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PubMed1992

Pharmacologic properties of the internal clock underlying time perception in humans.

Performance on temporal discrimination of time intervals in the range of milliseconds is interpreted by the assumption of an internal clock; the higher the clock rate the better the temporal resolution of the internal clock will be, which is equivalent to more accuracy in timing of brief intervals. Although there is some evidence from animal and human studies suggesting that the clock rate depends on the effective level of brain dopamine (DA), the findings are not conclusive. Therefore, an alternative interpretation of the pharmacologic properties of the internal clock has been introduced. According to this interpretation, the internal timing mechanism can be seen as a biological rhythm that is susceptible to chronomutagenic agents, i.e., pharmacologic compounds that are able to produce an alteration in the period of a biological rhythm. To elucidate the pharmacologic properties of the internal timing mechanism, in a double-blind study either 1750 mg of the DA antagonist alpha-methyl-p-tyrosine (AMPT), 0.65 g/kg ethanol which possesses chronomutagenic effects, or placebo were applied to 80 male subjects. As measures of performance, difference threshold estimates in relation to a 50- and a 1,000-ms standard interval and respective response latencies were computed. Furthermore, urinary levels of DA, DOPAC, and HVA were quantified by HPLC analysis. Although AMPT treatment resulted in a pronounced reduction of more than 50% for DA, DOPAC, and HVA, temporal discrimination was not affected. On the other hand, ethanol induced a significant impairment in performance on temporal discrimination in the range of milliseconds as compared to placebo. Neither temporal discrimination in the range of seconds nor response latencies were affected by the drugs applied in this experiment. Our findings suggest that the internal timing mechanism underlying temporal discrimination of intervals in the range of milliseconds is independent of the effective level of brain DA. More likely, pharmacologically induced changes in clock rate appear to depend on the chronomutagenic effects of the drug applied. Furthermore, the absence of ethanol-induced changes in performance on temporal discrimination of longer intervals in the range of seconds supports the assumption of two distinct timing mechanisms underlying temporal discrimination in the millisecond and second range.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2006

Cellular senescence impairs circadian expression of clock genes in vitro and in vivo.

Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity.

Animals↗
PubMed2004

Finding new clock components: past and future.

The molecular mechanism of circadian clocks has been unraveled primarily by the use of phenotype-driven (forward) genetic analysis in a number of model systems. We are now in a position to consider what constitutes a clock component, whether we can establish criteria for clock components, and whether we have found most of the primary clock components. This perspective discusses clock genes and how genetics, molecular biology, and biochemistry have been used to find clock genes in the past and how they will be used in the future.

Animals↗
PubMed2005

Multiple effects of melatonin on rhythmic clock gene expression in the mammalian pars tuberalis.

In mammals, changing day length modulates endocrine rhythms via nocturnal melatonin secretion. Studies of the pituitary pars tuberalis (PT) suggest that melatonin-regulated clock gene expression is critical to this process. Here, we considered whether clock gene rhythms continue in the PT in the absence of melatonin and whether the effects of melatonin on the expression of these genes are temporally gated. Soay sheep acclimated to long photoperiod (LP) were transferred to constant light for 24 h, suppressing endogenous melatonin secretion. Animals were infused with melatonin at 4-h intervals across the final 24 h, and killed 3 h after infusion. The expression of five clock genes (Per1, Per2, Cry1, Rev-erbalpha, and Bmal1) was measured by in situ hybridization. In sham-treated animals, PT expression of Per1, Per2, and Rev-erbalpha showed pronounced temporal variation despite the absence of melatonin, with peak times occurring earlier than predicted under LP. The time of peak Bmal1 expression remained LP-like, whereas Cry1 expression was continually low. Melatonin infusion induced Cry1 expression at all times and suppressed other genes, but only when they showed high expression in sham-treated animals. Hence, 3 h after melatonin treatment, clock gene profiles were driven to a similar state, irrespective of infusion time. In contrast to the PT, melatonin infusions had no clear effect on clock gene expression in the suprachiasmatic nuclei. Our results provide the first example of acute sensitivity of multiple clock genes to one endocrine stimulus and suggest that rising melatonin levels may reset circadian rhythms in the PT, independently of previous phase.

Analysis of Variance↗
PubMed2006

The circadian clock modulates core steps in long-term memory formation in Aplysia.

