Biomedical subjects

M Menaker

Publications and source records attributed to M Menaker.

At least 73 records · Page 4Linked to original sources

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↗

PubMed1988

A mutation of the circadian system in golden hamsters.

A mutation has been found that dramatically shortens the period of the circadian locomotor rhythm of golden hamsters. The pattern of inheritance of this mutation suggests that it occurred at a single, autosomal locus (tau). Wild-type animals have rhythms with free-running periods averaging about 24 hours; animals heterozygous for the mutation have periods of about 22 hours, whereas homozygous animals have rhythms with periods close to 20 hours. Animals that carry the mutant alleles exhibit abnormal entrainment to 24-hour light:dark cycles or are unable to entrain.

Activity Cycles↗

PubMed1988

Dose-response relationship between light irradiance and the suppression of plasma melatonin in human volunteers.

This study tested the capacity of different irradiances of monochromatic light to reduce plasma melatonin in normal humans. Six healthy male volunteers, 24-34 years old, were exposed to 0.01, 0.3, 1.6, 5, or 13 microW/cm2 of 509 nm monochromatic light for 1 h during the night on separate occasions. Light irradiance depressed plasma melatonin in a dose-response pattern. The data indicate that the mean threshold irradiance for suppressing melatonin is between 1.6 and 5 microW/cm2. Individual variations in threshold responses to monochromatic light were observed among the volunteers.

Adult↗

PubMed1987

Pineal indole metabolism in the mouse.

The activity of two pineal enzymes serotonin N-acetyltransferase (SNAT) and hydroxyindole-O-methyltransferase, (HIOMT) and the pineal content of serotonin (5-HT) and N-acetylserotonin (NAS) were measured in several strains of mice (Mus domesticus) in order to compare melatonin synthetic pathways among them. Of the strains we examined, C57BL/6J, AKR/J, BALB/c, NZB/BLNJ and wild mice, only wild mice synthesize pineal melatonin. Wild mice had high activity of both SNAT and HIOMT; NZB had SNAT activity but did not have HIOMT; the three other strains had neither SNAT nor HIOMT; the activity of SNAT in wild mice showed a clear daily rhythm but HIOMT activity did not show any significant daily changes. The pineal content of 5-HT in wild and NZB mice was higher during the day than during the night, however in C57BL and AKR, 5-HT levels were higher during the night than during the day. As expected NAS was found in wild and NZB mice.

Acetylserotonin O-Methyltransferase↗

PubMed1987

Kynurenic acid blocks suprachiasmatic nucleus responses to optic nerve stimulation.

An in vitro slice preparation of the mouse hypothalamus was used to determine the effects of pharmacological agents on the field potentials that are evoked in the suprachiasmatic nucleus (SCN) by stimulation of the optic nerve. Postsynaptic components of these responses were identified by lowering the concentration of calcium in the superfusate. Bath application of kynurenate, an antagonist of excitatory amino acid neurotransmission, reversibly blocked postsynaptic responses in the SCN. The evoked responses in the SCN were not affected by the acetylcholinergic agents (+)-tubocurarine, scopolamine, physostigmine, or carbachol. These results suggest that excitatory amino acid receptors mediate responses of SCN neurons to retinal input, but do not support a role for acetylcholine.

Animals↗

PubMed1987

Activity and reproductive state in the hamster: independent control by social stimuli and a circadian pacemaker.

Entrainment of circadian rhythms by social communication between male and female Syrian hamsters (Mesocricetus auratus) was tested by recording the wheel-running activity of pairs kept in the same cage but separated by a wire mesh barrier. Before pairing, males and females were synchronized to light/dark cycles that were 180 degrees out of phase, and at the time of pairing the hamsters were placed into constant darkness (DD). The activity rhythms of males and females housed in a cage alone (isolated) were also recorded. The freerunning periods of paired and isolated hamsters were not different over six weeks in DD, and no phase-shifts of the paired animals' rhythms were seen, indicating that the close proximity of a hamster of the opposite sex had no effect on the timing of the other's activity/rest rhythm. This was not due to a lack of communication between the paired males and females. Males showed four-day cycles in the amount and distribution of activity which corresponded to the estrous cycle of the female, and regression of the reproductive system which occurred in the isolated hamsters was delayed in both the paired males and females. Despite the fact that locomotor activity and reproduction are each regulated in part by a circadian pacemaker, social stimuli can affect both of these without influencing the circadian pacemaker that underlies the activity/rest rhythm.

Animals↗

PubMed1987

The intergeniculate leaflet partially mediates effects of light on circadian rhythms.

Photic signals affect circadian activity rhythms by both phasic and tonic mechanisms that modulate pacemaker phase and period. In mammals, the effects of light on circadian activity are mediated by the retina, which communicates with the suprahiasmatic nucleus (SCN) by two different anatomical routes: the retino-hypothalamic tract (RHT), originating in the retina, and the geniculo-hypothalamic tract (GHT), arising from a retino-recipient nucleus, the intergeniculate leaflet (IGL). We assessed the roles of these two afferent systems in mediating phasic and tonic effects of light on circadian activity in IGL-lesioned animals. Destruction of the IGL significantly affected phase shifts produced by brief light pulses (phasic effect) and modified the change in period (tau) of the free-running activity rhythm produced by changing the level of constant light (LL) (tonic effect). Phase advances produced by brief light pulses were decreased in amplitude while phase delays were increased in IGL-lesioned animals as compared to controls. The free-running period in constant dark (tau DD) of IGL-lesioned animals was greater than tau DD of controls, and the lengthening of tau normally produced by LL was not observed or was greatly reduced in IGL-lesioned animals. Entrainment to light-dark cycles was unaffected by the lesions, as were other aspects of the circadian activity rhythm that normally change in response to LL (e.g., activity-rest ratio, total activity, splitting). Our data support the interpretation that the IGL plays a significant role in relaying information regarding illumination intensity to the SCN.

Animals↗

PubMed1986

Dynamics of noradrenergic circadian input to the chicken pineal gland.

To analyze the dynamics of sympathetic input to the chicken pineal the concentrations of catecholamines, indoleamines and some of their metabolites were determined by high performance liquid chromatography with electrochemical detection (HPLC-EC) in the pineal glands of young chickens killed at different times of day. Rhythmic variations over 24 h were observed in tissue levels of dopamine (DA), 5-hydroxytryptamine (5-HT), N-acetylserotonin (NAS) and 5-hydroxyindoleacetic acid (5-HIAA), while norepinephrine (NE) concentrations exhibited no significant change. DA content peaked 2 h after onset of darkness and NAS was detectable only during the night. A bimodal pattern of 5-HT and 5-HIAA levels was observed with peak tissue levels occurring at dawn and dusk. To determine the possible differential effects of light on these biogenic amines, birds were sacrificed at midday, midnight and at midnight following a 1 h exposure to light, and their pineals processed for HPLC-EC. NE, DA and 5-HT levels were similar at midday and midnight, while 5-HIAA and NAS were elevated during the night. Midnight illumination decreased NE and NAS levels, increased 5-HT and 5-HIAA levels and had no effect on DA levels. Temporal variations in NE turnover were determined by pretreating young chickens with alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, and measuring the rates of decline in NE content over 2 h at midday and midnight in birds held on light cycles and at mid-subjective day in birds held in constant darkness (DD).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