Pineal transplantation to the brain of pinealectomized lizards: Effects of circadian rhythms of locomotor activity.

Pinealectomized lizards (Podarcis sicula) whose locomotor rhythms were recorded in constant temperature (29°C) and darkness were subdivided into 2 groups of hosts: Each belonging to the 1st group (experimentals) received from a donor a pineal gland, and each belonging to the 2nd one (controls) received a piece of cerebellum. Pineal transplantation induced drastic changes in the free-running period (τ) of locomotor rhythms, which were significantly greater than the τ changes induced by cerebellum transplantation. Either application or removal of melatonin implants left the locomotor rhythms of the controls completely undisturbed, showing that in absence of melatonin rhythms (pinealectomy alone abolishes blood-borne melatonin rhythms) melatonin implants are ineffective. Melatonin rhythms, however, had to be present in the experimentals, because the circadian system reacts to melatonin implants by changing τ (as if melatonin rhythms had been suppressed) and to removal of the implants by again changing τ (as if melatonin rhythms had been restored). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Melatonin entrains the restored circadian activity rhythms of syrian hamsters bearing fetal suprachiasmatic nucleus grafts

A circadian pacemaker consists of at least three essential features: the ability to generate circadian oscillations, an output signal, and the ability to be entrained by external signals. In rodents, ablation of the suprachiasmatic nucleus (SCN) results in the loss of circadian rhythms in activity. Rhythmicity can be restored by transplanting fetal SCN into the brain of the lesioned animal, demonstrating the first two of the essential pacemaker features within the grafts. External signals, such as the light/dark cycle, have not, however, been shown to entrain the restored rhythms. Melatonin injections are an effective entraining stimulus in fetal and neonatal Syrian hamsters of the same developmental ages used to provide donor tissue for transplantation. Therefore, melatonin was used to test the hypothesis that SCN grafts contain an entrainable pacemaker. Daily injections of melatonin were given to SCN-lesioned hosts beginning on the day after transplantation of fetal SCN. Two groups that received melatonin at different times of day 12 hr apart each showed significantly clustered phases but with average phases that differed by 8.67 hr. Thus melatonin was able to entrain the restored circadian activity rhythms. In contrast to these initial injections, injections given 6 weeks after transplantation were unable to entrain or phase shift the rhythms. The results demonstrate that SCN grafts contain an entrainable circadian pacemaker. In addition, the results also indicate that the fetal SCN is directly sensitive to melatonin and, as with intact hamsters, sensitivity to melatonin is lost during SCN development.     

Melatonin acts at the suprachiasmatic nucleus to attenuate behavioral symptoms of infection.

In common with reproduction, immune function exhibits strong seasonal patterns, which are driven by annual changes in day length (photoperiod) and melatonin secretion. Whereas changes in melatonin communicate seasonal time into the reproductive axis via subcortical receptors, the relevant melatonin targets for communicating seasonal time into the immune system remain unspecified. The authors report that melatonin implants targeting the hypothalamic suprachiasmatic nuclei (SCN) induced a winter phenotype in the immune system. SCN melatonin implants attenuated infection-induced anorexia and cachexia, indicating that the SCN mediate the effects of melatonin on these behavioral and metabolic symptoms of infection. However, SCN melatonin implants failed to induce winter-like peripheral leukocyte concentrations or behavioral thermoregulatory responses to infection. In contrast, subcutaneous melatonin implants induced winter-like changes in all behavioral and immunological parameters. Melatonin acts directly at the SCN to induce seasonal changes in neural-immune systems that regulate behavior. The data identify anatomical overlap between neural substrates mediating the effects of melatonin on the reproductive and immune systems but also suggest that the SCN are not the sole mediator of photoperiodic effects of melatonin on immunity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

The tau mutation affects temperature compensation of hamster retinal circadian oscillators

Neural retinas of the golden hamster (Mesocricetus auratus) express circadian rhythms of melatonin synthesis when cultured in constant darkness. Retinas from wild-type hamsters synthesize melatonin with a period close to 24 h, while retinas obtained from hamsters homozygous for the circadian mutation tau, which shortens the free-running period of the circadian activity rhythm by 4 h, synthesize melatonin with a period close to 20 h. The retinal circadian oscillators of both wild-type and tau mutant hamsters are temperature compensated; however, temperature compensation is adversely affected by the mutation.     

