplitudes, increased variability in period lengths and altered growth rates. HYPOTHESIS: Postflight studies suggested that accelerative forces of launch could have induced rhythm alterations. Differences in growth rate may have been due to an alteration of metabolic rate. METHODS: Race tubes inoculated with bd or csp strains were flown aboard STS-32, exposed to ambient mid-deck temperatures throughout flight, and exposed to light only during marking procedures. Period, rhythm amplitude, and growth rate were determined and compared to orbital environmental controls (OES) and 25 degrees C ground controls (GC). RESULTS: Unlike the previous flight exposurement, the rhythm persisted quite normally. bd flight and OES cultures each displayed lengthened periods of a similar magnitude when compared to GC. The lengthened periods of csp flight cultures while longer than GC, were shorter than OES. Shuttle temperatures were relatively warm, however the increased period length in space was greater than predicted by the known Q10. Growth rates also increased substantially during flight, which could not be accounted for by thermal mechanisms alone. CONCLUSION: It is likely that some of the cultures may have entrained to the unexpected diurnal temperature variations; however, other cultures did not entrain, yet retained rhythmicity with increased periods. The results also suggest an increased metabolic rate during spaceflight.

Circadian Rhythm↗

PubMed2005

Characterizing the amplitude dynamics of the human core-temperature circadian rhythm using a stochastic-dynamic model.

Two measures, amplitude and phase, have been used to describe the characteristics of the endogenous human circadian pacemaker, a biological clock located in the hypothalamus. Although many studies of change in circadian phase with respect to different stimuli have been conducted, the physiologic implications of the amplitude changes (dynamics) of the pacemaker are unknown. It is known that phase changes of the human circadian pacemaker have a significant impact on sleep timing and content, hormone secretion, subjective alertness and neurobehavioral performance. However, the changes in circadian amplitude with respect to different stimuli are less well documented. Although amplitude dynamics of the human circadian pacemaker are observed in physiological rhythms such as plasma cortisol, plasma melatonin and core temperature data, currently methods are not available to accurately characterize the amplitude dynamics from these rhythms. Of the three rhythms core temperature is the only reliable variable that can be monitored continuously in real time with a high sampling rate. To characterize the amplitude dynamics of the circadian pacemaker we propose a stochastic-dynamic model of core temperature data that contains both stochastic and dynamic characteristics. In this model the circadian component that has a dynamic characteristic is represented as a perturbation solution of the van der Pol equation and the thermoregulatory response in the data that has a stochastic characteristic is represented as a first-order autoregressive process. The model parameters are estimated using data with a maximum likelihood procedure and the goodness-of-fit measures along with the associated standard error of the estimated parameters provided inference about the amplitude dynamics of the pacemaker. Using this model we analysed core temperature data from an experiment designed to exhibit amplitude dynamics. We found that the circadian pacemaker recovers slowly to an equilibrium level following amplitude suppression. In humans this reaction to perturbation from equilibrium value has potential physiological implications.

Body Temperature Regulation↗

PubMed1997

Afferent and efferent connections of the diencephalic prepacemaker nucleus in the weakly electric fish, Eigenmannia virescens: interactions between the electromotor system and the neuroendocrine axis.

The afferent and efferent connections of the gymnotiform central posterior nucleus of the dorsal thalamus and prepacemaker nucleus (CP/PPn) were examined by retrograde and anterograde transport of the small molecular weight tracer, Neurobiotin. The CP/PPn was identified by physiological assay and received a local iontophoretic injection of Neurobiotin. Retrogradely labeled somata were observed in the ventral telencephalon, hypothalamus, and the pretectal nucleus electrosensorius. Anterogradely labeled fibers were traced from the CP/PPn to the ventral telencephalon, the hypothalamus, the neuropil immediately adjacent to the most rostral subdivision of the nucleus electrosensorius, the optic tectum, and the pacemaker nucleus. Retrograde transport of tracer following injections into the ventral telencephalon, preoptic area, lateral hypothalamus, tectum, and pacemaker nucleus confirmed these efferent targets. A rostromedial subarea of the CP/PPn can be identified that projects to basal forebrain regions and to a lateral region of the CP/PPn that contains afferents to the pacemaker. Many of the targets, which are connected with the CP/PPn, have been linked to reproductive behavior or neuroendocrine control in other fishes. A comparative analysis reveals that the efferent pathways of the CP/PPn appear similar and may be homologous to efferent pathways of some components of the auditory thalamus among tetrapods.

Afferent Pathways↗