Biomedical subjects

M R Ralph

Publications and source records attributed to M R Ralph.

At least 19 recordsLinked to original sources

PubMed2002

Senescence, sleep, and circadian rhythms.

The goal of this review article is to summarize our knowledge and understanding of the overlapping (interdisciplinary) areas of senescence, sleep, and circadian rhythms. Our overview comprehensively (and visually wherever possible), emphasizes the organizational, dynamic, and plastic nature of both sleep and circadian timing system (CTS) during senescent processes in animals and in humans. In this review, we focus on the studies that deal with sleep and circadian rhythms in aged animals and how these studies have closely correlated to and advanced our understanding of similar processes in ageing humans. Our comprehensive summary of various aspects of the existing research on animal and human ageing, both normal and pathological, presented in this review underscores the invaluable advantage of close collaboration between clinicians and basic research scientists and the future challenges inherent in this collaboration. First, our review addresses the common age-related changes that occur in sleep and temporal organization of both animals and humans. Second, we examine the specific modifications that often accompany sleep and CTS during aging. Third, we discuss the clinical epidemiology of sleep dysfunctions during ageing and their current clinical management, both pharmacological and non-pharmacological. Finally, we predict the possible future promises for complementary and alternative medicine (CAM) that pave the way to the emergence of a "Holistic Sleep Medicine" approach to the treatment of sleep disorders in the ageing population. Further studies will provide additional valuable insights into the understanding of both sleep and circadian rhythms during senescence.

Aging↗

PubMed2001

Circadian phase-shifted rats show normal acquisition but impaired long-term retention of place information in the water task.

It is thought that circadian rhythms may influence learning and memory processes. However, research supporting this view does not dissociate a mnemonic impairment from other performance deficits. Furthermore, published reports do not specify the type of memory system influenced by the circadian system. The present study assessed the effects of phase shifting on acquisition and expression of place navigation in the water maze, a task sensitive to hippocampal dysfunction. The results showed that phase-shifting circadian rhythms in rats impaired the expression of place information on a retention test but not initial acquisition or encoding of place information. These results suggest that disruption of circadian rhythms may impair consolidation of previously encoded hippocampal place information.

Animals↗

PubMed2000

Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells.

Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. The bar-pressing rate was determined at a range of frequencies each day to evaluate the effects of infusions on reward. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Two control oligos had only slight effects (means of 5 and 11% for missense and sense oligos, respectively). After the infusion, the required frequency shifted back to baseline levels gradually over 1-5 d. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward.

Animals↗

PubMed2000

Circadian rhythms, aging and memory.

In human beings and animal models, cognitive performance is often impaired in natural and experimental situations where circadian rhythms are disrupted. This includes a general decline in cognitive ability and fragmentation of behavioural rhythms in the aging population of numerous species. There is some evidence that rhythm disruption may lead directly to cognitive impairment; however, this causal link has not been made for effects due to aging. We have tested this link by examining rhythms and performance on contextual conditioning with the conditioned place preference task, in elderly, age-matched hamsters. Young healthy hamsters developed a preference for a context that is paired with the opportunity to engage in wheel-running (experiment 1). Aged animals with consolidated locomotor rhythms developed similar degrees of preference, whereas the age-matched hamsters with fragmented rhythms did not (experiment 2). The degree of preference was also correlated with activity amplitude. These results support the notion that age-related rhythm fragmentation contributes to the age-related memory decline.

Aging↗

PubMed2000

Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau.

The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIepsilon), a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKIepsilon enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIepsilon can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIepsilon and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.

Alleles↗

PubMed2000

The effect of amphetamine on locomotion depends on the motor device utilized. The open field vs. the running wheel.

The effect of amphetamine on the level of locomotion exhibited on two different motor devices was examined in the Golden hamster. Increasing concentrations of the psychostimulant from 4 to 10 mg/kg significantly enhanced locomotor activity in hamsters exposed to an open field. A further increase to 25 mg/kg inhibited ambulatory activity to levels below the control baseline, while augmenting the occurrence of stereotypic behaviors. The activating effect of amphetamine on ambulatory activity was observed regardless of the time of testing (day or night) or lighting condition, with no apparent modulation by the circadian system. On the other hand, home-cage wheel-running activity was maximally inhibited by 10 mg/kg amphetamine, whereas a smaller dosage (1.5 mg/kg) had no effect over the wheel-running activity baseline of saline controls. Although both the running wheel and the open field quantify locomotion, the dissociation obtained shows that they measure different components of it. The results are interpreted within Lyon and Randrup's hypothesis on the actions of amphetamine (16).

