Martin Ralph | University of Toronto (original) (raw)

Papers by Martin Ralph

Monthly Weather Review, 2006

Observations from northern California during the California Landfalling Jets (CALJET) experiment ... more Observations from northern California during the California Landfalling Jets (CALJET) experiment are used to examine the mean characteristics of precipitation and their variances as functions of synoptic and topographic regimes. Ten cases involving the landfall of extratropical cyclones are analyzed with radar and rain gauge data collected at two sites: one in the coastal mountains north of San Francisco (CZD) and the other in the Central Valley just west of Sacramento (KDAX). Aside from the melting-layer bright band, the most striking feature in the 10-case composite vertical profile of radar reflectivity at CZD was a distinct change in slope about 2.5 km above the bright band. This “shoulder” is thought to represent a change in the growth rate of hydrometeors. Although the bright band was quite distinct, about one-third of the profiles in the composite did not exhibit this feature. These nonbrightband (NBB) profiles had a low-level slope where reflectivity increased with decreasin...

Pharmacology Biochemistry and Behavior, 1997

The cholinergic system is known to show deterioration during aging and Alzheimer's disease. In re... more The cholinergic system is known to show deterioration during aging and Alzheimer's disease. In response, a therapeutic approach to Alzheimer's disease has been to attempt to compensate for the decrease in central cholinergic function by potentiating the activity of the remaining intact cholinergic cells with cholinesterase inhibitors. In this study treatment with the long-lasting cholinesterase inhibitor metrifonate enhanced acquisition of eyeblink conditioning in aging rabbits without producing interfering side effects. The effects of metrifonate on central and peripheral cholinesterase activity were evaluated, as was the involvement of plasma atropine esterase activity on the central and peripheral response to metrifonate. Results demonstrate that metrifonate can produce predictable, dose-dependent ChE inhibition. Associative learning in the aging rabbit was improved by metrifonate-induced steady state ChE inhibition within a range of 30-80%. Metrifonate was behaviorally effective in the absence of the severe side effects which typically plague cholinesterase inhibitors, suggesting that metrifonate is a possible treatment for the cognitive deficits resulting from normal aging and Alzheimer's disease.

Chronobiology International, 2009

Circadian rhythms rely on the interaction of highly conserved transcription-translation loops. Ca... more Circadian rhythms rely on the interaction of highly conserved transcription-translation loops. Casein kinase I epsilon (CK1epsilon) post-transcriptionally regulates circadian rhythms by phosphorylating clock genes, and the tau mutation, an arginine to cysteine substitution at residue 128, results in a short circadian period, abnormal entrainment to light cycles, and potentiated resetting responses to light. Each of these effects could be attributed to changes in the regulation of the core molecular circadian loops. We now demonstrate that the mutation results in a heightened sensitivity to light, suggesting that CK1epsilon also regulates the photic entrainment pathway.

Neuroscience Letters, Jun 1, 1995

KN-62, an inhibitor of CaM kinase II, attenuated phase shifts induced by low intensity light puls... more 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.

The Journal of Neuroscience, Sep 1, 1991

Behavioral Neuroscience, 2004

Circadian rhythms in rodents respond to arousing, nonphotic stimuli that contribute to daily patt... more Circadian rhythms in rodents respond to arousing, nonphotic stimuli that contribute to daily patterns of entrainment. To examine whether the motivational significance of a stimulus is important for eliciting nonphotic circadian phase shirts in Syrian hamsters (Mesocricetus auratus), the authors compared responses to a highly rewarding stimulus (lateral hypothalamic brain stimulation reward [BSR]) and a highly aversive stimulus (footshock). Animals were housed on a 14:10-hr light-dark cycle until test day, when they were given a 1-hr BSR session (trained animals) or a 1-mA electric footshock at 1 of 8 circadian times, and were maintained in constant dark thereafter. Both BSR pulses and footshock produced nonphotic phase response curves. These results support the hypothesis that arousal resulting from the motivational significance of a stimulus is a major factor in nonphotic phase shifts.

