Generation and entrainment of circadian rhythms

1. The present brief review examines some of the new developments in the area of circadian rhythm research. 2. The discovery of the mouse clock and m-per genes and their similarity to other clock genes like per and tim has provided new insight into the control of rhythms in vertebrates. In mice, these genes are expressed in the site of the biological clock, the suprachiasmatic nucleus (SCN), and so will now become a focus of research into the generation of rhythmicity. 3. Because SCN cells expressing endogenous rhythms have a periodicity different from 24 h, there must be mechanisms in place to reset the rhythms on a daily basis. This is achieved in mammals by retinal light perception and neural transmission through several discrete pathways to the SCN. 4. The nature of the neurotransmitters involved in this transfer of environmental information to the timing system is controversial and may even very between similar species but, in the rat, there is compelling evidence that a serotonergic pathway is pre-eminent in mediating the effects of light. How the re-setting is achieved at the cellular level is not known.     

Photic entrainment of circadian rhythms in rodents

Photic entrainment of circadian rhythms occurs as a consequence of daily, light-induced adjustments in the phase and period of the suprachiasmatic nuclei (SCN) circadian clock. Photic information is acquired by a unique population of retinal photoreceptors, processed by a distinct subset of retinal ganglion cells, and conveyed to the SCN through the retinohypothalamic tract (RHT). RHT neurotransmission is mediated by the release of the excitatory amino acid glutamate and appears to require the activation of both NMDA- and non-NMDA-type glutamate receptors, the expression of immediate early genes (IEGs), and the synthesis and release of nitric oxide. In addition, serotonin appears to regulate the response of the SCN circadian clock to light through postsynaptic 5-HT1A or 5-ht7 receptors, as well as presynaptic 5-HT1B heteroreceptors on RHT terminals.     

The ventral lateral geniculate nucleus and the intergeniculate leaflet: interrelated structures in the visual and circadian systems

The ventral lateral geniculate nucleus (vLGN) and the intergeniculate leaflet (IGL) are retinorecipient subcortical nuclei. This paper attempts a comprehensive summary of research on these thalamic areas, drawing on anatomical, electrophysiological, and behavioral studies. From the current perspective, the vLGN and IGL appear closely linked, in that they share many neurochemicals, projections, and physiological properties. Neurochemicals commonly reported in the vLGN and IGL are neuropeptide Y, GABA, enkephalin, and nitric oxide synthase (localized in cells) and serotonin, acetylcholine, histamine, dopamine and noradrenalin (localized in fibers). Afferent and efferent connections are also similar, with both areas commonly receiving input from the retina, locus coreuleus, and raphe, having reciprocal connections with superior colliculus, pretectum and hypothalamus, and also showing connections to zona incerta, accessory optic system, pons, the contralateral vLGN/IGL, and other thalamic nuclei. Physiological studies indicate species differences, with spectral-sensitive responses common in some species, and varying populations of motion-sensitive units or units linked to optokinetic stimulation. A high percentage of IGL neurons show light intensity-coding responses. Behavioral studies suggest that the vLGN and IGL play a major role in mediating non-photic phase shifts of circadian rhythms, largely via neuropeptide Y, but may also play a role in photic phase shifts and in photoperiodic responses. The vLGN and IGL may participate in two major functional systems, those controlling visuomotor responses and those controlling circadian rhythms. Future research should be directed toward further integration of these diverse findings.     

Nonphotic entrainment of circadian activity rhythms in suprachiasmatic nuclei-ablated hamsters.

