Biomedical subjects

M Menaker

Publications and source records attributed to M Menaker.

At least 37 records · Page 2Linked to original sources

PubMed1994

Light-induced phase shifts in tau mutant hamsters.

Phase shifts produced by single 1-hr light pulses were compared in homozygous tau mutant and wild-type hamsters after several different kinds of pretreatment regimens. There was a dramatic increase in the magnitude of phase delays in the mutant hamsters as they were kept for progressively longer times in constant darkness (DD), and a smaller increase in the magnitude of phase advances. Under the same conditions a small increase in the magnitude of phase delays and no significant increase in phase advances occurred in the wild-type hamsters. After only 7 days in DD the phase response curves (PRCs) of mutant and wild-type hamsters were both type 1 and were indistinguishable from each other, whereas after 49 days in DD the PRCs of mutant hamsters had become type O. Mutant hamsters were entrained to eight different T-cycles (1 hr of light per cycle), released into DD, and given a phase delaying light pulse 7 days later. T-cycles which entrained the animals so that the 1 hr of light fell between 6 and 9 hours after the onset of activity suppressed the amplitude of phase delays, whereas T-cycles which entrained the animals so that the 1 hr of light fell at other times did not suppress phase delays. The implications of the data for entrainment theory and the mechanism of action of the tau gene are discussed.

Animals↗

PubMed1994

Ultradian endocrine rhythms are altered by a circadian mutation in the Syrian hamster.

A single gene defect of the circadian clock (tau mutation) has recently been described that results in a shortening of the circadian activity cycle of the Syrian hamster. In the homozygous animal, free running activity is shortened by 4 h, resulting in a circadian period of approximately 20 h. Here, we examine the effect of the tau mutation on noncircadian oscillators by comparing the frequency of episodic secretion of LH and cortisol in normal period wild-type (approximately 24-h circadian rhythm) and tau mutant (approximately 20-h circadian rhythm) castrate females. Animals were ovariectomized at 14 weeks of age and maintained thereafter under conditions of constant illumination. Wheel-running records were obtained, and only those animals exhibiting clear single bouts of circadian activity were used in the experiment. Two days after intraatrial cannulation, blood samples were collected for a 5-h period every 5 min during the subjective day at the same relative phase of the circadian cycle. Deconvolution analysis revealed that LH pulse frequency was significantly reduced in the tau mutant females (33.3 +/- 2.25- and 28.7 +/- 2.0-min interpulse intervals for tau and normal period females, respectively). Cortisol pulse frequency also exhibited significant differences, with a reduced pulse frequency (32.8 +/- 3.6- and 27.8 +/- 1.4-min interpulse intervals for tau and wild-type females, respectively). There were no significant differences with respect to secretory pulse amplitude, hormone half-life or estimated burst amplitude, or mass of hormone secreted per burst for either hormone. We conclude that a genetic defect that affects the circadian clock located in the suprachiasmatic nucleus may have a more general effect on neural oscillators, including those controlling episodic hormone secretion.

Activity Cycles↗

PubMed1993

Photic induction of Fos in the hamster suprachiasmatic nucleus is inhibited by baclofen but not by diazepam or bicucullin.

The present study makes use of the photic induction of Fos in the suprachiasmatic nucleus (SCN) to explore the pharmacology of retinal input to this circadian pacemaker. Our results demonstrate that the GABAA antagonist bicuculline and the benzodiazepine agonist diazepam, both of which prevent light-induced phase shifts, do not inhibit photic induction of Fos expression in the hamster SCN. In contrast, the GABAB agonist, baclofen, prevents both light-induced phase shifts and inhibits photic induction of Fos expression in the SCN. One explanation of this difference may be that baclofen acts to prevent photic information from reaching the SCN while bicuculline and diazepam act within the SCN at a point 'downstream' from Fos induction.

Animals↗

PubMed1993

Effects of imipramine on circadian rhythms in the golden hamster.

The effects of the antidepressant imipramine on circadian organization were studied in wild-type and tau-mutant golden hamsters. Chronic imipramine treatment in doses ranging from 0-50 mg kg-1.day-1 depressed general activity and body temperature and caused a reduction in body weight but had no significant effect on circadian organization. Imipramine treatment did not affect the rate of reentrainment after a 6-h advance in the light-dark cycle, did not alter the advanced-phase angle of entrainment of tau-mutant hamsters, did not affect the free-running period of wild type hamsters, and did not alter the phase-response curve to light pulses. Because imipramine, a clinically effective antidepressant, did not have any measurable effect on the circadian system in these experiments, our results do not provide support for the hypothesis that the antidepressant action of imipramine is mediated by alterations in the circadian system.