The circadian clock modulates the induction of long-term sensitization (LTS) in Aplysia such that long-term memory formation is significantly suppressed when animals are trained at night. We investigated whether the circadian clock modulated core molecular processes necessary for memory formation in vivo by analyzing circadian regulation of basal and LTS-induced levels of phosphorylated mitogen-activated protein kinase (P-MAPK) and Aplysia CCAAT/enhancer binding protein (ApC/EBP). No basal circadian regulation occurred for P-MAPK or total MAPK in pleural ganglia. In contrast, the circadian clock regulated basal levels of ApC/EBP protein with peak levels at night, antiphase to the rhythm in LTS. Importantly, LTS training during the (subjective) day produced greater increases in P-MAPK and ApC/EBP than training at night. Thus, circadian modulation of LTS occurs, at least in part, by suppressing changes in key proteins at night. Rescue of long-term memory formation at night required both facilitation of MAPK and transcription in conjunction with LTS training, confirming that the circadian clock at night actively suppresses MAPK activation and transcription involved in memory formation. The circadian clock appears to modulate LTS at multiple levels. 5-HT levels are increased more when animals receive LTS training during the (subjective) day compared with the night, suggesting circadian modulation of 5-HT release. Circadian modulation also occurred downstream of 5-HT release because animals treated with 5-HT to induce LTS exhibited significantly greater LTS when treated during the (subjective) day compared with the night. Together, our studies suggest that the circadian clock modulates LTS at multiple steps and locations during the formation of long-term memory.

Animals↗
PubMed2005

Modeling the VPAC2-activated cAMP/PKA signaling pathway: from receptor to circadian clock gene induction.

Increasing evidence suggests an important role for VPAC2-activated signal transduction pathways in maintaining a synchronized biological clock in the suprachiasmatic nucleus (SCN). Activation of the VPAC2 signaling pathway induces per1 gene expression in the SCN and phase-shifts the circadian clock. Mice without the VPAC2 receptor lack an overt, coherent circadian rhythm in clock gene expression, SCN neuron firing rate, and locomotor behavior. Using a systems approach, we have developed a kinetic model integrating VPAC2 signaling mediated by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and leading to induced circadian clock gene expression. We fit the model to experimental data from the literature for cAMP accumulation, PKA activation, cAMP-response element binding protein phosphorylation, and per1 induction. By linking the VPAC2 model to a published circadian clock model, we also simulated clock phase shifts induced by vasoactive intestinal polypeptide (VIP) and matched experimental data for the VIP response. The simulated phase response curve resembled the hamster response to a related neuropeptide, GRP1-27, and light. Simulations using pulses of VIP revealed that the system response is extraordinarily robust to input signal duration, a result with physiologically relevant consequences. Lastly, simulations using varied receptor levels matched literature experimental data from animals overexpressing VPAC2 receptors.

Animals↗
PubMed2003

Fine distribution of CLOCK protein in hepatocytes of hibernating dormice.

CLOCK protein is a member of the bHLH-PAS family of transcription factors, it is expressed in several tissues including the liver and is essential for normal circadian rhythms. In this study we investigate the distribution of CLOCK protein in hepatocytes of euthermic and hibernating edible dormice Glis glis as well as in hepatocytes taken from the hibernating animals submitted in vitro to experimental conditions mimicking the arousal process. Our results demonstrate that CLOCK protein is expressed in all animals and is mostly located in the nucleus, in particular, on perichromatin fibrils and nucleoli. During deep hibernation CLOCK protein becomes more abundant but an intracellular redistribution occurs: the protein significantly decreases in all cellular compartments, but it accumulates in the amorphous bodies. These nuclear bodies, typical of the hibernating state, probably represent storage sites for CLOCK protein to be quickly used upon arousal. Accordingly, in hepatocytes submitted to in vitro conditions mimicking arousal CLOCK protein levels rapidly reach the euthermic values, while amorphous bodies disappear.

Animals↗
PubMed2000

CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP.

DBP, the founding member of the PAR leucine zipper transcription factor family, is expressed according to a robust daily rhythm in the suprachiasmatic nucleus and several peripheral tissues. Previous studies with mice deleted for the Dbp gene have established that DBP participates in the regulation of several clock outputs, including locomotor activity, sleep distribution, and liver gene expression. Here we present evidence that circadian Dbp transcription requires the basic helix-loop-helix-PAS protein CLOCK, an essential component of the negative-feedback circuitry generating circadian oscillations in mammals and fruit flies. Genetic and biochemical experiments suggest that CLOCK regulates Dbp expression by binding to E-box motifs within putative enhancer regions located in the first and second introns. Similar E-box motifs have been found previously in the promoter sequence of the murine clock gene mPeriod1. Hence, the same molecular mechanisms generating circadian oscillations in the expression of clock genes may directly control the rhythmic transcription of clock output regulators such as Dbp.