Biological Rhythm Research, Apr 1, 2003

In hamsters, the expression of a learned preference for context depends upon a temporal match bet... more In hamsters, the expression of a learned preference for context depends upon a temporal match between the time of training and testing. In the present experiments, we investigated the role of the biological clock in the suprachiasmatic nucleus (SCN) as a provider of temporal information underlying this time dependent modulation of cognitive performance. Hamsters were tested using the conditioned place preference task (CPP) before and after ablation of the SCN. Arrhythmic animals continued to show time-of-day modulation of the CPP when trained and tested in the absence of the SCN. This supports the notion that time of day information is a component of context representation for the hamster (Antoniadis et al., 1999), and indicates that an oscillator outside of the SCN is responsible for time discrimination in reward-based learning.

Journal of Biological Rhythms, Aug 1, 1997

A role for nitric oxide in circadian responses to light has been indicated in previous studies. T... more 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, selec tively 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 data 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.

American Journal of Physiology-regulatory Integrative and Comparative Physiology, May 1, 2008

Sleep deprivation, shift work, and jet lag all disrupt normal biological rhythms and have major i... more Sleep deprivation, shift work, and jet lag all disrupt normal biological rhythms and have major impacts on health; however, circadian disorganization has never been shown as a causal risk factor in organ disease. We now demonstrate devastating effects of rhythm disorganization on cardiovascular and renal integrity and that interventions based on circadian principles prevent disease pathology caused by a short-period mutation (tau) of the circadian system in hamsters. The point mutation in the circadian regulatory gene, casein kinase-1⑀, produces early onset circadian entrainment with fragmented patterns of behavior in ϩ/tau heterozygotes. Animals die at a younger age with cardiomyopathy, extensive fibrosis, and severely impaired contractility; they also have severe renal disease with proteinuria, tubular dilation, and cellular apoptosis. On light cycles appropriate for their genotype (22 h), cyclic behavioral patterns are normalized, cardiorenal phenotype is reversed, and hearts and kidneys show normal structure and function. Moreover, hypertrophy does not develop in animals whose suprachiasmatic nucleus was ablated as young adults. Circadian organization therefore is critical for normal health and longevity, whereas chronic global asynchrony is implicated in the etiology of cardiac and renal disease.

Ageing Research Reviews, Jun 1, 2002

The goal of this review article is to summarize our knowledge and understanding of the overlappin... more 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.

Journal of Cardiac Failure, Aug 1, 2004

Life Sciences, Feb 1, 1997

Journal of Cardiac Failure, Aug 1, 2004

Elsevier eBooks, 1996

Publisher Summary This chapter focuses on some evidence for signal integration within the circadi... more Publisher Summary This chapter focuses on some evidence for signal integration within the circadian system at anatomical, cellular, and chemical levels of organization. It also examines the idea that a primary function of the temporal organization of photic and non-photic responsiveness is to precisely define the transitions among organisms' physiological day and night. The influence of non-photic events may be critically important for the day-to-day regulation of physiological and behavioral timing. Phase angle of entrainment is a primary phenotypic expression of the circadian system that is subject to natural selection, and numerous mechanisms may have evolved to adjust species-specific entrainment or to allow individuals to briefly adjust for the daily exigencies of their environment. The fact that circadian systems are designed to allow the interaction of photic and non-photic responses at many levels of organization attests to the need for integration in the regulation of entrainment. The accuracy and stability of entrainment, and the precision of some overt circadian rhythms, rely not only on the ability to respond to a Zeitgeber but also on the ability to integrate the variety of signals that may directly alter the phase or affect the responsiveness of the clock to other Zeitgeber and regulatory input.

PLOS Biology, Oct 28, 2010

Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report h... more Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN) of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cellautonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.

American Journal of Physiology-regulatory Integrative and Comparative Physiology, May 1, 1996

Synchronization of circadian rhythms is thought to be accomplished primarily through daily phase ... more 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.

Physiology & Behavior, Aug 1, 1998

Locomotor activity in rodents is restricted temporally by the animal's circadian system. The rela... more 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.