Examined the role of the suprachiasmatic nuclei (SCN) in nonphobic entrainment. The wheel-running activity of SCN-ablated hamsters was recorded in constant dark (DD) and then under prolonged schedules of 2-hr daily cage changes, restricted food availability, and daily light–dark (LD) cycles. Ss with very large lesions subsuming the SCN and surrounding areas exhibited significant, albeit unstable, circadian activity rhythms in DD. Some Ss with similar ablations also showed entrained rhythms to daily cage change schedules. Ss showed robust rhythms entrained to a daily feeding schedule. No Ss showed entrainment to LD cycles. Competent circadian oscillators evidently exist outside the SCN, at least 0.5 mm or more away, and at least some are nonphotically entrainable. Weaker entrainment in animals with larger lesions suggests that nonphotically entrainable oscillators also exist within the SCN or its immediate vicinity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Melatonin's role in vertebrate circadian rhythms

The circadian secretion of melatonin by the pineal gland and retinae is a direct output of circadian oscillators and of the circadian system in many species of vertebrates. This signal affects a broad array of physiological and behavioral processes, making a generalized hypothesis for melatonin function an elusive objective. Still, there are some common features of melatonin function. First, melatonin biosynthesis is always associated with photoreceptors and/or cells that are embryonically derived from photoreceptors. Second, melatonin frequently affects the perception of the photic environment and has as its site of action structures involved in vision. Finally, melatonin affects overt circadian function at least partially via regulation of the hypothalamic suprachiasmatic nucleus (SCN) or its homologues. The mechanisms by which melatonin affects circadian rhythms and other downstream processes are unknown, but they include interaction with a class of membrane-bound receptors that affect intracellular processes through guanosine triphosphate (GTP)-binding protein second messenger systems. Investigation of mechanisms by which melatonin affects its target tissues may unveil basic concepts of neuromodulation, visual system function, and the circadian clock.     

Morphine phase-shifts circadian rhythms in mice: role of behavioural activation

The effect of morphine on circadial wheel-running rhythms of C57BL/6j mice was examined. Mice received morphine (25 mg kg-1, i.p.) or saline at eight different circadian phases in constant dark. Morphine injections in the middle of the inactive period induced significant advance phase shifts, whereas injections at other times induced small delay shifts or no responses. This phase-response relationship was not altered by optic enucleation. Morphine also induced hyperactivity. Restriction of activity prevented phase shifts. The results indicate that morphine shifts circadian rhythms by its effects on behaviour, rather than by a direct action on the circadian pacemaker. Morphine may represent a useful tool for further study of behaviourally induced phase-resetting in this species.     

The suprachiasmatic nucleus and intergeniculate leaflet of Arvicanthis niloticus, a diurnal murid rodent from East Africa

Little is known about the neural substrates controlling circadian rhythms in day-active compared to night-active mammals primarily because of the lack of a suitable diurnal rodent with which to address the issue. The murid rodent, Arvicanthis niloticus, was recently shown to exhibit a predominantly diurnal pattern of activity and body temperature, and may be suitable for research on the neural mechanisms underlying circadian rhythms. This paper describes, in A. niloticus, the anatomy of two neural structures that play important roles in the control of circadian rhythms, the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL). Immunohistochemical techniques were used to examine the distribution of neuroactive peptides in the SCN and IGL, and retinal projections to these structures were traced with anterograde transport of the beta subunit of cholera toxin. In A. niloticus, distinct subdivisions of the SCN contained cell bodies with immunoreactive (IR) vasopressin, vasoactive intestinal polypeptide, gastrin-releasing peptide, and corticotropin-releasing factor. The SCN did not contain cell bodies with met-enkephalin-IR and substance P-IR, but did contain fibers with substance P-IR and neuropeptide Y-IR. Retinal fibers were present throughout the SCN, but were most densely concentrated along its ventral edge, particularly in the contralateral SCN. Retinal fibers also extended to a variety of hypothalamic regions outside the SCN, including the supraoptic nucleus and the subparaventricular region. The IGL contained cells with neuropeptide Y-IR and enkephalin-IR cells. Retinal fibers projected to both the ipsilateral and contralateral IGL. The anatomy of the SCN and IGL were compared and contrasted with that previously described for other nocturnal and diurnal species.     