Animals↗

PubMed2000

Circadian rhythms, aging and memory.

Aging↗

PubMed1999

Retinal GABA(A) receptors participate in the regulation of circadian responses to light.

A role for retinal gamma-aminobutyric acid Type A (GABA(A)) receptors in the regulation of circadian responses to light was examined. Intraocular injections of the GABA(A) antagonist, bicuculline, were performed during the early (Circadian Time [CT] 13.5) and late subjective night (CT 20), followed by a light pulse. Bicuculline significantly decreased the magnitude of phase delays induced by light to 65%, whereas it had no effect on phase advances. To explore the nature of the inhibition elicited by bicuculline, an intensity-response curve was performed. Intraocular injections of bicuculline inhibited phase delays only when induced by high-saturating light illuminances (20 and 100 lux). No effect was observed at light intensities < or = 5 lux. These results suggest that retinal GABA(A) receptors modulate the responsivity of the circadian system to light.

Animals↗

PubMed1998

Conservation of locomotor behavior in the golden hamster: effects of light cycle and a circadian period mutation.

Locomotor activity in rodents is restricted temporally by the animal' s circadian system. The relative stability of both the species-specific pattern and the amount of locomotor activity per cycle suggested that this behavior may be regulated by conservative mechanisms. In these experiments, the wheel-running behavior of golden hamsters carrying the circadian period mutation, tau, was analyzed in animals housed in a 24-h light:dark cycle (LD) and in constant dark (DD) conditions to determine which aspects of this behavior were conserved. In DD, apart from the change in period which defines the mutation, no main effects of allele combination were found in either average amount of activity, activity profile, or length of the activity phase. In LD, wild-type behavior did not differ from that in DD; however, heterozygous mutants exhibited early onsets of activity, significant fragmentation of both activity and rest, an increase in the duration of the active phase, and an overall decrease in the amount of activity. Despite these differences, the total amount of time spent on the wheel in LD or DD was the same for all environment/genotype combinations. The data show that a conservative mechanism that may influence daily patterns of locomotor behavior is related more to a drive to perform the behavior than the quantity or timing of the behavior itself.

Animals↗

PubMed1998

The significance of circadian organization for longevity in the golden hamster.

While functional roles for biological clocks have been demonstrated in organisms throughout phylogeny, the adaptive advantages of circadian organization per se are largely matters of conjecture. It is generally accepted, though without direct experimental evidence, that organisms derive primary benefits from the temporal organization of their physiology and behavior, as well as from the anticipation of daily changes in their environment and their own fluctuating physiological requirements. However, the consequences of circadian dysfunction that might demonstrate a primary adaptive advantage and explain the natural origins and apparent ubiquity of circadian systems have not been documented. The authors report that longevity in hamsters is decreased with a noninvasive disruption of rhythmicity and is increased in older animals given suprachiasmatic implants that restore higher amplitude rhythms. The results substantiate the importance of the temporal organization of physiology and behavior provided by the circadian clock to the health and longevity of an organism.

Aging↗

PubMed1997

Regulation of circadian photic responses by nitric oxide.

A role for nitric oxide in circadian responses to light has been indicated in previous studies. To determine the specific function of NO-, the authors manipulated NO- and nitric oxide synthase (NOS) activity prior to light pulses that would normally induce phase shifts. The NOS inhibitor, L-NAME, selectively attenuated phase advances of locomotor rhythms and had no effect on phase delays. The NO- donor, SNAP, potentiated both photic responses, and phase delays were larger than the maximum responses that could be obtained with light alone. The date suggest a model in which NO- participates in the adaptation of the system to environmental lighting conditions by regulating in a phase-dependent manner responsiveness to light.

Animals↗

PubMed1996

The circadian system of c-fos deficient mice.

We examined the role of c-fos in the synchronization of circadian rhythms to environmental light cycles using a line of gene-targeted mice carrying a null mutation at this locus. Circadian locomotor rhythms in mutants had similar periods as wild-type controls but took significantly longer than controls to entrain to 12:12 light-dark cycles. Light-induced phase shifts of rhythms in constant dark were attenuated in mutants although the circadian timing of phase delays and advances was not changed. A functional retinohypothalamic projection was indicated from behavioral results and light-induced jun-B expression in the SCN. The results indicate that while c-fos activation is not an absolute requirement for rhythm generation nor photic responses, it is required for normal entrainment of the mammalian biological clock.

Animals↗

PubMed1996

Regulation and integration in the mammalian circadian system.

