Biomedical subjects

M Menaker

Publications and source records attributed to M Menaker.

At least 55 records · Page 3Linked to original sources

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↗

PubMed1992

Circadian feeding and locomotor rhythms in pigeons and house sparrows.

Feeding and locomotor activities were measured simultaneously in homing pigeons (Columba livia) and house sparrows (Passer domesticus). Feeding, as well as locomotor activity, was found to be regulated by a circadian clock in both of these species. Implantation of melatonin-filled capsules or exposure to constant light abolished feeding and locomotor rhythms in both species. Removal of the pineal gland from pigeons did not abolish either rhythm, whereas pinealectomy abolished both feeding and locomotor rhythms in house sparrows. Although feeding rhythms were generally more robust than locomotor rhythms in both of these species, different feeding and locomotor free-running periods were not observed within any individual pigeon or house sparrow. These results are consistent with the hypothesis that each of these species has a single pacemaker that regulates the timing of feeding and locomotor activity, but they do not rule out the possibility that separate clocks regulate these behaviors.

Animals↗

PubMed1992

Temporal chimeras produced by hypothalamic transplants.

The expression of locomotor activity by golden hamsters is temporally controlled by circadian oscillators contained within the suprachiasmatic nuclei. A genetic mutation has been found that alters the freerunning period of the locomotor activity rhythm from the wild-type value of approximately 24 to approximately 20 hr in homozygous mutants. It has been shown previously that a transplant of fetal hypothalamic tissue containing the suprachiasmatic nuclei to a host rendered arrhythmic by a complete lesion of the suprachiasmatic nuclei restores rhythmicity with the freerunning period that is normally expressed by the donor genotype. We made partial lesions of the suprachiasmatic nuclei of wild-type hosts, which did not completely abolish their circadian rhythmicity, and then placed hypothalamic implants from homozygous mutant fetal donors into the lesion site. The resulting complex patterns of locomotor activity contain rhythmic components with periods of both host and donor circadian oscillators, and suggest the presence of both stimulatory and inhibitory inputs from the circadian system to the centers controlling locomotor behavior.

Animals↗

PubMed1991

NMDA receptor antagonists block the effects of light on circadian behavior in the mouse.

We report here the results of experiments designed to evaluate whether NMDA receptors mediate the phase shifting effects of light on the circadian rhythm of wheel-running activity in mice. Intraperitoneal administration of either the non-competitive NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine maleate (MK-801), or the competitive NMDA receptor antagonist, 3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) blocked light-induced phase advances and delays. Neither drug, by itself, caused any consistent effect on the phase of the rhythm. Furthermore, there was no significant difference between the effects of MK-801 on light-induced phase shifts in a retinally degenerate and retinally normal strain of C57 mouse. These data, coupled with previous findings, indicate that excitatory amino acid receptors play an important role in the transmission of light information from the retina to the circadian system.

Animals↗

PubMed1991

Circadian photoreception in the retinally degenerate mouse (rd/rd).

We have examined the effects of light on circadian locomotor rhythms in retinally degenerate mice (C57BL/6J mice homozygous for the rd allele: rd/rd). The sensitivity of circadian photoreception in these mice was determined by varying the irradiance of a 15 min light pulse (515 nm) given at circadian time 16 and measuring the magnitude of the phase shift of the locomotor rhythm. Experiments were performed on animals 80 days of age. Despite the loss of visual photoreceptors in the rd/rd retina, animals showed circadian responses to light that were indistinguishable from mice with normal retinas (rd/+ and +/+). While no photoreceptor outersegments were identified in the retina of rd/rd animals (80-100 days of age), we did identify a small number of perikarya that were immunoreactive for cone opsins, and even fewer cells that contained rod opsin. Using HPLC, we demonstrated the presence and photoisomerization of the rhodopsin chromophore 11-cis retinaldehyde. The rd/rd retinas contained about 2% of 11-cis retinaldehyde found in +/+ retinas. We have yet to determine whether the opsin immunoreactive perikarya or some other unidentified cell type mediate circadian light detection in the rd/rd retina.