Animals↗

PubMed1993

Independence of heart rate and circadian period in the golden hamster.

Cardiac contractions are under the influence of at least two processes of biological timing, one responsible for the mean level of heart rate (oscillations with a frequency of up to several hundred per minute) and another responsible for the circadian rhythm of heart rate (oscillations with a frequency of one per 24 h). To investigate whether the mean level of heart rate is proportional to the frequency of circadian oscillation, we compared the heart rates of normal golden hamsters (circadian period approximately 24 h) and tau-mutant hamsters (circadian period approximately 20 h). Neither in anesthetized preparations nor in freely moving animals was there a difference in heart rate between the two groups despite the 20% difference in circadian period. Thus the mean level of heart rate seems to be independent of the circadian period. It is likely that the tau gene, which affects the frequency of the circadian pacemaker, has no effect on the intrinsic frequency of the cardiac pacemaker. In vitro studies of isolated hearts or myocardial cell cultures are necessary to confirm this inference.

Animals↗

PubMed1993

Light-induced phase shifts and Fos expression in the hamster circadian system: the effects of anesthetics.

In the present study, we examined the effect of administration of anesthetics on light-induced phase shifts of the circadian system. This information is of critical importance, because many studies of light input to the mammalian suprachiasmatic nucleus (SCN) have been performed on anesthetized animals. We found that light-induced phase shifts were blocked by all drugs used at anesthetic doses. We then determined the effect of two of these agents on light induction of Fos-like immunoreactivity in the SCN. We found that the administration of sodium pentobarbital prevented light induction of Fos expression in the SCN, whereas the administration of urethane did not. These results raise cautions about the use of anesthetized animals to answer questions about the photic regulation of neuronal activity in the SCN.

Animals↗

PubMed1993

Circadian and daily rhythms of melatonin in the blood and pineal gland of free-running and entrained Syrian hamsters.

The aim of this study was to develop a radioimmunoassay for the measurement of endogenous circulating melatonin concentrations in the Syrian hamster, and then to determine the effect of various photic manipulations upon this endocrine signal. In experiment 1, pineal-intact or pinealectomized adult male Syrian hamsters, housed under a long photoperiod (LD; 16 h light:8 h darkness) for 2 weeks, were then either maintained on LD or transferred to a short photoperiod (SD; 8 h light:16 h darkness) for a further 8 weeks. The profile of serum melatonin concentrations was determined from blood samples taken by cardiac puncture at intervals over a 24-h period. Radioimmunoassay revealed that daytime concentrations were at or below the limit of sensitivity of the assay (< or = 50 pmol/l). Under both photoperiods, the concentration of melatonin in the serum of pineal-intact animals rose 4-5 h after the onset of darkness, and the peak amplitude of the melatonin rhythm was not significantly different between the SD- or LD-housed animals (200-250 pmol/l). Premature exposure of animals to light during the dark phase of LD caused a precipitous decline in circulating concentrations to daytime values within 15 min and they remained there for several hours. In animals which experienced an uninterrupted night on either LD or SD, the most striking difference in the rhythm of endogenous melatonin secretion was the duration. Animals housed under LD had high levels until the start of the light period, a peak duration of 3.7 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Phase-shifting mechanisms in the mammalian circadian system: new light on the carbachol paradox.

A variety of evidence now suggests that excitatory amino acid receptors mediate the effects of light on the circadian system of mammals. However, the ACh agonist carbachol is the only agent that has been reported to "mimic" the phase-shifting effects of light in vivo. Because the other published evidence for the involvement of ACh in light-mediated phase shifts is weak, we have referred to this situation as "the carbachol paradox." In the present study, we found that the administration of NMDA receptor antagonists could prevent carbachol-induced phase shifts of the circadian rhythm of wheel-running activity recorded from the hamster. In addition, we found that carbachol-induced phase shifts, unlike those produced by light, are not accompanied by induction of Fos-like immunoreactivity in the suprachiasmatic nucleus (SCN). Our data are simply explained by the assumption that the intraventricular administration of carbachol causes phase shifts through a pathway distinct from that of light. Alternatively, if carbachol is acting via the light input pathway, then it must do so by a mechanism independent of Fos induction in the SCN. In either case, elucidating the mechanisms by which carbachol acts in the circadian system may provide novel insights into the cellular events by which phase shifts are generated.