Journal of Comparative Physiology A-neuroethology Sensory Neural and Behavioral Physiology, Mar 1, 1990

The ocular circadian rhythm of compound action potential frequency in Bulla gouldiana is driven b... more The ocular circadian rhythm of compound action potential frequency in Bulla gouldiana is driven by rhythmic changes in the membrane potential of putative circadian pacemaker cells. Changes in the membrane potential of these neurons is required for light-induced phase shifts of the rhythm. We have tested the proposition that these changes in membrane potential reflect underlying changes in ionic conductances. We have found that: 1. Membrane conductance in the dark is highest during the subjective night when the cells are hyperpolarized, decreases as the cells depolarize spontaneously near projected dawn and is lowest during the subjective day. The changes in membrane potential and conductance follow a similar time course. 2. Long pulses of light delivered to eyes during their subjective night produce a characteristic response: There is initially a large, phasic depolarization accompanied by a burst of CAPs; this is followed by a repolarizing phase during which CAP activity is reduced to zero; and finally a tonic depolarization develops that is accompanied by a resumption of CAP activity at a steady rate. 3. During the subjective night, the tonic depolarization is accompanied by a decrease in conductance compared to the previous dark value. However, light pulses of similar duration delivered to eyes during their subjective day causes tonic depolarizations and increased CAP activity, but no measurable change in conductance. 4. Membrane responses to light are sensitive to agents that reduce Ca2+ flux. Light pulses during the subjective night produce a phasic depolarization, but the repolarization phase is eliminated in low Ca2+/EGTA seawater and is reduced in 5 mM Ni2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurobiology of Learning and Memory, May 1, 2004

In golden hamsters, the expression of a conditioned place preference (CPP) or avoidance (CPA) is ... more In golden hamsters, the expression of a conditioned place preference (CPP) or avoidance (CPA) is regulated in a circadian pattern such that the preference and avoidance are exhibited strongly at the circadian time of prior training, but not at other circadian times. In the rat, reports are conflicting regarding whether time of day learning is evident. We investigated whether this conflict arises because different strains of rat have been used. In this experiment, Long Evans and Wistar rats were trained at a specific circadian time to discriminate between a context paired with food reward and an unpaired context. Animals were then tested for preference at the same or a different circadian time. Long Evans rats showed preference for the paired context at both times tested, whereas Wistar rats showed preference only when training and testing times matched. The results show that time of day learning can be generalized to rats using the Wistar strain.

Monthly Weather Review, 2006

Observations from northern California during the California Landfalling Jets (CALJET) experiment ... more Observations from northern California during the California Landfalling Jets (CALJET) experiment are used to examine the mean characteristics of precipitation and their variances as functions of synoptic and topographic regimes. Ten cases involving the landfall of extratropical cyclones are analyzed with radar and rain gauge data collected at two sites: one in the coastal mountains north of San Francisco (CZD) and the other in the Central Valley just west of Sacramento (KDAX). Aside from the melting-layer bright band, the most striking feature in the 10-case composite vertical profile of radar reflectivity at CZD was a distinct change in slope about 2.5 km above the bright band. This “shoulder” is thought to represent a change in the growth rate of hydrometeors. Although the bright band was quite distinct, about one-third of the profiles in the composite did not exhibit this feature. These nonbrightband (NBB) profiles had a low-level slope where reflectivity increased with decreasin...

Pharmacology Biochemistry and Behavior, 1997

The cholinergic system is known to show deterioration during aging and Alzheimer's disease. In re... more The cholinergic system is known to show deterioration during aging and Alzheimer's disease. In response, a therapeutic approach to Alzheimer's disease has been to attempt to compensate for the decrease in central cholinergic function by potentiating the activity of the remaining intact cholinergic cells with cholinesterase inhibitors. In this study treatment with the long-lasting cholinesterase inhibitor metrifonate enhanced acquisition of eyeblink conditioning in aging rabbits without producing interfering side effects. The effects of metrifonate on central and peripheral cholinesterase activity were evaluated, as was the involvement of plasma atropine esterase activity on the central and peripheral response to metrifonate. Results demonstrate that metrifonate can produce predictable, dose-dependent ChE inhibition. Associative learning in the aging rabbit was improved by metrifonate-induced steady state ChE inhibition within a range of 30-80%. Metrifonate was behaviorally effective in the absence of the severe side effects which typically plague cholinesterase inhibitors, suggesting that metrifonate is a possible treatment for the cognitive deficits resulting from normal aging and Alzheimer's disease.