Animals↗

PubMed1991

Excitatory amino acid receptors may mediate the effects of light on the reproductive system of the golden hamster.

Seasonal regulation of reproduction occurs in golden hamsters (Mesocricetus auratus) in response to changes in day length (photoperiod). We report here the results of experiments designed to evaluate whether excitatory amino acid neurotransmission is involved in mediating the effects of light on reproduction. We found that MK-801, a specific antagonist of the N-methyl-D-aspartate subclass of excitatory amino acid receptors, blocked the stimulatory action of short pulses of light on gonadal function in hamsters maintained in short days. Furthermore, MK-801 also inhibited the light-induced decline in pineal melatonin content. These findings suggest that excitatory amino acids may mediate the effects of light on the reproductive system.

Amino Acids↗

PubMed1990

Do NMDA receptors mediate the effects of light on circadian behavior?

We report here the results of experiments designed to evaluate whether a specific NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine maleate (MK-801), blocks the phase shifting effects of light on the circadian rhythm of wheel-running activity in golden hamsters. Intraperitoneal administration of (+)-MK-801 produced a dose-dependent blockade of both light-induced phase advances and delays. The effect was stereoselective and treatment with related compounds, phenylcyclidine and ketamine, also blocked light-induced phase shifts. MK-801, by itself, did not cause any consistent effect on the phase of the rhythm. These data, coupled with previous findings, indicate that excitatory amino acid receptors play an important role in the transmission of light information from the retina to the circadian system.

Animals↗

PubMed1990

Transplanted suprachiasmatic nucleus determines circadian period.

The pacemaker role of the suprachiasmatic nucleus in a mammalian circadian system was tested by neural transplantation by using a mutant strain of hamster that shows a short circadian period. Small neural grafts from the suprachiasmatic region restored circadian rhythms to arrhythmic animals whose own nucleus had been ablated. The restored rhythms always exhibited the period of the donor genotype regardless of the direction of the transplant or genotype of the host. The basic period of the overt circadian rhythm therefore is determined by cells of the suprachiasmatic region.

Animals↗

PubMed1990

Circadian locomotor rhythms in the desert iguana. I. The role of the eyes and the pineal.

The pineal and the eyes are known to be important components in the circadian system of some species of lizards; their effects may be mediated by the hormone melatonin. We examined the role played by these structures in the desert iguana (Dipsosaurus dorsalis). Surgical removal of the pineal had no effect on circadian locomotor rhythms, even though this procedure abolished the circadian rhythm of melatonin in the blood. Furthermore, when the isolated pineal of Dipsosaurus was studied in organ culture, it showed no circadian rhythm of melatonin secretion, as do pineals of some other lizard species, although it did produce large quantities of this hormone. Bilateral ocular enucleation had only small effects on the freerunning period of locomotor rhythms, without affecting melatonin levels in the blood. Behavioral circadian rhythms persisted in desert iguanas subjected to both enucleation and pinealectomy. These data suggest that neither the pineal nor the eyes are central components of the circadian pacemaking system in Dipsosaurus, nor is melatonin critically involved in maintaining its organization.

Animals↗

PubMed1990

Circadian locomotor rhythms in the desert iguana. II. Effects of electrolytic lesions to the hypothalamus.

Desert iguanas, Dipsosaurus dorsalis, displaying freerunning circadian locomotor rhythms in conditions of constant darkness and temperature received electrolytic lesions to the hypothalamus. The locomotor activity of those lizards (N = 9) which sustained 80% or more damage to the suprachiasmatic nucleus (SCN) became arrhythmic whereas all animals that sustained less than 35% damage to the SCN remained rhythmic, even though they sustained significant damage to nearby regions of the hypothalamus and preoptic area. These results suggest strongly that the SCN plays a role in the regulation of circadian rhythms in the desert iguana. Taken together with other evidence, they support the view that this structure is homologous to the mammalian SCN, which acts as a pacemaker in the circadian system.

Animals↗

PubMed1989

Responses of the suprachiasmatic nucleus to retinohypothalamic tract volleys in a slice preparation of the mouse hypothalamus.