Animals↗

PubMed1993

Mutant circadian period as a marker of suprachiasmatic nucleus function.

Fetal suprachiasmatic nucleus (SCN) tissue transplanted into the third ventricle of hamsters bearing complete SCN lesions restores the circadian locomotor rhythm with a period that depends exclusively on the genetically determined period of the tissue donor. If the host is only partially lesioned and thus retains rhythmicity with its own genetically determined period, an implant from an animal of a different genotype can induce a second rhythm with a period determined by the donor genotype. Both rhythms can be present simultaneously in the record of such a "temporal chimera," interacting only superficially (i.e., not at the level of the pacemaker). Our data support the interpretation that under such circumstances the graft is able to capture part of the locomotor output of the circadian system, but does not make functional connections with the host SCN pacemaking system.

Animals↗

PubMed1992

Body temperature rhythm of the tree shrew, Tupaia belangeri.

The circadian rhythm of body temperature of the tree shrew Tupaia belangeri was studied by telemetry. The amplitude of the daily (or circadian) variation was found to be much larger than that of most endotherms (amplitude approximately 5 degrees C) and the bimodal shape of the rhythm differed from the cosine waveform that characterizes the temperature rhythms of most other species. In free-running conditions, as well as in the entrained state, the temperature rhythm remained synchronized to the rhythm of locomotor activity.

Animals↗

PubMed1992

Regulation of melatonin production by light, darkness, and temperature in the trout pineal.

The pineal gland of the rainbow trout, Salmo gairdneri, when kept under in vitro perifusion culture conditions, displays a consistently elevated level of melatonin production in darkness (Gern and Greenhouse 1988). Upon light exposure melatonin production falls and stabilizes at a new lower level that is dependent upon the irradiance of the stimulus. To achieve the maximal response for each irradiance, the duration of the stimulus must exceed 30 min. The response amplitude is maximally sensitive to photons presented over durations of 30-45 min; is very insensitive to shorter light exposures; and is maintained with no evidence of adaptation over longer exposures. Temperature plays a role in regulation of melatonin production both in darkness and during light exposure; increased temperature increases melatonin production in darkness and also increases the sensitivity of the response to light. The action spectrum for the response is best fit by the Dartnall nomogram for a vitamin A1 based rhodopsin with peak sensitivity near 500 nm. The possible adaptive significance of control of melatonin synthesis by light and temperature is considered.

Animals↗

PubMed1992

Social stimuli fail to act as entraining agents of circadian rhythms in the golden hamster.

The ability of social stimuli to act as entraining agents of circadian rhythms was investigated in golden hamsters (Mesocricetus auratus). In a first experiment, pairs of male hamsters (one of them enucleated and the other intact) were maintained under a ligh-dark (LD) cycle with a period of 23.3 h. Running-wheel activity was recorded to determine the effect of social interaction on the free-running circadian rhythm of activity. In several pairs, general activity and body temperature were also recorded. In all pairs the intact animals entrained to the LD cycle, whereas the activity rhythms of the enucleated animals free-ran with periods of approximately 24 h and showed no apparent sign of synchronization or relative coordination with the other member of the pair. In a second experiment, male hamsters maintained in constant darkness received pulses of social interaction, which have been reported to induce phase shifts of the activity rhythm. Consistent phase shifts in the running-wheel activity rhythm were not induced by the social pulses in our experiment. These results suggest strongly that social stimuli are not effective entraining agents of circadian rhythms in the golden hamster.

Animals↗

PubMed1992

Effects of physiological cycles of infused melatonin on circadian rhythmicity in pigeons.

The role of the hormone melatonin in the circadian system of pigeons (Columba livia) was investigated. Using an automatic infusion system, melatonin at physiological levels was delivered for 10 h each day to cannulated, pinealectomized (P-X) pigeons in constant darkness. These cyclic infusions of melatonin entrained feeding rhythms in P-X pigeons while vehicle infusions were ineffective entraining agents. When the retinae of P-X pigeons were removed (E-X), feeding rhythms were abolished in constant darkness. When cyclic melatonin infusions were delivered to these birds (E-X and P-X), feeding rhythmicity was restored whereas vehicle infusions alone did not restore rhythmicity. When melatonin infusions were terminated in E-X/P-X pigeons, feeding rhythms persisted for several days but eventually decayed. Blood melatonin levels were measured in both P-X and E-X/P-X birds infused cyclically with exogenous melatonin and were found to be within the physiological range both in level and pattern. These results strongly suggest that endogenous melatonin, released by the pineal gland and the retinae, regulates the timing of feeding rhythms by entraining other oscillators in the circadian system of the pigeon.