Daily wheel running activity modifies the period of free-running rhythm in rats via intergeniculate leaflet

The period of free-running rhythms (tau) in rats, as measured using a running wheel, is different from that measured using an Automex. The aim of this work was to examine the effects of lesions of the intergeniculate leaflet (IGL) on the tau of these two activity rhythms. When blind rats were transferred from a cage with a running wheel to a cage without a running wheel, the tau lengthened. The tau of the wheel-running activity was associated with the number of wheel revolutions per day. A complete lesion of the IGL lengthened the tau of the wheel-running activity, and caused a reduction in the number of wheel revolutions per day in all rats. In rats housed in cages without a running wheel, locomotor activity was reduced by IGL lesions, although the tau was unaffected. When IGL-lesioned rats were transferred from a cage with a running wheel to a cage without a running wheel, no further change was observed. These results indicate that the tau is modified by the daily activity of wheel-running, but not by general locomotor activity, and that the IGL may be involved in this modification.     

Effect of a skeleton photoperiod on the daylength-dependent response to oestrogen in canaries (Serinus canarius)

We have analyzed the sequence complexity and diversity of poly(A)-containing mRNA derived from two highly differentiated chicken tissues. Two independent approaches were used in our analyses. The first involves the annealing of cDNA copies of mRNA to a vast excess of the template RNA; the second procedure uses hybridization between highly radioactive single-copy genomic DNA and mRNA. The results obtained using these two experimental approaches are in good accord and reveal the presence of 12,000-15,000 diverse mRNA species in both chicken liver and oviduct. In both cell types, the kinetics of annealing of cDNA to its template mRNA demonstrate discrete frequency classes with most of the different mRNA species present in fewer than 10 copies per cell. 70% of oviduct mRNA, however, consists of about 10 abundant RNA species, which probably are responsible for the synthesis of the egg white proteins. The diversity of mRNA species in chicken liver and oviduct was further studied by heterologous annealing reactions between cDNA or singlecopy genomic DNA and a vast excess of mRNA. These studies demonstrate that 85% of the different mRNA sequences detected are present in both liver and oviduct, and suggest that the vast majority of the information expressed as mRNA is required for the maintenance of cellular functions common to all tissues.     

Phytochromes and cryptochromes in the entrainment of the Arabidopsis circadian clock

Circadian clocks are synchronized by environmental cues such as light. Photoreceptor-deficient Arabidopsis thaliana mutants were used to measure the effect of light fluence rate on circadian period in plants. Phytochrome B is the primary high-intensity red light photoreceptor for circadian control, and phytochrome A acts under low-intensity red light. Cryptochrome 1 and phytochrome A both act to transmit low-fluence blue light to the clock. Cryptochrome 1 mediates high-intensity blue light signals for period length control. The presence of cryptochromes in both plants and animals suggests that circadian input pathways have been conserved throughout evolution.     

Adjustment of the human melatonin and cortisol rhythms to shortening of the natural summer photoperiod

Fifteen human subjects were exposed to natural outdoor summer light from 0415 h until 2000 h for 4 days and then from 0800 h until 1600 h for another 4 days. Following shortening of the natural summer photoperiod, times of the morning salivary melatonin decline and cortisol rise did not change whereas the time of the evening melatonin rise phase advanced by about 1.5 h within 1 day and further did not change significantly. Consequently, the melatonin signal duration extended markedly within 1 day. The data show that the compressed melatonin rhythm waveform in humans experiencing a long natural summer photoperiod from sunrise until sunset may change rapidly following a shortening of the photoperiod.     

Interconnections among nuclei of the subcortical visual shell: the intergeniculate leaflet is a major constituent of the hamster subcortical visual system