Chronobiology International, 2009

Circadian rhythms rely on the interaction of highly conserved transcription-translation loops. Ca... more Circadian rhythms rely on the interaction of highly conserved transcription-translation loops. Casein kinase I epsilon (CK1epsilon) post-transcriptionally regulates circadian rhythms by phosphorylating clock genes, and the tau mutation, an arginine to cysteine substitution at residue 128, results in a short circadian period, abnormal entrainment to light cycles, and potentiated resetting responses to light. Each of these effects could be attributed to changes in the regulation of the core molecular circadian loops. We now demonstrate that the mutation results in a heightened sensitivity to light, suggesting that CK1epsilon also regulates the photic entrainment pathway.

Neuroscience Letters, Jun 1, 1995

KN-62, an inhibitor of CaM kinase II, attenuated phase shifts induced by low intensity light puls... more 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.

The Journal of Neuroscience, Sep 1, 1991

Behavioral Neuroscience, 2004

Circadian rhythms in rodents respond to arousing, nonphotic stimuli that contribute to daily patt... more Circadian rhythms in rodents respond to arousing, nonphotic stimuli that contribute to daily patterns of entrainment. To examine whether the motivational significance of a stimulus is important for eliciting nonphotic circadian phase shirts in Syrian hamsters (Mesocricetus auratus), the authors compared responses to a highly rewarding stimulus (lateral hypothalamic brain stimulation reward [BSR]) and a highly aversive stimulus (footshock). Animals were housed on a 14:10-hr light-dark cycle until test day, when they were given a 1-hr BSR session (trained animals) or a 1-mA electric footshock at 1 of 8 circadian times, and were maintained in constant dark thereafter. Both BSR pulses and footshock produced nonphotic phase response curves. These results support the hypothesis that arousal resulting from the motivational significance of a stimulus is a major factor in nonphotic phase shifts.

Biological Rhythm Research, Apr 1, 2003

In hamsters, the expression of a learned preference for context depends upon a temporal match bet... more In hamsters, the expression of a learned preference for context depends upon a temporal match between the time of training and testing. In the present experiments, we investigated the role of the biological clock in the suprachiasmatic nucleus (SCN) as a provider of temporal information underlying this time dependent modulation of cognitive performance. Hamsters were tested using the conditioned place preference task (CPP) before and after ablation of the SCN. Arrhythmic animals continued to show time-of-day modulation of the CPP when trained and tested in the absence of the SCN. This supports the notion that time of day information is a component of context representation for the hamster (Antoniadis et al., 1999), and indicates that an oscillator outside of the SCN is responsible for time discrimination in reward-based learning.

Journal of Biological Rhythms, Aug 1, 1997

A role for nitric oxide in circadian responses to light has been indicated in previous studies. T... more 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, selec tively 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 data 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.

American Journal of Physiology-regulatory Integrative and Comparative Physiology, May 1, 2008

Sleep deprivation, shift work, and jet lag all disrupt normal biological rhythms and have major i... more Sleep deprivation, shift work, and jet lag all disrupt normal biological rhythms and have major impacts on health; however, circadian disorganization has never been shown as a causal risk factor in organ disease. We now demonstrate devastating effects of rhythm disorganization on cardiovascular and renal integrity and that interventions based on circadian principles prevent disease pathology caused by a short-period mutation (tau) of the circadian system in hamsters. The point mutation in the circadian regulatory gene, casein kinase-1⑀, produces early onset circadian entrainment with fragmented patterns of behavior in ϩ/tau heterozygotes. Animals die at a younger age with cardiomyopathy, extensive fibrosis, and severely impaired contractility; they also have severe renal disease with proteinuria, tubular dilation, and cellular apoptosis. On light cycles appropriate for their genotype (22 h), cyclic behavioral patterns are normalized, cardiorenal phenotype is reversed, and hearts and kidneys show normal structure and function. Moreover, hypertrophy does not develop in animals whose suprachiasmatic nucleus was ablated as young adults. Circadian organization therefore is critical for normal health and longevity, whereas chronic global asynchrony is implicated in the etiology of cardiac and renal disease.

