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Biomedical subjects

M Menaker

Publications and source records attributed to M Menaker.

At least 19 recordsLinked to original sources
PubMed1999

Free running circadian rhythms of melatonin, luteinizing hormone, and cortisol in Syrian hamsters bearing the circadian tau mutation.

The tau mutation of Syrian hamsters induces a robust reduction in the period of circadian activity rhythms, from 24 h (wild-type; tau++) to 22 h (heterozygote; tauS+) and 20 h (homozygous mutant, tauSS). Here, we examine the effect of this mutation on circadian rhythms of LH, melatonin, and cortisol in ovariectomized hamsters. Free running circadian rhythms were observed in all three hormones. In each genotype, endocrine rhythms were synchronized with concurrently assessed activity rhythms, suggesting a shared period around 20 h in tauSS, 22 h in tausS+, and 24 h in tau++. Phasing with respect to the activity rhythm was generally similar in tau++ and mutant genotypes. However, melatonin concentrations rose significantly earlier in tauSS than in tau++ animals. Explanted pineals from both genotypes exhibited a similar time course of response to norepinephrine administration, suggesting that the phase advance of melatonin production observed in tauSS in vivo is not a direct effect of the tau mutation within the pinealocyte. The demonstration of reduced period endocrine rhythms in the mutant genotypes extends previous behavioral studies and, together with recent work on rhythmicity in the isolated retina, suggests an ubiquitous influence of the tau mutation on the processes of circadian rhythm generation in this species.

Animals↗
PubMed1998

Rhythmic properties of the hamster suprachiasmatic nucleus in vivo.

We recorded multiple unit neural activity [multiunit activity (MUA)] from inside and outside of the suprachiasmatic nucleus (SCN) in freely moving male golden hamsters housed in running-wheel cages under both light/dark cycles and constant darkness. The circadian period of MUA in the SCN matched the period of locomotor activity; it was approximately 24 hr in wild-type and 20 hr in homozygous tau mutant hamsters. The peak of MUA in the SCN always occurred in the middle of the day or, in constant darkness, the subjective day. There were circadian rhythms of MUA outside of the SCN in the ventrolateral thalamic nucleus, the caudate putamen, the accumbens nucleus, the medial septum, the lateral septum, the ventromedial hypothalamic nucleus, the medial preoptic region, and the stria medullaris. These rhythms were out-of-phase with the electrical rhythm in the SCN but in-phase with the rhythm of locomotor activity, peaking during the night or subjective night. In addition to circadian rhythms, there were significant ultradian rhythms present; one, with a period of approximately 80 min, was in antiphase between the SCN and other brain areas, and another, with a period of approximately 14 min, was in-phase between the SCN and other brain areas. The periods of these ultradian rhythms were not significantly different in wild-type and tau mutant hamsters. Of particular interest was the unique phase relationship between the MUA of the bed nucleus of the stria terminalis (BNST) and the SCN; in these two areas both circadian and ultradian components were always in-phase. This suggests that the BNST is strongly coupled to the SCN and may be one of its major output pathways. In addition to circadian and ultradian rhythms of MUA, neural activity both within and outside the SCN was acutely affected by locomotor activity. Whenever a hamster ran on its wheel, MUA in the SCN and the BNST was suppressed, and MUA in other areas was enhanced.

Activity Cycles↗
PubMed1998

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.

Analysis of Variance↗
PubMed1998

The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration.

Melatonin is synthesized rhythmically under control of circadian oscillators by the retinas of non-mammalian vertebrates. Here we report that the retinas of some strains of laboratory mice exhibit robust circadian rhythms of melatonin synthesis which can be entrained by light in vitro. The rd mutation results in progressive loss of the rod and later cone photoreceptors. In mice homozygous for rd retinal melatonin synthesis is rhythmic at postnatal day 28 but not in older animals. Apparently rod photoreceptors are necessary for the expression of the circadian rhythm of melatonin synthesis but not for the synthesis itself. The many genetic and molecular tools available in the mouse can now be applied to analysis of the retinal circadian oscillator.

Animals↗
PubMed1998

Effects of a circadian mutation on seasonality in Syrian hamsters (Mesocricetus auratus).