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Animals↗

PubMed1996

cGMP-dependent protein kinase inhibitors block light-induced phase advances of circadian rhythms in vivo.

Synchronization of circadian rhythms is thought to be accomplished primarily through daily phase delays and advances of the endogenous circadian clock that, in mammals, is located in the hypothalamic suprachiasmatic nucleus (SCN). In the SCN, numerous second messenger pathways may participate in photic signal transduction. In these studies, the involvement of cyclic nucleotide-dependent kinases was examined in vivo using inhibitors of adenosine 3',5'-cyclic monophosphate (cAMP)- and guanosine 3',5'-cyclic monophosphate (cGMP)-dependent kinase (PKA and PKG, respectively). In constant dark, selective and nonselective inhibitors of PKG injected near the SCN of hamsters had no effect on phase delays produced by light pulses given in the early subjective night (early in the animals' active period) but significantly attenuated phase advances induced late in the subjective night. PKA inhibition had no effect at either time point. In addition, cGMP agonists had no effect on rhythmicity in the absence of light. The results suggest that PKG activity is necessary, but not sufficient, for normal photic responsiveness and that PKA activity is not required. The phase dependence of the effect of PKG inhibition supports the notion that photic entrainment is influenced by biochemical pathways that differentially regulate sensitivity in a phase-dependent manner.

Alkaloids↗

PubMed1996

Pacemaker interactions in the mammalian circadian system.

Circadian rhythms in mammals are generated by pacemaker cells located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The identity of these cells, however, is not known, and little information exists regarding the mechanisms by which they communicate with each other and with the organism. Nonetheless, pacemaker interactions must occur to produce single, coherent rhythms of behavior and physiology. Recently it has become possible to observe the result of these interactions using circadian chimeras, animals with two clocks with distinct periods, that have been produced by SCN transplantation. Using the tau mutation in golden hamsters, chimeras expressing two circadian rhythms of behavior simultaneously were created. The two rhythms exhibited complex interactions including cases of relative coordination. This basic result indicates that pacemaker interactions are rhythmic and phase dependent. Further analysis should help to elucidate the nature of the coupling signal and the identity of the pacemaker cells.

Animals↗

PubMed1996

Let there be light: signal transduction in a mammalian circadian system.

Mammalian circadian rhythms are controlled by a biological clock located in the hypothalamic suprachiasmatic nuclei (SCN). This clock is entrained by light through a retinohypothalamic pathway that interacts with the SCN through glutamate neurotransmission. Light pulses during the subjective night induce phase shifts of behavioral rhythms, and also trigger intracellular changes such as the expression of immediate-early genes and activation of transcription factors. In this review, we present a model of the signal transduction pathway leading to photic synchronization of the circadian clock, including the activity of specific second messenger systems, gene expression, and interaction between potential agents capable of producing phase shifts.

Animals↗

PubMed1995

Circadian responses to light: the calmodulin connection.

KN-62, an inhibitor of CaM kinase II, attenuated phase shifts induced by low intensity light pulses and reduced light-induced phosphorylation of the transcription factor, CREB, in the suprachiasmatic nucleus. The calmodulin inhibitor, W-7, had similar effects: neither drug produced a complete block of photic responses. The results support the hypothesis that circadian responses to light are mediated in part by CaM kinase activity and CREB, and suggest that other signal transduction pathways also take part.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1995

Circadian pacemakers in vertebrates.

The identification and isolation of circadian pacemaker cells is of critical importance to studies of circadian clocks at all phylogenetic levels. In the vertebrate classes, a few structures of diencephalic origin have been implicated as potential sites but for only two, the avian pineal and the mammalian suprachiasmatic nucleus (SCN), has a pacemaker role in addition to oscillatory behaviour been demonstrated by the transfer of pacemaker properties from one organism to another. Studies of the mammalian system in particular have benefited from the ability to restore circadian function using transplantation of tissue from the SCN and from the availability of a hamster period mutant, tau, that allows donor-derived and host-derived rhythms to be distinguished easily. Initial cross-genotype transplantation studies and the subsequent creation of circadian chimeras expressing two phenotypes simultaneously demonstrated the pacemaker capability of the SCN, and demonstrated the relative autonomy of this nucleus as a pacemaking structure. Despite an abundance of information regarding the anatomy, physiology and pharmacology of these nuclei, the identity of the pacemaker cells and their methods of communication with each other and the organism remain obscure. None the less, it is possible under certain conditions to create chimeras with two clocks that interact. The behaviour of these animals provides a unique opportunity to study the nature and timing of pacemaker communication.

Animals↗