Immunogold localisation of the intermediate chain within the protein complex of cytoplasmic dynein

Seasonal differences exist in the attractiveness of scents in meadow voles, Microtus pennsylvanicus. To determine whether photoperiodically induced changes in the attractiveness of a sex-specific scent is governed by melatonin, we implanted long-photoperiod male and female scent donors with a Silastic implant containing a 10-mm active length of melatonin, a 20-mm active length of melatonin, or no melatonin. The first experiment shows that 8 weeks of melatonin treatment is sufficient to induce long-photoperiod voles to produce scents that are no longer attractive to the opposite sex. The second experiment shows that a similar time course of melatonin treatment was sufficient to induce long-photoperiod females treated with melatonin to produce scents that are attractive to short-photoperiod females. Melatonin implants lowered the gonadal hormone titers and reduced the weight of the gonads of treated long-photoperiod voles to titers and weights that are characteristic of short-photoperiod voles. In both experiments, the behavioral and physiological effects were independent of whether scent donors received 10- or 20-mm implants of melatonin. Together, the results of the two experiments reveal that melatonin mediates the photoperiodically induced changes in gonadal hormone titers that control the seasonal differences in the sexual attractiveness of the anogenital area scent produced by meadow voles.     

Circadian rhythms in cultured mammalian retina

Many retinal functions are circadian, but in most instances the location of the clock that drives the rhythm is not known. Cultured neural retinas of the golden hamster (Mesocricetus auratus) exhibited circadian rhythms of melatonin synthesis for at least 5 days at 27 degrees celsius. The rhythms were entrained by light cycles applied in vitro and were free-running in constant darkness. Retinas from hamsters homozygous for the circadian mutation tau, which shortens the free-running period of the circadian activity rhythm by 4 hours, showed a shortened free-running period of melatonin synthesis. The mammalian retina contains a genetically programmed circadian oscillator that regulates its synthesis of melatonin.     

Olfactory bulbectomy impedes social but not photic reentrainment of circadian rhythms in female Octodon degus

Recent studies demonstrated that nonphotic (social) cues markedly accelerate reentrainment to large phase shifts of the light-dark (LD) cycles in female Octodon degus and that such changes are likely effected by chemosensory stimuli. This experiment investigated the effects of olfactory bulbectomies on (1) socially facilitated reentrainment rates of circadian rhythms following a 6-h phase advance of the LD cycle, (2) photic reentrainment rates of circadian rhythms following a 6-h advance of the LD cycle, (3) photic entrainment, and (4) the circadian period (tau) of activity rhythms in constant darkness (DD). olfactory bulbectomies (BX) blocked socially facilitated reentrainment rates but did not alter reentrainment rates of circadian rhythms to photic cues alone. In addition, BX lowered mean daily locomotor activity levels and decreased the amplitude of the activity rhythm in degus housed in entrained (LD 12:12) conditions but did not alter the phase of activity onset or offset, duration (alpha) of activity, or mean daily core body temperature. Bulbectomies also failed to modify tau of free-running activity rhythms. This experiment confirms that the olfactory bulbs and chemosensory cues are necessary for socially facilitated reentrainment. In contrast to their effects in nocturnal rodents, BX do not produce significant circadian photic changes in diurnal degus. This is the first experiment to determine that chemosensory stimuli modulate the circadian system in a diurnal rodent.     

Photoaffinity labeling of DNA polymerase from Thermus thermophilus and DNA template by photoreactive analogs of dCTP

The aim of this study was to evaluate the influence of nicotine on the daily rhythms of heart rate, body temperature and locomotor activity in unrestrained rats by use of implanted radiotelemetry transmitters. The study was divided into three seven-day periods: a control period, a treatment period and a recovery period. The control period was used for baseline measurement of heart rate, body temperature and locomotor activity. During the treatment period three rats received nicotine (1 mg kg(-1), s.c.) at 0900 h. Three rats received saline under the same experimental conditions. Heart rate, body temperature and locomotor activity were continuously monitored and plotted every 10 min. During the three periods a power spectrum analysis was used to determine the dominant period of rhythmicity. If daily rhythms of heart rate, body temperature and locomotor activity were detected, the characteristics of these rhythms, i.e. the mesors, amplitudes and acrophases, were determined by cosinor analysis, expressed as means +/- s.e.m. and compared by analysis of variance. Nicotine did not suppress daily rhythmicity but induced decreases of amplitudes and phase-advances of acrophases for heart rate, body temperature and locomotor activity. These perturbations might result from the effects of nicotine on the suprachiasmatic nucleus, the hypothalamic clock that co-ordinates biological rhythms.     

PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A

Our previous study has shown that the phases of circadian rhythms of ocular melatonin and dopamine are always opposite and intraocular melatonin injection suppresses dopamine release. Therefore, it is possible that dopamine rhythms result from inhibitory action of melatonin. We have examined this possibility in the following experiments. In the first experiment effects of continuous light on melatonin and dopamine release were examined. The data indicated that continuous light exposure resulted in loss of circadian rhythmicity of melatonin and dopamine by suppressing melatonin and enhancing dopamine levels throughout the day. To further examine the effects of light in the second experiment, 2 h light pulse was applied during the night, then temporal changes of melatonin and dopamine release were studied. The light pulse rapidly suppressed melatonin release, whereas it rapidly increased dopamine release. These changes occurred within 30 min in both melatonin and dopamine. However, the recovery after the cessation of the light stimulus was slower in melatonin than dopamine. In the third experiment it was tested if dopamine release was increased by lowering melatonin release with an intraocular injection of the D2 agonist, quinpirol. Although quinpirol strongly inhibited melatonin release independently of the time of injection, dopamine did not always increase by the inhibition of melatonin. These results indicate that ocular dopamine rhythms are not simply produced by melatonin inhibitory action.     

Cell adhesion molecules in vasculitis

Daytime sleepiness is a common complaint in blind subjects. Abnormally timed melatonin has been invoked as a possible cause of both daytime sleepiness and nighttime awakening. In free-running blind individuals, there is an opportunity to assess the relationship between endogenous melatonin rhythms and subjective sleepiness and naps. The aim of this study was to characterize melatonin rhythms and simultaneously to evaluate subjective napping. A total of 15 subjects with no conscious light perception (NPL) were studied for 1 month. Prior to the study, sleep disorders were assessed using the Pittsburgh Sleep Quality Index. Cosinor and regression analysis revealed that 9 of the 15 NPL subjects had free-running 6-sulphatoxymelatonin (aMT6s) rhythms (period [tau] range = 24.34 to 24.79 h), 3 were entrained with an abnormal phase, and 3 were normally entrained. Most of the subjects (13 of 15) had daytime naps; the 2 individuals who did not made conscious efforts not to do so. Subjects with abnormal aMT6s rhythms had more naps of a longer duration than did those with normal rhythms. Free-running nap rhythms occurred only in subjects with free-running aMT6s rhythms. The 2 abnormally entrained subjects who napped did so at times that coincided with high levels of aMT6s (mean aMT6s acrophase [phi] +/- SD = 14.30 +/- 1.08 h, 20.30 +/- 0.62 h; mean nap time +/- SD = 14.01 +/- 3.60 h, 18.23 +/- 3.20 h, respectively). Regardless of aMT6s rhythm abnormality, significantly more naps occurred with a 4-h period before and after the estimated aMT6s acrophase. In 4 free-running subjects, aMT6s acrophase (phi) passed through an entire 24-h period. When aMT6s was in a normal phase position (24:00 to 06:00 h), night-sleep duration tended to increase with a significant reduction in the number and duration of naps. Sleep onset and offset times tended to advance and delay as the aMT6s rhythms advanced and delayed. Our results show a striking relationship between the timing of daytime production of melatonin and the timing of daytime naps. This suggests that abnormally timed endogenous melatonin may induce sleepiness in blind subjects.     

Broad, but not universal, transcriptional requirement for yTAFII17, a histone H3-like TAFII present in TFIID and SAGA

1. In 2 experiments with Single Comb White Leghorn hens, the effects of different light:dark cycles (LD-cycles) upon oviposition patterns and plasma melatonin rhythms were studied. In experiment 1, a 28-h ahemeral LD-cycle (12L:16D) was used. In experiment 2, a normal 24-h LD-cycle (16L:8D) was applied and the effects of a sudden 8-h forward or backward shift of the 8-h dark period (that is phase-advanced or phase-delayed LD-cycle) were studied. 2. The oviposition patterns as well as the plasma melatonin rhythms were fully synchronised with both LD-cycles (24-h or 28-h). The 2 rhythms were gradually re-synchronised after phase shifts, and the melatonin response phase-led the oviposition response by 2 cycles. Thus, the change of the melatonin rhythm coincided with the change of the (presumed) open period for LH-release. 3. In the unchanged 24-h LD-cycle, ovipositions occurred almost exclusively (98.9%) during light hours, whereas in the 28-h LD-cycle, ovipositions occurred primarily (84.5%) during the last 9 h of the dark period. 4. In both LD-cycles and after changes of the LD-cycle, light always suppressed plasma melatonin, regardless of previous light history. During dark periods, concentrations were elevated but, interestingly, only if darkness had also been experienced during the same time period 24 h earlier. This indicates that light has a direct inhibiting effect upon pineal melatonin release, while actual melatonin release during darkness is controlled by an endogenous clock.     