The electrophysiological responses of the mouse suprachiasmatic nucleus (SCN) to stimulated synaptic input from the retinohypothalamic tract (RHT) were investigated using a hypothalamic slice preparation that includes the entire SCN, optic chiasm and optic nerves. Extracellular recordings of single-unit activity reveal a population of neurons in the ventrolateral SCN that are activated at a median latency of 10 ms after stimulation of the contralateral optic nerve. These neurons apparently receive direct excitatory input from RHT synapses. Other SCN neurons are activated at longer latencies, possibly through input from interneurons. The population field potentials evoked in the SCN by optic nerve volleys consist of a calcium-insensitive transient generated by optic tract axons in the chiasm, followed by calcium-sensitive waves generated by postsynaptic activity. The postsynaptic waves have the form of a field EPSP, negative in the dorsolateral SCN and positive in the ventrolateral SCN, upon which is superimposed a population spike of opposite polarity. The population spike occurs at the same latency as the monosynaptic single unit responses, which were all found near or ventral to the point of reversal of field potential. These findings suggest that neurons in the ventrolateral SCN are excited by synapses on dorsally extended dendrites. The conduction velocity of the RHT in the optic nerve was found to be 0.59 +/- 0.03 mm/ms, while that of the optic tract volley was 2.4 +/- 0.75 mm/ms. The low conduction velocity of the RHT indicates that, within the optic nerve, these axons are thin and/or unmyelinated in the optic nerve.

Action Potentials↗

PubMed1989

Effects of excitatory amino acid receptor antagonists and agonists on suprachiasmatic nucleus responses to retinohypothalamic tract volleys.

A slice preparation of the mouse hypothalamus that includes the suprachiasmatic nuclei (SCN), the optic chiasm and the optic nerves was used for pharmacologic investigations of the nature of the receptors mediating the excitation of SCN neurons by input from the retinohypothalamic tract (RHT). Bath application of cis-2,3-piperidinedicarboxylic acid, a non-selective antagonist of excitatory amino acid receptors, reversibly blocked the postsynaptic component of the field potentials evoked in the dorsolateral SCN by stimulation of the optic nerve. The selective antagonist of N-methyl-D-aspartate receptors, 2-amino-5-phosphonovaleric acid, had no effect on SCN responses. Glutamic acid diethyl ester and 2-amino-4-phosphonobutyric acid also were without effect, but gamma-D-glutamylglycine caused a small decrease in the amplitude of the postsynaptic wave. Addition of the agonists, kainate and N-methyl-D,L-aspartate, to the superfusate also blocked the postsynaptic response. Kainate was the most potent agonist. L-Glutamate was without effect at up to 100 microM. These results indicate that postsynaptic responses in the SCN to retinohypothalamic tract volleys are mediated by a non-NMDA class of excitatory amino acid receptors.

Animals↗

PubMed1989

GABA regulation of circadian responses to light. I. Involvement of GABAA-benzodiazepine and GABAB receptors.

Light-induced phase shifts of the circadian locomotor rhythm of hamsters can be blocked by agents that alter GABA neurotransmission. The GABA antagonist bicuculline blocks phase delays induced by light and the benzodiazepine diazepam, which can potentiate GABA activity, blocks light-induced phase advances. In the experiments reported here, we found that the bicuculline blockade of phase delays was reduced by agents that mimic or potentiate GABA activity. Conversely, the diazepam blockade of phase advances was reduced by both competitive and noncompetitive antagonists of GABA. This indicates that the GABA-benzodiazepine receptor-ionophore complex is the most likely site of action for the effects of these drugs on circadian rhythms. However, competitive GABA agonists did not mimic the blocking effects of benzodiazepines, nor did the antagonist picrotoxin mimic the blocking effect of bicuculline. Therefore, the classic action of GABA, increased chloride conductance, may not be the effector mechanism in this case. We also found that the GABAB agonist baclofen blocked both phase advances and delays and that the blockade of advances was reversed by the antagonist delta-aminovaleric acid. Taken together, these results indicate that GABA is involved in the regulation of circadian responses to light and that the regulation is mediated by both GABAA and GABAB receptors.

Amino Acids↗