bluuebunny/crossref_metadata_2025 huggingface dataset:
Clean Thoughts about Dirty Genes
Authors: van Gelder Russell N. , Hogenesch John B.
Published: May 2004

The mouse has joined the fruit fly, bread mold, and cyanobacteria as a tractable genetic system for studying mechanisms of circadian rhythms. The circadian rhythms of “knock-out” mice for specific clock genes, however, have demonstrated significant variability between laboratories. In this brief review, the authors discuss possible sources of this variability, focusing particularly on questions of modifier loci of circadian rhythms that vary between inbred mouse strains. They conclude with a short list of recommendations for researchers working on circadian rhythms in mixed-strain mice.
Relationships between the Circadian Rhythms of Finger Temperature, Core Temperature, Sleep Latency, and Subjective Sleepiness
Authors: Gradisar Michael , Lack Leon
Published: May 2004

Skin temperature circadian rhythms have been explored relatively recently. It has been suggested that distal and proximal skin temperature changes play a role in the regulation of the core temperature circadian rhythm and sleepiness. The authors investigated the circadian finger and core temperature rhythms in conjunction with the circadian rhythms of subjective and objective sleepiness. Fourteen healthy, young, good sleepers participated in a modified constant-routine procedure in which palmar finger temperature, rectal temperature, subjective sleepiness, and objective sleep latency were measured halfhourly across a 48-h period of enforced wakeful bed rest. Individual curves were adjusted to the group mean temperature minimum time of 0500 h and averaged to create the 4 mean curves. The 5 possible cross-correlation curves between these 4 measures were calculated for half-hourly phase lags from 12 h before to 12 h after the group mean core temperature minimum time. Maximum cross-correlations for each curve suggested that finger temperature preceded core temperature by 3 h ( r = -0.22), and subjective sleepiness followed core temperature by 0.5 h( r = -0.33) and objective sleepiness by 2 h ( r = 0.29). Although these data are correlational, they are consistent with the notion that finger temperature changes drive core temperature changes, which determine changes of subjective and objective sleepiness.
Influence of the Corticosterone Rhythm on Photic Entrainment of Locomotor Activity in Rats
Authors: Sage Dominique , Ganem Julien , Guillaumond Fabienne , Laforge-Anglade Geneviève , François-Bellan Anne-Marie , Bosler Olivier , Becquet Denis
Published: May 2004

The question of involvement of glucocorticoid hormones as temporal signals for the synchronization of the timekeeping system was addressed in rats with different corticosterone status. The authors showed that adrenalectomy had no effects on the synchronization of wheel-running activity rhythms to a steady-state LD 12:12 cycle, regardless of whether it was compensated for by a corticosterone replacement therapy that either reinstated constant plasma concentrations of the hormone or mimicked its natural rhythm. However, after a 12-h phase shift (daylight reversal), the lack of circulating corticosterone induced a significant shortening of the resynchronization rate (less than 3 days vs. 7 days). Normalization required restoration of a rhythmic corticosterone secretion that was synchronized to the new photoperiod. Under constant darkness, the corticosterone rhythm did not show any synchronizing effect, providing evidence that it participates in entrainment of the locomotor activity rhythm through modulation of light effects. It is proposed that, under stable lighting conditions, circulating glucocorticoids contribute to stabilizing activity rhythms by reinforcing resistance of the circadian timing system to variations of the photoperiod. Experimental evidence that serotonergic neurons are involved in relaying their modulatory effects to the clock is also presented.
Expression of haPer1 and haBmal1 in Syrian Hamsters: Heterogeneity of Transcripts and Oscillations in the Periphery
Authors: Tong Yanhong , Guo Hongnian , Brewer Judy McKinley , Lee Han , Lehman Michael N. , Bittman Eric L.
Published: May 2004

The molecular biology of circadian rhythms has been extensively studied in mice, and the widespread expression of canonical circadian clock genes in peripheral organs is well established in this species. In contrast, much less information about the peripheral expression of haPer1, haPer2, and haBmal1 is available in Syrian hamsters despite the fact that this species is widely used for studies of circadian organization and photoperiodic responses. Furthermore, examination of oscillating expression of these genes in mouse testis has generated discrepant results, and little is known about gonadal expression of haPer1 and haBmal1 or their environmental control. To address these questions, the authors examined the pattern of haPer1 and haBmal1 in heart, kidney, liver, muscle, spleen, and testis of hamsters exposed to DD. In most organs, Northern blots suggested the existence of single transcripts of each of these messenger RNAs (mRNAs). haPer1 peaked in late subjective day and haBmal1 during the late subjective night. Closer inspection of SCN and muscle haPer1, however, revealed the existence of two major transcripts of similar size, as well as minor transcripts that varied in the 3′-untranslated region. In hamster testis, two haPer1 transcripts were found, both of which are truncated relative to the corresponding mouse transcript and both of which contain a sequence homologous to intron 18 of mPer1. Neither testis transcript contains a nuclear localization signal, and haPer1 transcripts lacked the putative C-terminal CRY1-binding domain. Furthermore, the testis deviated from the general pattern in that haPer1 and haBmal1 both peaked in the subjective night. In situ hybridization revealed that haPer1, but not haBmal1, showed a heterogeneous distribution among seminiferous tubules. Hamster testis also expresses 2 haPer2 transcripts, but no circadian variation is evident. In a second experiment, long-term exposure to DD sufficient to induce gonadal regression was found to eliminate circadian oscillations of both testicular haPer1 transcripts. In contrast, gonadal regression was accompanied by a more robust rhythm of haBmal1.
Retinal Circadian Clocks and Control of Retinal Physiology
Authors: Green Carla B. , Besharse Joseph C.
Published: May 2004