Animals↗
PubMed2002

In vivo disruption of Xenopus CLOCK in the retinal photoreceptor cells abolishes circadian melatonin rhythmicity without affecting its production levels.

Xenopus laevis retinas, like retinas from all vertebrate classes, have endogenous circadian clocks that control many aspects of normal retinal physiology occurring in cells throughout all layers of the retina. The localization of the clock(s) that controls these various rhythms remains unclear. One of the best studied rhythmic events is the nocturnal release of melatonin. Photoreceptor layers can synthesize rhythmic melatonin when these cells are in isolation. However, within the intact retina, melatonin is controlled in a complex way, indicating that signals from many parts of the retina may contribute to the production of melatonin rhythmicity. To test this hypothesis, we generated transgenic tadpoles that express different levels of a dominant negative Xenopus CLOCK specifically in the retinal photoreceptors. Eyes from these tadpoles continued to produce melatonin at normal levels, but with greatly disrupted rhythmicity, the severity of which correlated with the transgene expression level. These results demonstrate that although many things contribute to melatonin production in vivo, the circadian clock localized in the retinal photoreceptors is necessary for its rhythmicity. Furthermore, these data show that the control of the level of melatonin synthesis is separable from the control of its rhythmicity and may be controlled by different molecular machinery. This type of specific "molecular lesion" allows perturbation of the clock in intact tissues and is valuable for dissection of clock control of tissue-level processes in this and other complex systems.

Animals↗
PubMed1996

Regulation of a specific circadian clock output pathway by lark, a putative RNA-binding protein with repressor activity.

An endogenous clock within the Drosophila brain regulates circadian rhythms in adult eclosion and locomotor activity. Although molecular elements of the Drosophila circadian clock have been well characterized, little is known about the clock output pathways that mediate the control of rhythmic events. Previous genetic analysis indicates that a gene known as lark encodes an element of the clock output pathway regulating adult eclosion. We now present evidence that lark encodes a novel member of the RNA recognition motif (RRM) class of RNA-binding proteins. Similar to other members of this protein superfamily, lark contains two copies of a bipartite consensus RNA-binding motif. Unlike any other RRM family member, however, lark protein also contains a distinct class of nucleic acid binding motif, a retroviral-type zinc finger, that is present in the nucleocapsid protein of retroviruses and in several eukaryotic proteins. In contrast to identified clock elements, lark mRNA does not exhibit diurnal fluctuations in abundance in late pupae or in adult heads. Thus rhythmic transcription of the gene does not contribute to the temporal regulation of eclosion by lark protein. Gene dosage experiments show that decreased or increased lark product, respectively, leads to an early or late eclosion phenotype, indicating that the protein negatively regulates the eclosion process. It is postulated that lark is required for the posttranscriptional repression of genes encoding other elements of this clock output pathway.

Amino Acid Sequence↗
PubMed1997

Clock drawing test in elderly schizophrenia patients.

OBJECTIVE: Clock drawing has been studies in Alzheimer's disease but not in elderly schizophrenics. We examined clock drawing ability in elderly schizophrenia patients and sought possible correlations with demographic, clinical and cognitive variables. DESIGN: Retrospective analysis of the clock drawing item from the Cambridge Cognitive Examination (CAMCOG) presented to three independent raters. SETTING: Long-stay 'open' departments of a public psychiatric hospital in Israel. PATIENTS: Thirty-one physically well psychiatric inpatients suffering from schizophrenia (DSM-III-R, APA), between ages 60 and 76 years. MEASURES: The Clock Drawing Interpretation Scale (CDIS). RESULTS: The mean CDIS score was 14.4 (out of 20), and 61-84% of patients scored beneath the normal range (> 18). Interrater reliability was high (0.91-0.96). A moderate but significant correlation was found between CDIS and duration of illness as well as total scores on the Manchester Scale, the CAMCOG and the Mini-Mental State Examination, but not with the other variables studies. CONCLUSIONS: Clock drawing skills of a significant portion of long-term institutionalized elderly schizophrenics are impaired. When this test is used as a screening device for Alzheimer's disease in these patients, the results should be interpreted cautiously. Clock drawing abilities in these patients seem to be related to cognitive and non-cognitive (psychiatric state) factors, as well as to illness duration.

Aged↗
PubMed2000

Clock-drawing: is it the ideal cognitive screening test?

