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Biomedical subjects

M Menaker

Publications and source records attributed to M Menaker.

At least 19 recordsLinked to original sources
PubMed1996

The tau mutation shortens the period of rhythmic photoreceptor outer segment disk shedding in the hamster.

The outer segments of vertebrate retinal photoreceptors undergo periodic shedding of membrane from their distal tips. This circadian rhythm of disk shedding persists with a period of about 24 h in the absence of external time cues. A circadian oscillator controlling photoreceptor disk shedding may exist in the eye, but in addition, the circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) may also influence ocular rhythms including that of disk shedding. The tau mutation directly affects the SCN, and shortens the period of locomotor activity from 24 h in wild-type hamsters to 20 h in homozygous mutants. Here we show that homozygous tau-mutant hamsters in a 20-h light/dark cycle exhibit a 20-h oscillation in the rate of disk shedding, with peak phagosome numbers in the retinal pigmented epithelium occurring just after light onset. The numbers of phagosomes are significantly elevated from mid-dark levels prior to light onset, indicating that the disk shedding cycle anticipates dawn. Under conditions of constant darkness, the disk shedding rhythm in tau-mutant hamsters persists with a period of approximately 20 h. These results indicate that a rhythm of retinal photoreceptor outer segment disk shedding exists in the hamster eye, and that the period of this rhythm is shortened by the tau mutation.

Adaptation, Ocular↗
PubMed1996

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.

Animals↗
PubMed1996

Light perception in the vertebrate brain: an ultrastructural analysis of opsin- and vasoactive intestinal polypeptide-immunoreactive neurons in iguanid lizards.

Recent biochemical and immunocytochemical evidence indicates that a population of circadian and reproductive rhythm-entraining photoreceptors lies in the basal diencephalon of iguanid lizards. Here, we report the results of correlated light and electron microscopy of opsin-immunoreactive cells in the basal brain, and we discuss their ultrastructural relationship to known photoreceptors. Cerebrospinal fluid (CSF)-contacting bipolar neurons in the lizards Anolis carolinensis and Iguana iguana were immunolabeled with antisera generated against vertebrate retinal opsins and vasoactive intestinal polypeptide (VIP). Within the brain, opsin-immunoreactive cells were found exclusively in the ependyma of the basal region of the lateral ventricles (adjacent to nucleus paraolfactorius/nucleus ventromedialis and neostriatum/paleostriatum). Cells in the same anatomical location and with the same morphology were labeled with anti-VIP antisera. These cells possessed a dendritic process that extended toward the lateral ventricle, ending in a bulbous terminal that protruded into the ventricle. Axonal processes travelled ventrally and caudally. The entire cell, including the axonal process, exhibited opsin-like and VIP-like immunoreactivity. By light microscopy, opsin-like immunostaining appeared punctate, with immunoreactivity greatest in the bulbous terminal. Opsin- and VIP-immunostained thick sections were resectioned, and individual cells observed by light microscopy were then characterized using electron microscopy. We found that all immunostained cells were morphologically similar and that they were morphologically distinct from neighboring nonimmunoreactive cells. CSF-contacting opsin- and VIP-immunoreactive cells lacked the membranous stacks characteristic of retinal photoreceptors but were ciliated and contained numerous large electron-dense vesicles. Multiple synaptic contacts were made on the soma and putative dendritic processes of opsin- and VIP-immunoreactive CSF-contacting neurons. Our results provide the first ultrastructural characterization of opsin-immunostained encephalic CSF-contacting neurons in a vertebrate animal, and they indicate that these putative photoreceptors share structural features with pineal photoreceptors and with certain invertebrate extraretinal photoreceptors, but they are morphologically and biochemically distinct from visual photoreceptors of the retina.

Animals↗
PubMed1996

The pineal complex and melatonin affect the expression of the daily rhythm of behavioral thermoregulation in the green iguana.

Daily variation in the body temperature of the green iguana (Iguana iguana) was studied by telemetry in laboratory photo-thermal enclosures under a 12Light:12Dark (L:D) photoperiod. The lizards showed robust daily rhythms of thermoregulation maintaining their body temperatures (Tb) at higher levels during the day than during the night. Some animals maintained rhythmicity when kept in constant darkness. On light:dark cycles parietalectomy produced only a transient increase of median Tb in the first or second night following the operation. Pinealectomized lizards on the other hand maintained their body temperatures as significantly lower levels during the day and at significantly higher levels during the night than did sham-operated or intact lizards. This effect was apparently permanent, since one month after pinealectomy lizards still displayed the altered pattern. Plasma melatonin levels in intact animals were high during the night and low during the day and were unaffected by parietalectomy. Pinealectomized lizards showed low levels of plasma melatonin during both the day and the night. A daily intraperitoneal injection of melatonin in pinealectomized animals given a few minutes after the light to dark transition decreased the body temperatures selected by the lizards during the night and increased the body temperatures selected during the following day. Control injections of saline solution had no effect. The significance of these results is discussed in relation to the role of the pineal complex and melatonin in the mediation of thermoregulatory behavior.

Animals↗
PubMed1996

Identification of an E689K substitution as the molecular basis of the human acid alpha-glucosidase type 4 allozyme (GAA*4).

We have identified the molecular basis of the GAA*4 allozyme as a G to A transition at nt2065 which predicts the substitution of glutamic acid by lysine at codon 689 (E689K). The conclusion that this change represents the molecular basis of the GAA*4 allozyme is based on 1) presence of the G2065A in homozygosity in a known GAA*4 homozygote, 2) transient expression studies showing normal enzyme activity expressed by cDNA containing the G2065A transition and 3) isoelectric focusing studies showing a more cathodal pattern for the expressed product as compared to the common GAA*1, analogous to the patterns seen in normal and known GAA*4 lymphoid cells.