Retinas of all classes of vertebrates contain endogenous circadian clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis, and cellular events such as rod disk shedding, intracellular signaling pathways, and gene expression. The vertebrate retina is an example of a “peripheral” oscillator that is particularly amenable to study because this tissue is well characterized, the relationships between the various cell types are extensively studied, and many local clock-controlled rhythms are known. Although the existence of a photoreceptor clock is well established in several species, emerging data are consistent with multiple or dual oscillators within the retina that interact to control local physiology. Aprominent example is the antiphasic regulation of melaton in and dopamine in photoreceptors and inner retina, respectively. This review focuses on the similarities and differences in the molecular mechanisms of the retinal versus the SCN oscillators, as well as on the expression of core components of the circadian clockwork in retina. Finally, the interactions between the retinal clock(s) and the master clock in the SCN are examined.
Photoperiodism in Neurospora Crassa
Authors: Tan Ying , Merrow Martha , Roenneberg Till
Published: May 2004

Plants and animals use day or night length for seasonal control of reproduction and other biological functions. Overwhelming evidence suggests that this photoperiodic mechanism relies on a functional circadian system. Recent progress has defined how flowering time in plants is regulated by photoperiodic control of output pathways, but the underlying mechanisms of photoperiodism remain to be described. The authors investigate photoperiodism in a genetic model system for circadian rhythms research, Neurospora crassa. They find that both propagation and reproduction respond systematically to photoperiod. Furthermore, a nonreproductive light-regulated function is also enhanced under certain photoperiodic conditions. All of these photoperiodic responses require a functional circadian clock, in that they are absent in a clock mutant. Night break experiments show that measuring night length is one of the mechanisms used for photoperiod assessment. This represents the first formal report of photoperiodism in the fungi.
Effects of Photoperiod on Rat Motor Activity Rhythm at the Lower Limit of Entrainment
Authors: Cambras Trinitat , Chiesa Juan , Araujo John , Díez-Noguera Antoni
Published: May 2004

The experiment described here studied the rat motor activity pattern as a function of the photoperiod of circadian light-dark cycles in the limits of entrainment (22-and 23-h periods). In most cases, the overt rhythm showed 2 circadian components: 1 that followed the external LD cycle and a 2nd rhythm that was free run. The expression of these components was directly dependent on the photoperiod, and there was a gradual transition in the manifestation of 1 or the other. The component with a period equal to that of the external cycle was more manifested under long photoperiods, while the other 1 was more expressed during short photoperiods. Also, the period of the free-running component was longer under T22 than T23. For each period, the free-running component was longer under a longer photoperiod. At first sight, the presence of these 2 components in most of the rats might appear to be due to the fact that in the limits of entrainment, some rats do not entrain and thus show a free-running rhythm plus masking. However, the gradation observed in the different patterns of the overt motor activity rhythm, especially those patterns related to the different balance between the 2 components and the length of the period of the free-running component under LD as a function of the photoperiod, suggests that the circadian system can be functionally dissociated.
Phase Relationships between Sleep-Wake Cycle and Underlying Circadian Rhythms in Morningness-Eveningness
Authors: Mongrain Valérie , Lavoie Suzie , Selmaoui Brahim , Paquet Jean , Dumont Marie
Published: May 2004

A shorter phase angle between habitual wake time and underlying circadian rhythms has been reported in evening types (E types) compared to morning-types (M types). In this study, phase angles were compared between 12 E types and 12 M types to verify if this difference was observed when the sleep schedule was relatively free from external social constraints. Subjects were selected according to their Morningness-Eveningness Questionnaire score (MEQ score). There were 6 men and 6 women in each group (ages 19-34 years), and all had a habitual sleep duration between 7 and 9 h. Sleep schedule was recorded by actigraphy and averaged over 7 days. Circadian phase was estimated by the hour of temperature minimum (Tmin) in a 26-h recording and by the timing of the onset of melatonin secretion (dim-light melatonin onset [DLMO]) measured in saliva samples. Phase angles were defined as the interval between phase markers and averaged wake time. Results showed that, in the present experimental conditions, phase angles were very similar in the 2 groups of subjects. However, results confirmed the previously reported correlation between phase and phase angle, showing that a later circadian phase was associated with a shorter phase angle. Gender comparisons showed that for a same MEQ score, women had an earlier DLMO and a longer phase angle between DLMO and wake time. Despite a significant difference in the averaged circadian phases between E-type and M-type groups, there was an overlap in the circadian phases of the subjects of the 2 groups. Further comparisons were made between the 2 circadian types, separately for the subgroups with overlapping or nonoverlapping circadian phases. In both subgroups, the significant difference between MEQ scores, bedtimes, and wake times were maintained in the expected direction. In the subgroup with nonoverlapping circadian phases, phase angles were shorter in E-type subjects, in accordance with previous studies. However, in the overlapping subgroup, phase angles were significantly longer in E types compared to M types. Results suggest that the morningness-eveningness preference identified by the MEQ score refers to 2 distinct mechanisms, 1 associated with a difference in circadian period and phase of entrainment and the other associated with chronobiological aspects of sleep regulation.
Are Humans Seasonally Photoperiodic?
Authors: Bronson F. H.
Published: May 2004