Regulation mechanism of melatonin rhythm in the pineal gland by light: experimental studies by in vivo microdialysis

Light has dual effects on the pineal melatonin; one is the entrainment of the circadian rhythm and the other is suppression of the melatonin synthesis. It is not known whether the entraining and suppressing effects of light are mediated by the same pathway or not. To elucidate the mechanism of the dual effects of light, (1) the sensitivity of the retina, (2) effects of acetylcholine agonist and, (3) the arrhythmicity induced by longterm continuous light, were studied by measuring melatonin continuously from a single rat by means of in vivo microdialysis. Pineal melatonin was suppressed by light more strongly at the late dark phase than at midnight, and by green light (520nm) than by red light (660nm). Pineal melatonin measured by microdialysis was decreased rapidly by a short light exposure and the melatonin rhythm was shifted on the following days. Microinjection of cholinergic agonist, carbachol, into the suprachiasmatic nucleus neither suppressed nor entrained the pineal melatonin rhythm. Immediately after the blinding, rats showed the circadian rhythm in pineal melatonin which had been abolished under long-term continuous light. While, it took several days for the locomotor rhythm to reappear. It is concluded that, (1) suppression of the pineal melatonin by light depends on the circadian phase and on the wavelength of light, (2) the threshold for light suppression is lower than that for phase-shift, (3) the melatonin rhythm starts to phase-shift on the following day of light pulse. (4) Acetylcholine is unlikely to be involved in the photic transmission both to the circadian clock and to the pineal, (5) arrhythmicity induced by long-term continuous light seems to be due to masking for the melatonin rhythm, and to uncoupling from the clock for the locomotor rhythm.     

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.     

Failure of heparin to inhibit the expression of the thrombin receptor following endothelial injury of the rabbit carotid artery

Rhythms of daily activity are found in all vertebrate species, some of them being diurnal (like humans, dogs, pigeons), others--nocturnal (like mice, rats and bats). Some species undergo very pronounced seasonal changes, as they hibernate in the winter or mate only at the specific seasons. The main regulator (a clock and a calendar) for daily and seasonal rhythms is the periodicity of the external light-darkness, reflected by the periodicity of melatonin secretion from the pineal gland, which is inhibited by light and induced during the darkness. In contrast to melatonin which peaks during the night both in diurnal and noctural species, the cyclicity of other hormones and several immune parameters correlates with the pattern of the animal locomotor activity-resting. The immune parameter that peaks at one time of day for a diurnal species peaks about 12 h later for a nocturnal one. Various immune parameters peak at various time points, anticipating an encounter with pathogens during the period of activity while energetically expensive resolution of the immune response during the resting. Daily and seasonal cyclicity of the immune functions are temporally integrated with other physiologic and behavioral processes and all of them are regulated and coordinated with daily and seasonal changes of an external environment by the neuroendocrine homeostatic system.     

Amplified amplitudes of circadian rhythms and nighttime hypotension in patients with chronic fatigue syndrome: improvement by inopamil but not by melatonin

Fatigue is an important symptom of a disturbed circadian rhythm. To date, no studies of circadian rhythms in patients with chronic fatigue syndrome (CFS) have been published. The objectives of the study were to study rhythms of heart rate and systolic and diastolic blood pressure in patients with chronic fatigue syndrome compared with age-matched normotensive controls and to study the effects of melatonin and inopamil on such rhythms. Ambulatory blood pressure (ABP) measurements (Space Lab, Inc, validated) of 18 patients with CFS were made according to the 1987 U.S. Center for Disease Control Criteria, and measurements of 12 age-matched normotensive controls were used in a cosinor analysis of the two groups. The effects of melatonin and inopamil on ABP were studied subsequently in four patients in an 8-week open-label evaluation. One patient was hypertensive (diastolic blood pressure > 90 mm Hg at least once every 4 hours), and was, therefore, excluded. The data of the remaining 17 patients (15 women, 2 men) revealed a significant 12-hour rhythm in heart rate and 24-hour rhythm in systolic and diastolic blood pressure with 95% confidence intervals not significantly different from sinusoidal patterns. Although these rhythms were synchronous with the control group rhythms, their amplitudes were not and showed, respectively, 2.8, 2.8, and 9.0 times the size of the control group rhythms (p < 0.001, p < 0.001, and p < 0.0001, respectively). Systolic blood pressures in the patients with CFS were consistently below 100 mm Hg during the nighttime. In a subsequent pilot study of four patients from the study population treated with melatonin 4 mg daily and inopamil 200 mg daily for 4 weeks, inopamil reduced nighttime hypotension (p < 0.05), whereas melatonin increased nighttime hypotension (p < 0.02). Patients with CFS have increased amplitudes of circadian rhythms and systolic blood pressures consistently below 100 mm Hg during the nighttime. Positive inotropic compounds may be beneficial in such patients, but melatonin may not be.     