The intergeniculate leaflet (IGL), a major constituent of the circadian visual system, is one of 12 retinorecipient nuclei forming a "subcortical visual shell" overlying the diencephalic-mesencephalic border. The present investigation evaluated IGL connections with nuclei of the subcortical visual shell and determined the extent of interconnectivity between these nuclei. Male hamsters received stereotaxic, iontophoretic injections of the retrograde tracer, cholera toxin beta fragment, or the anterograde tracer, Phaseolus vulgaris-leucoagglutin, into nuclei of the pretectum (medial, commissural, posterior, olivary, anterior, nucleus of the optic tract, posterior limitans), into the superior colliculus, or into the visual thalamic nuclei (lateral posterior, dorsal lateral geniculate, intergeniculate leaflet, ventral lateral geniculate). Retrogradely labeled cell bodies identified nuclei with afferents projecting to the site of injection, whereas the presence of anterogradely labeled fibers with terminals revealed brain nuclei targeted by neurons at the site of injection. The IGL projects bilaterally to all nuclei of the visual shell except the lateral posterior and dorsal lateral geniculate nuclei. The IGL also has afferents from the same set of nuclei, except the nucleus of the optic tract. The extensive bilateral efferent projections distinguish IGL from the ventral lateral geniculate nucleus. The superior colliculus, commissural pretectal, olivary pretectal, and posterior pretectal nuclei also project bilaterally to the majority of subcortical visual nuclei. The IGL has a well-established role in circadian rhythm regulation, but there is as yet no known function for it in the larger context of the subcortical visual system, much of which is involved in oculomotor control.     

The pineal and circadian rhythms of temperature selection and locomotion in lizards

The existence of a circadian rhythm of behavioral temperature selection has been demonstrated in lizards (Podarcis sicula) held on a thermal gradient in constant darkness. This rhythm becomes temporarily abolished during 1 week following parietalectomy and 2-3 weeks following pinealectomy. Parietalectomy does not affect the locomotor rhythm, while pinealectomy invariably lengthens the freerunning period of this rhythm. These results support the contention of separate control systems for the temperature selection rhythm and the locomotor rhythm. As neither rhythm is definitively abolished by parietalectomy and pinealectomy, other pacemaking components exist elsewhere in the circadian system of Podarcis sicula which can control both rhythms.     

Photic and circadian regulations of melatonin rhythms in fishes

Photic and circadian regulations of melatonin rhythms in the pineal organ and the retina of several teleosts were studied to investigate the regulatory mechanisms of melatonin rhythms in fishes. In the eyecup preparations of the goldfish, Carassius auratus, both time of day and lighting conditions affected melatonin production, with high melatonin production observed only in the dark-treated group incubated during the 'subjective' night. Thus, in the goldfish retina, local photoreceptors and an ocular circadian clock seem to regulate melatonin production, as in the zebrafish retina and in the pineal organ of a number of teleosts, including the goldfish. However, this circadian regulation of melatonin rhythms is not universal among fishes. Although the superfused pineal organ of the masu salmon Oncorhynchus masou secreted melatonin in a rhythmic fashion under light-dark (LD) cycles, the rhythm disappeared under constant darkness (DD), as in the rainbow trout, with a large amount of melatonin released both during the subjective day and the subjective night. These results suggest that all salmonids lack circadian regulation of melatonin rhythms. Furthermore, when ocular melatonin rhythms were compared in two cyprinids, the ugui Tribolodon hakonensis and the oikawa Zacco platypus occupying different ecological niches, ocular melatonin contents exhibited daily variations, with higher values during the dark phase of LD cycles in both species. The rhythmic changes persisted in the ugui under DD, with higher levels at subjective midnight than at subjective midday; however, ocular melatonin levels in the oikawa were consistently high under DD. Thus, the circadian regulation of melatonin rhythms in fishes is influenced not only by phylogeny, but also by the ecological niches of the animals. These results suggest that the physiological functions of melatonin in the circadian and photoperiodic systems differ among fishes.     

Efferent optic nerve fibers mediate circadian rhythms in the Limulus eye

When the horseshoe crab is kept in constant darkness, the lateral eye produces larger electroretinographic and optic nerve responses at night than during the day. These circadian rhythms are mediated by synchronous bursts of efferent impulses in the optic nerve trunk. The endogenous efferent activity appears to increase both the gain and the quantum catch of the photoreceptors.     