Humans exhibit seasonal variation in a wide variety of behavioral and physiological processes, and numerous investigators have suggested that this might be because we are sensitive to seasonal variation in day length. The evidence supporting this hypothesis is inconsistent. A new hypothesis is offered here—namely, that some humans indeed are seasonally photoresponsive, but others are not, and that individual variation may be the cause of the inconsistencies that have plagued the study of responsiveness to photoperiod in the past. This hypothesis is examined in relation to seasonal changes in the reproductive activity of humans, and it is developed by reviewing and combining five bodies of knowledge: correlations of human birthrates with photoperiod; seasonal changes in the activity of the neuroendocrine pathway that could link photoperiod to gonadal steroid secretion in humans; what is known about photoperiod, latitude, and reproduction of nonhuman primates; documentation of individual variation in photoresponsiveness in rodents and humans; and what is known about the evolutionary ecology of humans.
High Potassium Treatment Resets the Circadian Oscillator in Xenopus Retinal Photoreceptors
Authors: Hasegawa Minoru , Cahill Gregory M.
Published: May 2004

In vertebrate retina, light hyperpolarizes the photoreceptor membrane, and this is an essential cellular signal for vision. Cellular signals responsible for photic entrainment of some circadian oscillators appear to be distinct from those for vision, but it is not known whether changes in photoreceptor membrane potential play roles in photic entrainment of the photoreceptor circadian oscillator. The authors show that a depolarizing exposure to high potassium resets the circadian oscillator in cultured Xenopus retinal photoreceptor layers. A 4-h pulse of high [K+] (34 mM higher than in normal culture medium) caused phase shifts of the melatonin rhythm. This treatment caused phase delays during the early subjective day and phase advances during the late subjective day. In addition to the phase-shifting effect, high potassium pulses stimulated melatonin release acutely at all times. High [K+] therefore mimicked dark in its effects on oscillator phase and melatonin synthesis. These results suggest that membrane potential may play a role in photic entrainment of the photoreceptor circadian oscillator and in regulation of melatonin release.
In Vitro Circadian Rhythms of the Mammalian Suprachiasmatic Nuclei: Comparison of Multi-Unit and Single-Unit Neuronal Activity Recordings
Authors: Prosser Rebecca A.
Published: May 2004

The circadian clock in the mammalian suprachiasmatic nuclei (SCN) expresses 24-h rhythms when isolated in vitro. Numerous studies have demonstrated that recordings of SCN single-unit neuronal activity (SUA), when expressed as a population rhythm, can be used to reliably estimate SCN circadian clock phase in vitro. The main disadvantage of this technique is its laborious nature. Thus, the present experiments were designed to investigate whether in vitro multi-unit neuronal activity (MUA) recordings from the SCN could reliably substitute for SUA recordings. The results show that an MUA rhythm can be recorded from rat SCN for 3 days in vitro but that this rhythm is extremely variable; times of peak MUA in control experiments vary by 7 to 9 h each day. They also show that several serotonergic agents previously shown to consistently advance the SUA rhythm 2 to 3 h when applied during the day induce apparent advances in the MUA rhythm in some experiments; in other cases, however, there appears to be a delay or no change in the phase of the rhythm. Thus, the mean change in time of peak seen after these treatments was an advance of about 1 h. Finally, the results show that glutamate and optic chiasm stimulation applied during early subjective night can induce apparent delays in the MUA rhythm. The results of these experiments were less variable, so that the overall effect was a delay in peak MUA of 2.5 to 3.5 h. Nevertheless, these experiments still exhibited more variability than that generally seen in SUA experiments. Taken together, these results indicate that MUA recordings of the SCN exhibit significantly more variability than do SUA recordings. The extent of this variability leads to the conclusion that, using the techniques and equipment outlined here, MUA recordings are not an adequate substitute for SUA recordings when trying to estimate the phase of the SCN circadian clock.
Melatonin Rhythm Onset in the Adult Siberian Hamster: Influence of Photoperiod But Not 60-Hz Magnetic Field Exposure on Melatonin Content in the Pineal Gland and in Circulation
Authors: Yellon Steven M. , Truong Huy N.
Published: May 2004