In Syrian hamsters, exposure to short photoperiods or constant darkness induces a decrease in gonadotrophin secretion and gonadal regression. After 10-12 weeks, animals undergo spontaneous gonadal reactivation, gonadotrophin concentrations rise, and in males, testes size increases and spermatogenesis resumes. The tau mutation shortens the period of circadian wheel-running activity by 4 h in the homozygote. Here, we examine the impact of this mutation on the reproductive response to photoperiod change. Seventeen adult tau mutant and nine adult wild-type males were housed in complete darkness for 25 weeks and testes size determined at weekly intervals. Gonadal regression and subsequent recrudescence occurred in both groups of animals. Regression occurred more rapidly in tau mutants, with a nadir significantly earlier than wild-types but after a similar number of circadian cycles. Rates of testicular recrudescence were similar in both groups. Our data suggest that an acceleration of the circadian period increases the rate of reproductive inhibition in animals exposed to inhibitory photoperiods. Once initiated, the rate of spontaneous reactivation may be independent of the circadian axis.

Analysis of Variance↗
PubMed1998

Multioscillatory circadian organization in a vertebrate, iguana iguana.

The lizard Iguana iguana when kept in constant ambient temperature displays endogenously generated circadian rhythms of body temperature and locomotor activity. Although surgical removal of the parietal eye has only slight effects on overt circadian rhythmicity, subsequent pinealectomy completely abolishes the rhythm of body temperature. However, the rhythm of locomotor activity is only slightly affected by parietalectomy plus pinealectomy. Our results demonstrate that the pineal complex is centrally involved in the generation and control of the circadian rhythm of body temperature but is only marginally involved in locomotor rhythmicity. Plasma melatonin levels are not significantly reduced by parietalectomy, whereas pinealectomy dramatically lowers the level and completely eliminates the circadian rhythm of melatonin in the circulation. Isolated parietal eye, pineal, and retina all synthesize melatonin with robust circadian rhythmicity when maintained for >/=4 d in culture, although in the intact animal all or almost all of the circulating melatonin comes from the pineal. The circadian system of I. iguana is composed of multiple circadian oscillators that reside in different tissues and have specific and different roles.

Animal Structures↗
PubMed1998

Temporal distribution of partial seizures: comparison of an animal model with human partial epilepsy.

Seizures do not often strike randomly but may occur in circadian patterns. We compared daily times of partial seizures determined by continuous electroencephalography among patients with mesial temporal lobe epilepsy (MTLE; n = 64), those with extratemporal lobe (XTLE; n = 26) or lesional temporal lobe epilepsy (LTLE; n = 8), and a rat model similar to MTLE in which rats become epileptic after electrically induced limbic status epilepticus (postlimbic status [PLS]; n = 20). Rats were maintained on a 12-hour light/dark cycle with lights on at 0700 hours. The distributions of seizures were fitted by cosinor analysis to determine time of peak seizure incidence +/- 95% confidence interval (95% CI). The mean fraction +/- SD of seizures recorded during light was 63 +/- 17% in PLS animals and 60 +/- 21% in humans. Peak incidence of seizures for PLS rats (547 seizures) was 1645 (95% CI = 1448,1830) and for MTLE subjects (774 seizures) was 1500 (95% CI = 1324,1636). Seizures from XTLE (465 seizures) and LTLE (48 seizures) did not fit a cosinor model and occurred no more frequently during light than dark. In conclusion, limbic seizures in humans and PLS rats occur more often during light than dark and have similar cosinor daily distributions. The chronological similarity between human MTLE and PLS rat epilepsy suggests that limbic seizure occurrence has a relation to the circadian regulatory system.

Adult↗
PubMed1998

Circadian behavior and plasticity of light-induced c-fos expression in SCN of tau mutant hamsters.

In hamsters homozygous for the circadian clock mutation tau, the photic history dramatically affects the magnitude of light-induced circadian phase shifts. The maximum amplitude of phase shifts produced by 1-h light pulses presented at CT 14 was less than 2 h in animals that had been in DD for 2 days, whereas animals that had been kept in DD for 49 days could be shifted by more than 8 h. In this study, the authors compared the effect of previous light history on the amplitude of circadian phase shifts and on c-fos expression in the SCN of tau mutant hamsters. Although the maximum amplitude of behavioral phase shifts was drastically different between animals that had been held for either 2 or 49 days in DD, maximal fos induction was not significantly different in these two groups. However, photic thresholds for light-induced behavioral phase shifts, c-fos mRNA, and Fos immunoreactivity were closely correlated within both groups, and these thresholds were lower (more sensitive to light) after 49 than after 2 days in DD. The correlation between phase shifting and Fos induction thresholds, under conditions where both responses are dramatically altered by the previous light history, demonstrates an association between changes in circadian behavioral phase-shifting responses of tau mutant hamsters and plasticity of light-induced c-fos expression in SCN. However, because the maximum amplitudes of Fos induction and phase shifting were not correlated in animals that had been in DD for 2 days, we speculate that the level of c-fos expression does not directly determine phase shift amplitude.