Animals↗

PubMed1992

The circadian rhythm of body temperature.

This paper reviews the literature on the circadian rhythm of body temperature (CRT). The review starts with a brief discussion of methodological procedures followed by the description of known patterns of oscillation in body temperature, including ultradian and infradian rhythms. Special sections are devoted to issues of species differences, development and aging, and the relationships between the CRT and the circadian rhythm of locomotor activity, between the CRT and the thermoregulatory system, and between the CRT and states of disease. A section on the nervous control of the CRT is followed by summary and conclusions.

Animals↗

PubMed1992

Evidence for separate control of estrous and circadian periodicity in the golden hamster.

To study the relationship between estrous and circadian periodicity, we investigated the period of the estrous cycle in two types of female golden hamsters: normals (circadian period approximately 24 h) and tau mutants (circadian period approximately 20 h). Records of running wheel activity, general locomotor activity, body temperature, vaginal secretion, and sexual receptivity of hamsters kept under constant lighting conditions indicated an estrous period of approximately 96 h for both groups of animals. The fact that animals with different circadian periods have the same estrous period suggests the existence of separate mechanisms in the control of circadian and estrous periodicity. Circadian periodicity is determined by a pacemaker located in the suprachiasmatic nuclei, whereas estrous periodicity is determined by positive and negative feedback loops involving the hypothalamus, pituitary, and gonads. Coupling of the two mechanisms takes place under at least some conditions, but additional research is necessary to elucidate the mechanisms by which this is accomplished.

Animals↗

PubMed1992

Protein differences in tau mutant hamsters: candidate clock proteins.

In the tau mutant hamster, the period of the circadian rhythm is shortened from about 24 h to about 22 h in heterozygotes and to about 20 h in homozygotes. Understanding the biochemical basis of the period changes in the tau mutant may elucidate the regulation of the vertebrate pacemaker. Using two-dimensional gel electrophoresis, we have found two sets of proteins that differ between the different genotypes. P33tau (about 33 kDa; pI 6.5) was found in all gels from wild type and heterozygous animals, but was absent in gels from all except one of the homozygous mutant animals. P32tau (about 32 kDa; pI 4.8) was a chain of spots, which showed a striking difference in pattern between gels from wild type animals and from mutant animals. P33tau was greatly enriched in soluble cellular fractions, whereas P32tau was found only in insoluble fractions. These differences between P33tau and P32tau were apparent in gels from both SCN and cortical tissue, suggesting that both proteins are distributed throughout the brain. These proteins should be useful as new tools to explore the biochemistry of circadian pacemakers.

Animals↗

PubMed1992

Nonphotic phase shifting in hamster clock mutants.

Golden hamsters with the tau mutation were kept in the dark and induced to become active through confinement to a novel running wheel for 3 hr. The response of the mutants to this nonphotic phase-shifting stimulus differed from that of wild-type hamsters. The mutants showed larger phase shifts, and their phase response curves differed in shape, with an advance portion at about circadian time 24, a phase at which wild types show delays. The results establish that the tau mutation, in addition to its already known effects, alters the response of the circadian system to nonphotic events.

Animals↗

PubMed1992

NMDA as well as non-NMDA receptor antagonists can prevent the phase-shifting effects of light on the circadian system of the golden hamster.

The present experiments were designed to evaluate whether the intraventricular administration of excitatory amino acid (EAA) receptor antagonists would prevent light-induced phase shifts of the circadian rhythm of wheel-running activity in the hamster. Administration of the non-N-methyl-D-aspartate (non-NMDA) antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) blocked light-induced phase advances and delays. Similarly, administration of the competitive NMDA receptor antagonist, 3(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP), prevented light-induced phase advances and delays. Neither drug by itself caused any consistent effect on the phase of the rhythm. These data provide further evidence that EAA receptors mediate the effects of light on the circadian system, and suggest that both NMDA and non-NMDA receptor types may be involved.

Animals↗