To determine the relationship between pineal melatonin production and its appearance in circulation, the rising phase of the pineal and serum melatonin rhythm was studied in the adult Siberian hamster. Melatonin concentrations increased in the pineal gland and in serum at 1.50 and 1.75 h, respectively, relative to lights off in long days (16 h of light/day) and at 2.00 and 2.75 h, respectively, in short days (10 h of light/day). Thus, a photoperiod-dependent melatonin rise in circulation lagged production by the pineal gland by 0.50 h—a delay of 0.75 h in short-day hamsters versus 0.25 h in long-day hamsters. Following initiation of this rise, concentrations that were typical of the nighttime peak were achieved within 2 h of melatonin rhythm onset, regardless of photoperiod. To determine whether clock control of the rising phase of the melatonin rhythm, in the absence of photoperiod cues, may be disrupted by perturbations in the ambient magnetic field, hamsters in constant darkness were acutely exposed to a 1-Gauss, 60-Hz magnetic field for 15 min or were daily exposed to this treatment for 14 or 21 days. Neither the melatonin rise in pineal content or circulation during subjective night was affected by acute or chronic magnetic field exposures; testes regression similarly occurred in sham and daily magnetic field-exposed hamsters in constant darkness. These findings indicate that magnetic field exposures are unlikely to serve as a zeitgeber for the circadian mechanism that controls onset of the melatonin rhythm; rather, photoperiod is a predominant cue that may differentially regulate the rising phase of melatonin production in the pineal gland and concentration in circulation.
Alterations of Estrous Activity in the Ewe by Circadian-Based Manipulation of the Endogenous Pacemaker
Authors: Guerin Michael V. , Matthews Colin D.
Published: May 2004

The timing of reproductive activity in the seasonal breeding Romney Marsh ewe depends on the measurement of photoperiodic time. In this experiment, artificial light and dark signals are provided in a measured sequence at an inappropriate time of year to induce breeding out of phase with environmental photoperiod. The endogenous circadian responses and reproductive effects are documented. One group (Group A, control) of 6 Romney Marsh ewes was held in natural photoperiod throughout the experiment. For 8 weeks centered about the winter solstice (Stage 1), an additional 18 animals (Groups B, C, and D) were exposed to an artificial earlier dawn. Measurements of endogenous melatonin performed under acutely extended darkness confirmed a phase advance of the endogenous circadian pacemaker of the suprachiasmatic nucleus compared to control animals. In Stage 2, to the summer solstice (21 December), Group B animals were returned to natural photoperiod, Group C animals were subjected to an earlier artificial dusk, and Group D animals were subjected to an artificial delayed dawn. Melatonin measurements during Stage 2 confirmed that onset and offset times for Group C were earlier and that onset and offset times for Group D were delayed compared to corresponding times for Group B animals. Ovarian activity was monitored throughout. During Stage 2, Groups C and D commenced reproductive activity in mid-spring, and this continued until the experimental conditions changed. Groups A and B commenced reproductive activity at the normal timing in the subsequent autumn. Although not exclusive, these results are consistent with a coincidence model to explain the timing of seasonal breeding in this species with a dusk-located phase of the endogenous pacemaker sensitive to both light and melatonin. The temporal relationship between circadian alterations and the environmental photoperiod warrants further investigation as an explanation for seasonal breeding.
Testing the Hypothesis of a Circadian Phase Disturbance Underlying Depressive Mood in Nonseasonal Depression
Authors: Gordijn Marijke C. M. , Beersma Domien G. M. , Korte Henk J. , Van den Hoofdakker Rutger H.
Published: May 2004

In a crossover design, 8 nonseasonal depressed subjects, selected on the presence of diurnal mood variations, and 8 sex and age-matched controls were exposed to dim light (< 10 lux) in the evening (18:00-21:00 h) and bright light (2500 lux) in the morning (ML, 6:00-9:00 h), to dim light in the morning and bright light in the evening (EL), or to dim light both in the evening and in the morning (DL) during 3 consecutive days in each of these conditions. There were no initial phase differences between depressed and healthy subjects in the timing of dim light melatonin onset, sleep termination, and body temperature. The phase shifts after EL and ML in both healthy and depressed subjects were as expected on the basis of a human phase response curve. On average, there was no therapeutic effect of the light exposure in the depressed patients. Two patients improved, but these effects do not seem to be related to shifts in the circadian system.
Decreased Light Intensity Alters the Perception of Day Length by Male European Starlings (Sturnus vulgaris)
Authors: Bentley George E. , Goldsmith Arthur R. , Dawson Alistair , Briggs Charlotte , Pemberton Miranda
Published: May 2004

The breeding season of wild starlings is controlled by photoperiod. Full breeding condition is attained during exposure to lengthening days in the spring, and photorefractoriness ensues. The reproductive system of starlings will not subsequently be stimulated by long day lengths until photorefractoriness is dissipated by the short day lengths experienced in the autumn and winter. Unlike most studies on avian photoperiodism, this investigation involved manipulation of light intensity of a fixed photoperiod rather than of photoperiod itself. Photo sensitive starlings transferred from short days to long days of different light intensities underwent graded reproductive responses according to the light intensity they experienced. Testes size in the group in the lowest intensity (3 lux) increased faster than that in controls on short days of normal intensity, but they did not become photorefractory. Testes size increased in the groups on 13, 45, and 108 lux and subsequently became photorefractory. However, the 13-and 45-lux groups required more time to become photorefractory than did the 108-lux group. The responses observed were similar to those seen in starlings exposed to different photoperiods (e.g., 11 h light:13 h dark [11L:13D], 13L:11D, 16L:8D, 18L:6D), even though all were on the same 18L:6D photoperiod. Initially, the results appear to challenge the external coincidence model for photoperiodic time measurement, but consideration of the phase response curve of the circadian rhythm of photoinducibility in starlings and the way in which it might be affected by low light intensities refute this challenge.
Photoreception in Entrainment of Rhythms and Photoperiodic Regulation of Diapause in a Hemipteran, Graphosoma lineatum
Authors: Nakamura Keiji , Hodkova Magdalena
Published: May 2004