The effects of lithium ions on circadian rhythms (author's transl)

Lithium ions lengthen the critical dark period in short-day plants, increase the period length of circadian rhythms in Kalanchoe plants, in the rodent Meriones and influence the activity rhythm of birds. In the case of the Kalanchoe rhythm, mainly the process of the petal opening is affected.     

The role of vasopressin in modulating circadian rhythm responses to phase shifts

Telemetered body temperature (BT), heart rate (HR), and motor activity (AC) data were collected in vasopressin-containing, Long-Evans (LE) and vasopressin-deficient, Brattleboro (DI) rats. In Experiment 1, the rats were initially exposed to a 12 h/12 h light/dark cycle under ad-libitum feeding and were then subjected to either a phase-advance or phase-delay shift of 6 h. After the phase-advance shift, neither strain adapted; however, after the phase-delay shift, both strains adapted rapidly. In Experiment 2, the animals were subjected to either a nocturnal or a diurnal restricted-feeding paradigm and were then exposed to either a phase-advance or phase-delay shift with synchronized feeding. In the nocturnal restricted-feeding paradigms, both strains rapidly adapted to both shifts. Concerning diurnal restricted-feeding, DI animals readily entrained to the presentation of food in both shifts; whereas, LE animals exhibited a confused rhythmicity. In Experiment 3, animals were subjected to a phase-advance shift, while the time of feeding was held constant. Following the shift, LE animals responded to the onset of the dark at the new time; yet, were still influenced by the presentation of food. The DI animals maintained the preshift circadian pattern and continued to be dominated by the presentation of food. These experiments indicate that circadian rhythms of LE animals are dominated by the light entrainable oscillator (LEO) in ad-libitum feeding and by both the LEO and food entrainable oscillator (FEO) in restricted-feeding. On the other hand, the circadian rhythms of DI animals are dominated by the FEO unless food is provided ad-libitum. The demonstrated role of vasopressin in synchronizing circadian rhythms to the LEO may be of significance in understanding human circadian rhythm disturbances, such as jet lag.     

Maternal entrainment of the developing circadian system in the Siberian hamster (Phodopus sungorus)

The aim of these studies was to investigate maternal entrainment of developing circadian locomotor activity rhythms in the Siberian hamster. In Experiment 1, mothers were transferred from a 16:8 LD cycle into constant dim red light (DD) from the day of parturition, and wheel-running activity of the mother and pups was individually monitored from the time of weaning. The phases of the individual pups' rhythms were found to be synchronized both to the phase of the mother and to the phase of lights off (ZT 12) of the photo cycle that the mother was exposed to until the day of parturition. To investigate whether this synchrony might reflect direct effects of light acting upon the fetal circadian system in late gestation, the experiment was repeated but with mothers placed into DD early in pregnancy (< or = day 7 of gestation). The results were similar to the first study, suggesting that the mother rather than the photo cycle during the latter part of gestation entrains the developing circadian system. The third experiment investigated whether this entrainment occurred during the postnatal period. Breeding pairs were maintained on alternative light-dark cycles, LD and DL, that were 12 h out of phase. Litters born to mothers on one light-dark cycle were exchanged on the day of birth with foster mothers from the reversed light-dark cycle, then raised in DD. Control litters exchanged between mothers from the same light-dark cycle had similar litter synchrony as shown by nonfostered litters of Experiment 1. However, pups cross-fostered with mothers on reversed LD cycles showed a very different distribution of pup phases. Pups were not synchronized to their natural mother but to their foster mother. Moreover, pups were more scattered over the 24-h period and were found to be significantly synchronized to the phase of the reversed LD cycle. These results demonstrate the occurrence of postnatal entrainment in the Siberian hamster. The increased scatter produced by the cross-fostering paradigm results from some litters being completely entrained to the phase of the foster mother, some with an intermediate distribution between the phase of the natural and foster mothers, and a minority being associated with the phase of the natural mother. These results suggest that Siberian hamster pups are initially synchronized either prenatally or at birth but that the mother continues to provide entrainment signals during the postnatal period.