OBJECTIVE: The clock-drawing test has achieved widespread clinical use in recent years as a cognitive screening instrument and a significant amount of literature relates to its psychometric properties and clinical utility. This review aims to synthesize the available evidence and assess the value of this screening test according to well-defined criteria. DESIGN: A Medline and Psycho-info literature search of all languages was done from 1983 to 1998 including manual cross-referencing of bibliographies. A brief summary of all original scoring systems is provided as well as a review of replication studies. Psychometric data including correlations with other cognitive tests were recorded. Qualitative aspects of the test are also described. RESULTS: Among published studies, the mean sensitivity (85%) and specificity (85%) of the clock-drawing test are impressive. Correlations with the Mini-Mental State Examination and other cognitive tests was high, generally greater than r = 0.5. High levels of inter-rater and test-re-test reliability and positive predictive value are recorded and despite significant variability in the scoring systems, all report similar psychometric properties. The clock test also shows a sensitivity to cognitive change with good predictive validity. CONCLUSIONS: The clock-drawing test meets defined criteria for a cognitive screening instrument. It taps into a wide range of cognitive abilities including executive functions, is quick and easy to administer and score with excellent acceptability by subjects. Together with informant reports, the clock-drawing test is complementary to the widely used and validated Mini-Mental State Examination and should provide a significant advance in the early detection of dementia and in monitoring cognitive change. A simple scoring system with emphasis on the qualitative aspects of clock-drawing should maximize its utility.

Aged↗
PubMed2005

GABA modulates Drosophila circadian clock neurons via GABAB receptors and decreases in calcium.

Circadian clocks play vital roles in the control of daily rhythms in physiology and behavior of animals. In Drosophila, analysis of the molecular and behavioral rhythm has shown that the master clock neurons are entrained by sensory inputs and are synchronized with other clock neurons. However, little is known about the neuronal circuits of the Drosophila circadian system and the neurotransmitters that act on the clock neurons. Here, we provide evidence for a new neuronal input pathway to the master clock neurons, s-LN(v)s, in Drosophila that utilizes GABA as a slow inhibitory neurotransmitter. We monitored intracellular calcium levels in dissociated larval s-LN(v)s with the calcium-sensitive dye Fura-2. GABA decreased intracellular calcium in the s-LN(v)s and blocked spontaneous oscillations in calcium levels. The duration of this response was dose-dependent between 1 nM and 100 microM. The response to GABA was blocked by a metabotropic GABA(B) receptor (GABA(B)-R) antagonist, CGP54626, but not by an ionotropic receptor antagonist, picrotoxin. The GABA(B)-R agonist, 3-APMPA, produced a response similar to GABA. An antiserum against one of the Drosophila GABA(B)-Rs (GABA(B)-R2) labeled the dendritic regions of the s-LN(v)s in both adults and larvae, as well as the dissociated s-LN(v)s. We found that some GABAergic processes terminate at the dendrites of the LN(v)s, as revealed by GABA immunostaining and a GABA-specific GAL4 line (GAD1-gal4). Our results suggest that the s-LN(v)s receive slow inhibitory GABAergic inputs that decrease intracellular calcium of these clock neurons and block their calcium cycling. This response is mediated by postsynaptic GABA(B) receptors.

Animals↗
PubMed2001

Carbon monoxide and nitric oxide: interacting messengers in muscarinic signaling to the brain's circadian clock.

Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas l-NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-beta, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.

Animals↗
PubMed1987

Man's place in Hominoidea as inferred from molecular clocks of DNA.

Divergence dates among primates were estimated by molecular clock analysis of DNA sequence data. A molecular clock of eta-globin pseudogene was calibrated by setting the date of divergence between Catarrhini and Platyrrhini at 38 million years (Myr) ago. The clock gave dates of 25.3 +/- 2.4, 11.9 +/- 1.7, 5.9 +/- 1.2, and 4.9 +/- 1.2 Myr ago ( +/- refers to standard error) for the separation of rhesus monkey, orangutan, gorilla, and chimpanzee, respectively, from the line leading to humans. In placing confidence intervals of the estimates in a robust way, a bootstrap method was used. The 95% confidence intervals are 20.5-29.5, 9.0-14.8, 4.1-7.8, and 3.1-7.0 Myr ago for the separation of rhesus monkey, orangutan, gorilla, and chimpanzee, respectively. By a molecular clock dating of the Prosimii-Anthropoidea splitting, it was suggested that the evolutionary rate of the eta-globin gene was high early in primate evolution and subsequently decreased in the line of Anthropoidea. And, by a relative rate test using bootstrap sampling, the possibility of further decrease of the rate (more than 10%) in the line of Hominoidea compared with that of Cercopithecoidea was suggested. Therefore, the above dating of the splittings within Hominoidea may be biased slightly toward younger dates. On the other hand, mitochondrial DNA (mtDNA) seems to have evolved in mammals with a more uniform rate than the eta-globin gene. The ratio of the dates of orangutan splitting to chimpanzee splitting is larger for the mtDNA clock than that for the eta-globin clock, suggesting the possibilities of mtDNA introgression among the early hominids and the early African apes, and/or of mtDNA polymorphism within the common ancestral species of orangutan and the African apes that obscures the date of the true species separation of orangutans.