The role of compound eyes in photoperiodic regulation of diapause and entrainment of circadian rhythms was studied in a hemipteran, Graphosoma lineatum. Bilateral removal of compound eyes resulted in the loss of locomotor rhythmicity under both 24-h light cycle and constant darkness. The arrhythmicity was associated with the loss of photoperiodic regulation of diapause. Females with removed compound eyes had similar incidence of oviposition under diapause preventing long-day photoperiod (light:dark [LD] 18:6) and diapause inducing short-day photoperiod (LD 12:12). By contrast, both locomotor rhythmicity and photoperiodic regulation of diapause were maintained after unilateral removal of compound eyes. The results suggest that the compound eye–optic lobe axis is involved in the transmission of light signals for both entrainment of rhythms in locomotor activity and photoperiodism. The compound eyes probably act as photoreceptors in both transmission chains. Sites of the clocks for the two phenomena are discussed.
Molecular Circadian Oscillators: An Alternative Hypothesis
Authors: Roenneberg Till , Merrow Martha
Published: May 2004

Results from experiments in different organisms have shown that elements of input pathways can themselves be under circadian control and that outputs might feed back into the oscillator. In addition, it has become clear that there might be redundancies in the generation of circadian rhythmicity, even within single cells. In view of these results, it is worth reevaluating our current working hypotheses about the pacemaker's molecular mechanisms and the involvement of single autoregulatory genes. On one hand, redundancies in the generation of circadian rhythmicity might make the approach of defining a discrete circadian oscillator with the help of single gene mutations extremely difficult. On the other hand, many examples show that components of signal transduction pathways can indeed be encoded by single genes. The authors have constructed a model placing an autoregulatory gene and its products on an input pathway feeding into a separate oscillator. The behavior of this model can explain the majority of results of molecular circadian biology published to date. In addition, it shows that different qualities of the circadian system might be associated with different cellular functions that can exist independently and, only if put together, will lead to the known circadian phenotype.
Behavior of SCN-Lesioned Chipmunks in Natural Habitat: A Pilot Study
Authors: DeCoursey Patricia J. , Krulas Jill R.
Published: May 2004

The necessity of a circadian pacemaker, the suprachiasmatic nuclei (SCN), for survival was evaluated in a population of approximately 65 wild eastern chipmunks, Tamias striatus. The research involved over 3000 h of fieldwork between May 1995 and October 1997 on a study siteat Mountain Lake Biological Station, Virginia. The 28 chipmunks randomly designated as project animals included 10 SCN-lesioned chipmunks, 5 surgical controls (shamlesioned), and 13 intact controls. Visual observation, live trapping, and radio telemetric tracking were used to assess 6aspects of survival and reproduction. Upon release after surgery, every animal returned to its den site and was able to maintain its home territory. In warm months from May through October, all chipmunks were active above ground with a strictly day-active pattern. During the remainingcold months, they were normothermic but relatively torpid in their underground densfor extendedperiods of time. Short-term mortality for the initial 3 months included only a single intact control chipmunk; loss for the extended period from August 1995 to October 1996 was 40% for the SCN-lesioned animals, 0% for surgical controls, and 15.4% for the intact controls.Survival differences were not significant between surgical control and intact control groups but were significant ([.alpha] = .10) between SCN-lesioned and pooled control groups. Annual bodyweight patterns were similar for both groups. Most individuals in both SCN-lesioned and controlgroups were reproductively active in the spring and fall breeding periods. Lack of major differences may be attributable to the exceptionally favorable conditions for survival such as a veryabundant fallacorn crop, medium population size, and absence of heavy predation.
Exogenous Melatonin Enhances Cell-Mediated, but Not Humoral, Immune Function in Adult Male Deer Mice (Peromyscus maniculatus)
Authors: Demas Gregory E. , Nelson Randy J.
Published: May 2004