Ageing Research Reviews, Jun 1, 2002

The goal of this review article is to summarize our knowledge and understanding of the overlappin... more 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.

Journal of Cardiac Failure, Aug 1, 2004

Life Sciences, Feb 1, 1997

Journal of Cardiac Failure, Aug 1, 2004

Elsevier eBooks, 1996

Publisher Summary This chapter focuses on some evidence for signal integration within the circadi... more Publisher Summary This chapter focuses on some evidence for signal integration within the circadian system at anatomical, cellular, and chemical levels of organization. It also examines the idea that a primary function of the temporal organization of photic and non-photic responsiveness is to precisely define the transitions among organisms' physiological day and night. The influence of non-photic events may be critically important for the day-to-day regulation of physiological and behavioral timing. Phase angle of entrainment is a primary phenotypic expression of the circadian system that is subject to natural selection, and numerous mechanisms may have evolved to adjust species-specific entrainment or to allow individuals to briefly adjust for the daily exigencies of their environment. The fact that circadian systems are designed to allow the interaction of photic and non-photic responses at many levels of organization attests to the need for integration in the regulation of entrainment. The accuracy and stability of entrainment, and the precision of some overt circadian rhythms, rely not only on the ability to respond to a Zeitgeber but also on the ability to integrate the variety of signals that may directly alter the phase or affect the responsiveness of the clock to other Zeitgeber and regulatory input.

PLOS Biology, Oct 28, 2010

Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report h... more Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN) of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cellautonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.

American Journal of Physiology-regulatory Integrative and Comparative Physiology, May 1, 1996

Synchronization of circadian rhythms is thought to be accomplished primarily through daily phase ... more 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.

Physiology & Behavior, Aug 1, 1998

Locomotor activity in rodents is restricted temporally by the animal's circadian system. The rela... more 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.

Journal of Comparative Physiology A-neuroethology Sensory Neural and Behavioral Physiology, Mar 1, 1990

The ocular circadian rhythm of compound action potential frequency in Bulla gouldiana is driven b... more The ocular circadian rhythm of compound action potential frequency in Bulla gouldiana is driven by rhythmic changes in the membrane potential of putative circadian pacemaker cells. Changes in the membrane potential of these neurons is required for light-induced phase shifts of the rhythm. We have tested the proposition that these changes in membrane potential reflect underlying changes in ionic conductances. We have found that: 1. Membrane conductance in the dark is highest during the subjective night when the cells are hyperpolarized, decreases as the cells depolarize spontaneously near projected dawn and is lowest during the subjective day. The changes in membrane potential and conductance follow a similar time course. 2. Long pulses of light delivered to eyes during their subjective night produce a characteristic response: There is initially a large, phasic depolarization accompanied by a burst of CAPs; this is followed by a repolarizing phase during which CAP activity is reduced to zero; and finally a tonic depolarization develops that is accompanied by a resumption of CAP activity at a steady rate. 3. During the subjective night, the tonic depolarization is accompanied by a decrease in conductance compared to the previous dark value. However, light pulses of similar duration delivered to eyes during their subjective day causes tonic depolarizations and increased CAP activity, but no measurable change in conductance. 4. Membrane responses to light are sensitive to agents that reduce Ca2+ flux. Light pulses during the subjective night produce a phasic depolarization, but the repolarization phase is eliminated in low Ca2+/EGTA seawater and is reduced in 5 mM Ni2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurobiology of Learning and Memory, May 1, 2004

In golden hamsters, the expression of a conditioned place preference (CPP) or avoidance (CPA) is ... more In golden hamsters, the expression of a conditioned place preference (CPP) or avoidance (CPA) is regulated in a circadian pattern such that the preference and avoidance are exhibited strongly at the circadian time of prior training, but not at other circadian times. In the rat, reports are conflicting regarding whether time of day learning is evident. We investigated whether this conflict arises because different strains of rat have been used. In this experiment, Long Evans and Wistar rats were trained at a specific circadian time to discriminate between a context paired with food reward and an unpaired context. Animals were then tested for preference at the same or a different circadian time. Long Evans rats showed preference for the paired context at both times tested, whereas Wistar rats showed preference only when training and testing times matched. The results show that time of day learning can be generalized to rats using the Wistar strain.