Animals↗
PubMed2003

Photoperiodic regulation of diapause in linden bugs: are period and Clock genes involved?

Although photoperiodism is undoubtedly one of the most important functions of the circadian system, the role of circadian clock genes remains unclear. We compared the expression of period and Clock genes in the head of the linden bug, Pyrrhocoris apterus, kept under diapause promoting short days (SD) and diapause-preventing long days (LD), using an RNase protection assay. There was only a weak diurnal rhythm in both period and Clock mRNA under LD and no rhythm under SD. Under SD, however, the level of period mRNA was about tenfold and that of clock mRNA about twofold higher than under LD. In a mutant that does not undergo diapause, even under SD, levels of both transcripts were low in both photoperiods. The differential regulation of the levels of two clock gene transcripts in a photoperiodic mutant, demonstrated for the first time in an animal species, strongly indicates a link between photoperiod, the magnitude of clock gene expression, and developmental outputs.

Animals↗
PubMed2005

Daily coordination of cancer growth and circadian clock gene expression.

BACKGROUND: Circadian coordination in mammals is accomplished, in part, by coordinate, rhythmic expression of a series of circadian clock genes in the central clock within the suprachiasmatic nuclei (SCN) of the hypothalamus. These same genes are also rhythmically expressed each day within each peripheral tissue. METHODS: We measured tumor size, tumor cell cyclin E protein, tumor cell mitotic index, and circadian clock gene expression in liver and tumor cells at six equispaced times of day in individual mice of a 12-h light, 12-h dark schedule. RESULTS: We demonstrate that C3HFeJ/HeB mice with transplanted syngeneic mammary tumor maintain largely normal circadian sleep/activity patterns, and that the rate of tumor growth is highly rhythmic during each day. Two daily 2.5-fold peaks in cancer cell cyclin E protein, a marker of DNA synthesis, are followed by two daily up-to-3-fold peaks in cancer cell mitosis (one minor, and one major peak). These peaks are, in turn, followed by two prominent daily peaks in tumor growth rate occurring during mid-sleep and the second, during mid-activity. These data indicate that all therapeutic targets relevant to tumor growth and tumor cell proliferation are ordered in tumor cells within each day. The daily expression patterns of the circadian clock genes Bmal1, mPer1, and mPer2, remain normally circadian coordinated in the livers of these tumor bearing mice. Bmal1 gene expression remains circadian rhythmic in cancer cells, although damped in amplitude, with a similar circadian pattern to that in normal hepatocytes. However, tumor cell mPer1 and mPer2 gene expression patterns fail to maintain statistically significant daily rhythms. CONCLUSION: We conclude that, if core circadian clock gene expression is essential to gate tumor cell proliferation within each day, then there may be substantial redundancy in this timing system. Alternatively, the daily ordering of tumor cell clock gene expression may not be essential to the daily gating of cancer cell DNA synthesis, mitosis and growth. This would indicate that host central SCN-mediated neuro-humoro-behavioral controls and/or daily light-induced changes in melatonin or peripherally-induced rhythms such as those resulting from feeding, may be adequate for the daily coordination of cancer cell expression of proliferation related therapeutic targets.

Animals↗
PubMed1993

Aging alters the entraining effects of an activity-inducing stimulus on the circadian clock.

In young hamsters, a single injection of the short-acting benzodiazepine, triazolam, can induce permanent phase shifts in the circadian clock, while repeated injections of triazolam entrain the circadian clock to the period of the injections. Triazolam appears to act on the circadian clock by inducing an acute increase in the activity of the animals, which in turn phase-shifts the circadian clock. Surprisingly, single injections of benzodiazepines do not phase-shift the activity rhythm of old hamsters, despite the fact that such treatment induces similar acute changes in the activity state of young and old animals. We compared the entraining effects of repeated injections of triazolam on the circadian clock of young and old hamsters; while six out of seven young hamsters were entrained to the triazolam injections, only one out of seven old animals was entrained by this treatment. Three of the remaining six old hamsters showed a lengthening of the activity rhythm, while no consistent effect on the period of the activity rhythm was observed in the remaining three old animals. These results indicate that the circadian system of old hamsters becomes selectively unresponsive to synchronizing signals mediated by the activity-rest state, and suggest that aging is associated with a weakened coupling between the activity-rest cycle and the circadian clock.

Aging↗