Many nontropical rodent species display seasonal changes in reproductive physiology and metabolism, as well as in immune function. Field studies of seasonal changes in immune function typically report decreased immune function in the short days of winter compared to summer; presumably, reduced immunity in winter reflects increased glucocorticoid secretion in response to environmental stressors. In contrast, laboratory studies of photoperiodic changes in immunity invariably demonstrate increased immune function in short compared to long days. Although the precise mechanisms regulating short-day enhancement of immune function are not known, it is hypothesized that increased immunity is due to the increased duration of melatonin secretion in short compared to long days. However, melatonin can act both directly (i.e, via melatonin receptors located on lymphatic tissue) and indirectly (i.e., via alterations in gonadal steroids) to affect immune function. The present study examined the effects of exogenous melatonin administration on both cell-mediated and humoral immune function in adult male deer mice ( Peromyscus maniculatus), as well as the role of gonadal steroid hormones in mediating these effects. Mice either were castrated to remove circulating androgens or received sham operations and were implanted with empty capsules or capsules containing melatonin. Individual mice implanted with melatonin underwent reproductive regression and displayed enhanced splenocyte proliferation to the T-cell mitogen concanavalin A; antigen-specific serum immunoglobulin M production was unaffected by melatonin treatment. Castration had no effect on either cell-mediated or humoral immune function. Taken together, these results suggest that exogenous melatonin enhances cell-mediated, but not humoral, immune function in adult male deer mice and that this effect is independent of gonadal steroid hormones. These results are consistent with a direct effect of melatonin on immunity.
Histamine Phase Shifts the Hamster Circadian Pacemaker via an NMDA Dependent Mechanism
Authors: Meyer Jennifer L. , Hall Adam C. , Harrington Mary E.
Published: May 2004

The SCN acts as the central pacemaker for circadian rhythms in mammals. Histamine has been shown to affect circadian rhythms both in vivo and in vitro. We investigated the mechanism by which histamine phase shifts circadian rhythms in vitro. Hypothalamic slices containing the SCN were prepared from golden hamsters, and spontaneous firing rates of individual cells were recorded on the second day in vitro. Application of histamine (1 μM – 10 mM) at the extrapolated time of 2 h after lights off (ZT 14) on day 1 in vitro delayed the time of peak firing in a dose-dependent manner. Pre-exposure to the N-methyl-D-aspartate (NMDA) receptor antagonist (±)-2-amino-5-phosphonopentanoic acid (AP-5; 100 μM – 1mM) 5 min before histamine (1 μM) was applied to the slice blocked the phase-delaying effects of histamine. Application of the H1 blocker mepryamine (100 nM) or the H2 blocker cimetidine (10 μM) followed by histamine had no effect on the phase delay induced by histamine. In whole cell recordings from acutely dissociated neurons of hamster SCN, histamine (50 [.mu]M) was shown to potentiate NMDA-evoked currents by 52 ± 12%. These experiments demonstrate that histamine phase shifts of the circadian clock are dependent on NMDA receptor activation and that histamine can directly potentiate NMDA currents in SCN neurons. Histamine may alter circadian clock function by acting directly on NMDA receptors, possibly via binding to the polyamine site.
The timSL Mutant Affects a Restricted Portion of the Drosophila melanogaster Circadian Cycle
Authors: Rutila Joan E. , Maltseva Olga , Rosbash Michael
Published: May 2004

The circadian rhythm genes period ( per) and timeless ( tim) are central to contemporary studies on Drosophila circadian rhythms. Mutations in these genes give rise to arrhythmic or period-altered phenotypes, and per and tim gene expression is under clock control. per and tim proteins (PER and TIM) also undergo circadian changes in level and phosphorylation state. The authors previously described a period-altering tim mutation, timSL, with allele-specific effects in different per backgrounds. This mutation also affected the TIM phosphorylation profile during the mid-late night. The authors show here that the single amino acid alteration in TIM-SL is indeed responsible for the phenotype, as a timSL transgene recapitulates the original mutant phenotype and shortens the period of perL flies by 3 h. The authors also show that this mutation has comparable effects in a light-dark cycle, as timSL also accelerates the activity offset during the mid-late night of perL flies. Importantly, timSL advances predominantly the mid-late night region of the perL phase response curve, consistent with the notion that this portion of the cycle is governed by unique rate-limiting steps. The authors propose that TIM and PER phosphorylation are normally rate determining during the mid-late night region of the circadian cycle.
Roles of Suprachiasmatic Nuclei and Intergeniculate Leaflets in Mediating the Phase-Shifting Effects of a Serotonergic Agonist and Their Photic Modulation during Subjective Day
Authors: Challet Etienne , Scarbrough Kathryn , Penev Plamen D. , Turek Fred W.
Published: May 2004

Serotonin (5-HT) has been implicated in the phase adjustment of the circadian system during the subjective day in response to nonphotic stimuli. Two components of the circadian system, the suprachiasmatic nucleus (SCN) (site of the circadian clock) and the intergeniculate leaflet (IGL), receive serotonergic projections from the median raphe nucleus and the dorsal raphe nucleus, respectively. Experiment 1, performed in golden hamsters housed in constant darkness, compared the effects of bilateral microinjections of the 5-HT1A/7 receptor agonist, 8-hydroxydipropylaminotetralin (8-OH-DPAT; 0.5 μg in 0.2 μL saline per side), into the IGL or the SCN during the mid-subjective day. Bilateral 8-OH-DPAT injections into either the SCN or the IGL led to significant phase advances of the circadian rhythm of wheel-running activity ( p < .001). The phase advances following 8-OH-DPAT injections in the IGL were dose dependent ( p < .001). Because a light pulse administered during the middle of the subjective day can attenuate the phase-resetting effect of a systemic injection of 8-OH-DPAT, Experiment 2 was designed to determine whether light could modulate 5-HT agonist activity at the level of the SCN and/or the IGL. Serotonergic receptor activation within the SCN, followed by a pulse of light (300 lux of white light lasting 30 min), still induced phase advances. In contrast, the effect of serotonergic stimulation within the IGL was blocked by a light pulse. These results indicate that the respective 5-HT projections to the SCN and IGL subserve different functions in the circadian responses to photic and nonphotic stimuli.
Human Perception of Short and Long Time Intervals: Its Correlation with Body Temperature and the Duration of Wake Time
Authors: Aschoff Jürgen
Published: May 2004