Asian People↗
PubMed1995

Circadian rhythm of body temperature in an ectotherm (Iguana iguana).

Ectothermic animals regulate their body temperatures primarily by behavioral adjustment in relation to the thermal characteristics of the environment. Several studies have shown that some vertebrate ectotherms may show a daily pattern of body temperature selection when given a choice of environmental temperature. The pattern of body temperature selection free-runs when the animals are kept in constant darkness, demonstrating the existence of circadian regulation. To test whether there might also be a low amplitude circadian rhythm of body temperature itself, we examined the pattern of body temperature and locomotor activity of the lizard Iguana iguana held in a constant environmental temperature. Both variables were recorded for 3 days in a light:dark cycle and then for 10 days in constant dim light (0.1 lux). Under these conditions the body temperature of the lizard oscillates with a circadian period as does the locomotor behavior. These results demonstrate for the first time that ectothermic animals may display physiologically generated circadian rhythms of body temperature similar to those recorded in endotherms. In some animals the circadian rhythms of body temperature and locomotor activity showed different free-running periods, demonstrating that the body temperature rhythm was not caused by locomotor activity and suggesting internal desyncronization of the two rhythms.

Animals↗
PubMed1994

Ontogeny of light-induced Fos-like immunoreactivity in the hamster suprachiasmatic nucleus.

Light induction of Fos within the Syrian hamster suprachiasmatic nucleus (SCN) occurred first at postnatal day 4. The number of cells with light-induced Fos-like immunoreactivity (Fos-LI) per unit volume of SCN increased with age. Blinding experiments were used to demonstrate that the eye, though possessing an immature retina, appears to be necessary for light induction of Fos. In neonatal hamsters, environmental cycles (e.g., light and darkness) may be able to reinforce the effect of maternal melatonin in synchronizing the pup's clock.

Aging↗
PubMed1994

Complete suprachiasmatic lesions eliminate circadian rhythmicity of body temperature and locomotor activity in golden hamsters.

The effects of suprachiasmatic and control lesions on the circadian rhythms of locomotor activity and body temperature were studied in golden hamsters (Mesocricetus auratus) maintained in constant light as well as constant darkness. Large suprachiasmatic lesions, but not control lesions, eliminated circadian rhythmicity in locomotor activity as well as in body temperature. Analysis of the "robustness" of the rhythms of locomotor activity and body temperature in unlesioned and lesioned animals suggests that, because body temperature rhythmicity is more robust than locomotor rhythmicity, lesions that spare a small number of suprachiasmatic cells might abolish the latter but not the former. Our results do not support the hypothesis that the body temperature rhythm is controlled by a circadian pacemaker distinct from the main pacemaker located in the suprachiasmatic nuclei.

Animals↗
PubMed1994

Feeding rhythms in constant light and constant darkness: the role of the eyes and the effect of melatonin infusion.

Exposure to constant light abolishes circadian behavioral rhythms of locomotion and feeding as well as circulating melatonin rhythms in pigeons (Columba livia). To determine if feeding rhythmicity could be maintained in pigeons exposed to constant light, periodic infusions; (10 h/day) of melatonin were administered to pinealectomized and bilaterally retinectomized/pinealectomized pigeons under conditions of both constant darkness and constant light. The infusions were sufficient to entrain rhythmicity in pinealectomized pigeons in constant darkness and to restore and maintain rhythmicity in bilaterally retinectomized/pinealectomized pigeons in constant darkness. On subsequent exposure to constant light, rhythmicity remained phase locked to the melatonin infusions in bilaterally retinectomized/pinealectomized pigeons but was abolished in sighted pinealectomized birds. These results suggest that while endogenous melatonin rhythms are both necessary and sufficient to maintain behavioral rhythms in DD, their effect can be overridden by constant light but only if perceived by the eyes. Thus, constant light may abolish behavioral rhythmicity in intact pigeons (and perhaps in other species) by a mechanism other than suppression of endogenous melatonin rhythmicity. Such a mechanism might involve direct stimulation of locomotor or feeding activity by retinally perceived (but not by extra-retinally perceived) light, or alternatively by suppression of a hypothalamic oscillator that receives its major light input from the retinae.

Animals↗
PubMed1994

Retinohypothalamic projections and immunocytochemical analysis of the suprachiasmatic region of the desert iguana Dipsosaurus dorsalis.

Two separate and distinct retinal projections to the hypothalamus in the iguanid lizard Dipsosaurus dorsalis were described using horseradish peroxidase and cobalt-filling techniques. Both of the projections were unilateral and completely crossed; one terminated in the supraoptic nucleus and the other in the suprachiasmatic nucleus. Immunocytochemical analysis showed that the supraoptic nucleus contained cell bodies and fibers that cross-react with antibodies raised against arginine vasopressin, while the suprachiasmatic nucleus contained arginine vasopressin-like immunoreactive fibers emanating from cells in the nearby paraventricular nucleus. The suprachiasmatic nucleus contained a dense plexus of fibers that cross-reacted with neuropeptide-Y antibody. Antiserum against vasoactive intestinal polypeptide showed no reactivity in any part of the forebrain, while antiserum against serotonin showed sparse and uniform reactivity throughout the forebrain, including the suprachiasmatic nucleus. These results, together with other data, indicate that the suprachiasmatic nucleus of D. dorsalis is homologous to the suprachiasmatic nuclei of rodents, structures known to contain circadian pacemakers. We suggest that the suprachiasmatic nucleus may play a similar role in the circadian system of D. dorsalis.

Afferent Pathways↗
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↗