Animals↗
PubMed1997

Is energy expenditure in the hamster primarily under homeostatic or circadian control?

1. In order to discriminate between homeostatic and circadian control of energy expenditure, this paper considers whether a shorter circadian cycle will produce a proportional reduction in energy expenditure (so that expenditure per unit time is conserved) or alternatively whether energy expenditure will be compressed into the shorter cycle (so that energy expenditure per cycle is conserved). To answer this question, we measured energy expenditure in tau mutant hamsters (whose free-running circadian period has been reduced to about 20 h by a single gene mutation) and wild-type hamsters (whose free-running circadian period is about 24 h). 2. In one experiment, the circadian rhythm of running-wheel activity of tau mutant hamsters was compared with that of wild-type hamsters. The rate of running was not affected by the mutation and, consequently, the total amount of activity per cycle was significantly less in mutants than in wild-type hamsters, whereas the total amount of activity per unit time was nearly the same. 3. In a second experiment, we measured energy expenditure by indirect calorimetry. Metabolic rate was not affected by the mutation and, consequently, the total amount of energy expended per cycle was significantly less in mutants than in wild-type hamsters but equivalent per unit time. 4. Because the amount of energy expenditure and locomotor activity was found to be proportional to the circadian cycle, we conclude that expenditure per unit time-rather than expenditure per circadian cycle-is conserved in the mutant animals. Therefore, we infer that energy expenditure in hamsters is primarily under homeostatic, not circadian, control. Further research is necessary to determine whether this inference can be applied to other species.

Animals↗
PubMed1997

Photoperiodic time measurement in tau mutant hamsters.

Photoperiodic regulation of testicular function was investigated in homozygous tau mutant hamsters; these animals have an innate circadian period of about 20 h. In 20-h light:dark (LD) cycles, the minimum photoperiod required to prevent testicular regression was between 10.0 and 11.5 h per 20-h cycle (equivalent to 12.0-13.8 circadian hours). This was proportionally similar to the minimum photoperiod necessary to prevent regression in wild-type hamsters maintained in 24-h LD cycles. To examine the shape of the photoperiodic photosensitivity curve in homozygous tau mutant hamsters, the authors measured the effects of different T cycles on testicular maintenance. Entrainment to LD 1:18.0 and LD 1:20.5 partially or completely prevented gonadal regression in homozygous tau mutant hamsters, but LD 1:19.4 did not prevent regression. When considered in terms of circadian time, the photoperiodic photosensitivity curve for homozygous tau mutant hamsters was similar to that described previously for wild-type hamsters. The results indicate that, as in wild-type hamsters, photoperiodic regulation of reproduction is regulated by circadian photosensitivity in homozygous tau mutant hamsters. Because tau mutant hamsters measure day length against a time base of 20 h, the circadian pacemaker that measures day length might be the same as that which generates circadian rhythmicity in locomotor activity. The authors' data leave open the question of whether the tau mutation has had effects on the control of reproduction that are not directly attributable to its effects on the period of the circadian oscillator.

Animals↗
PubMed1997

Evolution of circadian organization in vertebrates.

Circadian organization means the way in which the entire circadian system above the cellular level is put together physically and the principles and rules that determine the interactions among its component parts which produce overt rhythms of physiology and behavior. Understanding this organization and its evolution is of practical importance as well as of basic interest. The first major problem that we face is the difficulty of making sense of the apparently great diversity that we observe in circadian organization of diverse vertebrates. Some of this diversity falls neatly into place along phylogenetic lines leading to firm generalizations: i) in all vertebrates there is a "circadian axis" consisting of the retinas, the pineal gland and the suprachiasmatic nucleus (SCN), ii) in many non-mammalian vertebrates of all classes (but not in any mammals) the pineal gland is both a photoreceptor and a circadian oscillator, and iii) in all non-mammalian vertebrates (but not in any mammals) there are extraretinal (and extrapineal) circadian photoreceptors. An interesting explanation of some of these facts, especially the differences between mammals and other vertebrates, can be constructed on the assumption that early in their evolution mammals passed through a "nocturnal bottleneck". On the other hand, a good deal of the diversity among the circadian systems of vertebrates does not fall neatly into place along phylogenetic lines. In the present review we will consider how we might better understand such "phylogenetically incoherent" diversity and what sorts of new information may help to further our understanding of the evolution of circadian organization in vertebrates.

Animals↗
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↗