Time estimation was studied in seven human subjects during prolonged sojourn is isolation from time cues. They wore rectal temperature probes throughout the experiments, and during wakefulness recorded each time they thought one hour had passed. At the end of each of these subjective hours they produced a subjective 5 or 10 sec interval. The produced intervals on the 1-h task were not related to body temperature but were correlated with and proportional to the duration of waketime in all subjects. The produced 5 and 10 sec intervals were in all subjects negatively correlated with rectal temperature, but were not associated with wake time. Brief and long time intervals are subjectively experienced via different mechanisms.
Thermoperiodic Responses in Insects and Mites Simulated with the Double Circadian Oscillator Clock
Authors: Nunes Marlies Vaz
Published: May 2004

The “double circadian oscillator model” for the photoperiodic clock has been used to simulate thermoperiodic responses in insects and mites. Two assumptions have been made: (1) the clock measures cryophase in a similar way to scotophase, and (2) temperature cycles are able to entrain the clock in a similar way to LD cycles. Simulations showed that Assumption 1 causes the “critical cryophase” to be of about equal duration as the critical night length. Assumption 2 is not always needed if diapause incidences in DD are high at low temperatures but low or zero at high temperatures. The latter assumption is needed, however, if high diapause occurs in thermoperiodic cycles in DD, whereas nondiapause occurs in DD with both high and low constant temperatures. The model accounts for the observation that the amplitude of the temperature cycle is important in some insects, whereas the temperature of the cryophase is crucial in others.
Effect of Sustained Nocturnal Transbuccal Melatonin Administration on Sleep and Temperature in Elderly Insomniacs
Authors: Dawson Drew , Rogers Naomi L. , van den Heuvel Cameron J. , Kennaway David J. , Lushington Kurt
Published: May 2004

Previous research has suggested a role for the pineal hormone melatonin in the control of the body's sleep-wake and thermoregulatory systems. In the elderly population, there have been reports of decreased nighttime secretion of melatonin and suggestions that this may, in turn, be responsible for the increased incidence of sleep disorders reported by this age group. On this basis, it has been suggested that augmented nocturnal melatonin levels may improve sleep quality in age-related sleep disorders. Following screening assessments, 12 elderly (> 55 years) subjects with sleep maintenance insomnia were treated with either 0.5 mg transbuccal melatonin or a placebo for two sessions of 4 consecutive nights, at least 3 days apart. Subjects self-selected lights-out times, and sleep was assessed using standard polysomnographic (PSG) measures. Body temperature was measured continually from 2100 to 0700 h, and sleep quality was assessed from PSG variables measured. Nightly urine samples were assayed for the melatonin metabolite 6-sulfatoxy-melatonin (aMT.6S). Compared to the placebo, transbuccal melatonin administration significantly increased mean nocturnal aMT.6S excretion (mean ± SEM: 194.2 ± 16.5 vs. 42.5 ± 7.7 nmol). In addition, there was a significant reduction in core body temperature relative to the placebo condition ( p < .05). However, sustained transbuccal melatonin treatment had no positive significant effect on any PSG measure of sleep quality. The results from the present study suggest that sustained nocturnal administration of melatonin, in the low pharmacological range, might be of limited clinical benefit in this subject population.
Novel Effects on the Gonyaulax Circadian System Produced by the Protein Kinase Inhibitor Staurosporine
Authors: Comolli James C. , Hastings J. Woodland
Published: May 2004

The protein kinase inhibitor staurosporine was found to cause a dramatic increase in the free-running period (FRP) of circadian rhythms in the dinoflagellate Gonyaulax polyedra, and its effect was similar when added at different phases of the circadian cycle. Chronic exposure to staurosporine lengthened the FRP by as much as 7 h without significantly affecting the amplitude or waveform of the bioluminescence rhythm. The effect on the length of the FRP occurred only above a threshold concentration, and it lasted for a limited number of cycles that depended on the dose of the drug. The FRP lengthening was not evident until 23 to 26 h after staurosporine addition, even though the drug entered Gonyaulax cells in 1 h or less. When tested in combination with bright light pulses, staurosporine was found to enhance both light-induced phase advances and delays, indicating that the drug acts on circadian phototransduction. At concentrations that alter the FRP and the response to light pulses, staurosporine appears to act on a small number of protein kinases, attenuating the activity of two individual protein kinases without affecting overall phosphate incorporation into proteins in vitro.
Melatonin Suppression by Illumination of Upper and Lower Visual Fields
Authors: Lasko Thomas A. , Kripke Daniel F. , Elliot Jeffrey A.
Published: May 2004