Differences in tryptophan binding to hepatic nuclei of NZBWF1 and Swiss mice: insight into mechanism of tryptophan''s effects

Catecholamine receptors of multiple classes have been shown to influence pineal melatonin synthesis in a species-specific manner. In these experiments, the effects of catecholamine receptor agonists on circadian melatonin rhythms of zebrafish (Danio rerio) pineal in vitro were examined. Cyclic application of adrenergic receptor agonists (norepinephrine, phenylephrine, clonidine, and isoproterenol) had no effect on zebrafish pineal melatonin release, nor on the circadian oscillator that regulates melatonin rhythms. Pineal melatonin release was partially suppressed by quinpirole, a D2 dopamine receptor agonist, but cyclic application of quinpirole did not reset the pineal circadian oscillator. Pineal melatonin release was unaffected by either dopamine or SKF38393, a D1 receptor agonist, suggesting that the effects of quinpirole were not mediated by dopamine receptors. The regulatory mechanisms underlying pineal melatonin rhythms appear to differ among teleosts.     

Group interviewing for the purpose of selection

Relation between retinal melatonin and corneal mitotic rhythms in the Japanese quail was investigated in experiments manipulating the ocular physiology by treatments with formoguanamine hydrochloride (FG) and eye-lid suture. In experiment 1, we investigated the effects of FG, which is known to induce photoreceptor degeneration, on retinal melatonin and corneal mitotic rhythms. FG-treatment completely abolished the retinal melatonin rhythms in both LD 12:12 and constant darkness (DD), but the corneal mitotic rhythm was maintained with high mitotic rate in darkness under a LD cycle and subjective night under DD. The result suggests that 1) the photoreceptor cells in the retina are the site for melatonin production and/or for the oscillator which drives the circadian rhythm in retinal melatonin, and 2) melatonin is not involved in generation of the corneal mitotic rhythm. In experiment 2, we investigated the effects of eye-lid suture, which is known to induce eye enlargement and bulgy cornea, on the retinal melatonin and corneal mitotic rhythms. Eye-lid suture abolished the corneal mitotic rhythm in both LD and DD, with a high mitotic rate being maintained throughout 24 hr. But retinal melatonin maintained its rhythm with high levels in darkness under a LD cycle and in subjective night under DD. The result suggests that 1) bulgy cornea in the sutured eye was induced by the increase in mitotic rate in the light period, and 2) disappearance of the corneal mitotic rhythm does not have a relation to retinal melatonin. These results suggest that retinal melatonin is not involved in generation of the corneal mitotic rhythm and that there are two circadian clock systems in the eye.     

Influence of arousal, previous experience, and age on surgery preparation of same day of surgery and in-hospital pediatric patients.

Two pediatric surgery populations (aged 4–17 yrs) were studied to determine differences in retention of preparatory information as influenced by time of preparation, arousal levels, previous surgery experience, and age. Ss were divided into those having same-day surgery (12 experimentals and 12 controls) and those remaining in the hospital after surgery (21 experimentals and 21 controls). Experimental Ss were individually prepared with a 10-min hospital-relevant film, while controls viewed a 10-min non-hospital-relevant film. Findings show that experimentals retained more hospital-relevant information following preparation than controls. Older Ss retained more information than younger ones regardless of population. Physiological arousal differences were noted with those in-hospital patients who viewed the relevant experimental film, showing significantly greater decreases in sweating than Ss viewing the film on the same day as surgery. It is suggested that the film may have had a greater impact given the context in which Ss found themselves. The nonrelevant control film served as a distraction for those having surgery immediately on admission, as reflected by a reduction of their hospital fears. Ss with previous surgical experience who were exposed to the relevant film showed significantly greater increases in sweating than those without previous experience regardless of time of film preparation. Consequently, the relevant film may have had a sensitizing effect on Ss previously exposed to surgery. (11 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)