As a guide to optimizing the geometry of bright light treatment, 12 healthy subjects were studied three times in the laboratory from 11 p.m. to 2 a.m. On three evenings, in counterbalanced orders, subjects received 500 lux in the upper visual field, 500 lux in the lower visual field, or 5 lux while watching television. In the upper visual field, 500 lux significantly suppressed melatonin, as compared to 500 lux in the lower visual field or to 5 lux. In the lower visual field, 500 lux produced intermediate suppression of borderline significance. The results suggest that bright light treatment of depression or circadian phase disorders might be most effective when applied in the upper visual field.
A Reexamination of the Role of GABA in the Mammalian Suprachiasmatic Nucleus
Authors: Gribkoff Valentin K. , Pieschl Rick L. , Wisialowski Todd A. , Park Won K. , Strecker George J. , de Jeu Marcel T. G. , Pennartz Cyriel M. A. , Dudek F. Edward
Published: May 2004

Three independent electrophysiological approaches in hypothalamic slices were used to test the hypothesis that [.gamma]-amino butyric acid (GABA)Areceptor activation excites suprachiasmatic nucleus (SCN) neurons during the subjective day, consistent with a recent report. First, multiple-unit recordings during either the subjective day or night showed that GABA or muscimol inhibited firing activity of the SCN population in a dose-dependent manner. Second, cell-attached recordings during the subjective day demonstrated an inhibitory effect of bath-or microapplied GABA on action currents of single SCN neurons. Third, gramicidin perforated-patch recordings showed that bicuculline increased the spontaneous firing rate during the subjective day. Therefore, electrophysiological data obtained by three different experimental methods provide evidence that GABA is inhibitory rather than excitatory during the subjective day.
Psychogenetically Selected (Roman High- and Low-Avoidance) Rats Differ in 24-Hour Sleep Organization
Authors: Steimer Thierry , Python Agathe , Driscoll Peter , de Saint Hilaire Zarah
Published: May 2004

A comparison of sleep organization in Roman high-(RHA/Verh) and low-(RLA/Verh) avoidance rats, which differ in the way they respond to environmental stimuli and in several neuroendocrine and neurochemical parameters, was carried out. EEG-sleep recordings were obtained from adult males over 12:12 light-dark periods to determine how these two psychogenetically selected rat lines might also differ in their sleep-wake cycle. There was no significant difference in total sleep time between the two lines. However, the (hypoemotional) RHA/Verh rats showed an overall increase (percentage of total sleep) in paradoxical sleep (PS) duration, with a concomitant decrease in slow-wave sleep (SWS). During the dark phase, RHA/Verh rats showed a shorter PS latency and a larger number of PS episodes. Hourly sleep scoring also revealed a more discontinuous pattern (total sleep and PS vs. SWS) during the dark phase in RHA/Verh rats. In relation to recognized neurochemical and neuroendocrine differences between them, these rat lines may prove useful in investigations of the neurobiological mechanisms underlying sleep regulation.
Linear Demasking Techniques Are Unreliable for Estimating the Circadian Phase of Ambulatory Temperature Data
Authors: Klerman Elizabeth B. , Lee Younsun , Czeisler Charles A. , Kronauer Richard E.
Published: May 2004

Clinical investigators often use ambulatory temperature monitoring to assess the endogenous phase and amplitude of an individual's circadian pacemaker for diagnostic and research purposes. However, an individual's daily schedule includes changes in levels of activity, in posture, and in sleep-wake state, all of which are known to have masking or evoked effects on core body temperature (CBT) data. To compensate for or to correct these masking effects, many investigators have developed “demasking” techniques to extract the underlying circadian phase and amplitude data. However, the validity of these methods is uncertain. Therefore, the authors tested a variety of analytic methods on two different ambulatory data sets from two different studies in which the endogenous circadian pacemaker was not synchronized to the sleep-wake schedule. In both studies, circadian phase estimates calculated from CBT collected when each subject was ambulatory (i.e., free to perform usual daily activities) were compared to those calculated during the same study when the same subject's activities were controlled. In the first study, 24 sighted young and older subjects living on a 28-h scheduled “day” protocol were studied for approximately 21 to 25 cycles of 28-h each. In the second study, a blind man whose endogenous circadian rhythms were not synchronized to the 24-h day despite his maintenance of a regular 24-h sleep-wake schedule was studied for more than 80 consecutive 24-h days. During both studies, the relative phase of the endogenous (circadian) and evoked (scheduled activity-rest) components of the ambulatory temperature data changed progressively and relatively slowly, enabling analysis of the CBT rhythm at nearly all phase relationships between the two components. The analyses of the ambulatory temperature data demonstrate that the masking of the CBT rhythm evoked by changes in activity levels, posture, or sleep-wake state associated with the evoked schedule of activity and rest can significantly obscure the endogenous circadian component of the signal, the object of study. In addition, the masking effect of these evoked responses on temperature depends on the circadian phase at which they occur. These nonlinear interactions between circadian phase and sleep-wake schedule render ambulatory temperature data unreliable for the assessment of endogenous circadian phase. Even when proposed algebraic demasking techniques are used in an attempt to reveal the endogenous temperature rhythm, the phase estimates remain severely compromised.