Phase-shifting effects of acute increases in activity on circadian locomotor rhythms in hamsters

Experiments were conducted in golden hamsters to examine the relationship between induced acute increases in locomotor activity and phase shifts in the circadian clock underlying the rhythm of activity. Injections of the short-acting benzodiazepine triazolam (TZ) 6 h before the onset of activity resulted in an acute increase in activity and a phase advance in the rhythm of activity; injections of TZ induced larger phase shifts in animals housed without running wheels than in those housed with wheels. Transfer to a cage with access to a running wheel for 1 h at different circadian times induced large phase advances (mean of 2 h) and small phase delays depending on the circadian time of transfer. Maximal mean phase advances resulted when animals were transferred to a cage with wheel 3 h before activity onset, and at this circadian time there was a significant correlation between the magnitude of the phase shift and the amount of increase over baseline activity for the first hour after transfer. These results indicate that access to a running wheel in animals housed without wheels can be a significant phase-shifting stimulus to the circadian clock and that the phase shifts induced by injection of TZ or transfer to a new cage with wheel are related to the activity state of the animal or to the amount of locomotor activity that is induced at particular times.

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Aging alters feedback effects of the activity-rest cycle on the circadian clock

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.263.4.r981 ◽

1992 ◽

Vol 263 (4) ◽

pp. R981-R986 ◽

Cited By ~ 10

Author(s):

O. Van Reeth ◽

Y. Zhang ◽

P. C. Zee ◽

F. W. Turek

Keyword(s):

Locomotor Activity ◽

Circadian Clock ◽

Phase Shifts ◽

Circadian System ◽

Phase Shifting ◽

Protein Synthesis Inhibitors ◽

Feedback Effects ◽

Age Related ◽

Level Of Activity ◽

Acute Change

Two different stimuli (i.e., benzodiazepines and dark pulses) inducing phase shifts in the circadian clock of young hamsters through changes in the level of activity do not induce phase shifts in old hamsters, despite the fact that these stimuli induce a similar acute change in locomotor activity in young and old animals. In contrast, old hamsters remain sensitive to the phase-shifting effects of stimuli clearly not associated with any change in locomotor activity (i.e., protein synthesis inhibitors or light). Thus the circadian system of old animals becomes selectively unresponsive to synchronizing signals mediated by the activity-rest state of the animals. Previous age-related changes in circadian rhythmicity that have been observed in mammals, including humans, may be related to a weakened coupling between the activity-rest cycle and the circadian clock.

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General Anaesthesia Shifts the Murine Circadian Clock in a Time-Dependant Fashion

Clocks & Sleep ◽

10.3390/clockssleep3010006 ◽

2021 ◽

Vol 3 (1) ◽

pp. 87-97

Author(s):

Nicola M. Ludin ◽

Alma Orts-Sebastian ◽

James F. Cheeseman ◽

Janelle Chong ◽

Alan F. Merry ◽

...

Keyword(s):

Circadian Clock ◽

General Anaesthesia ◽

Wheel Running ◽

Phase Shifts ◽

Time Dependent ◽

Suprachiasmatic Nuclei ◽

Response Curves ◽

Inhalational Anaesthetic ◽

Locomotor Rhythms ◽

Time Dependent Analysis

Following general anaesthesia (GA), patients frequently experience sleep disruption and fatigue, which has been hypothesized to result at least in part by GA affecting the circadian clock. Here, we provide the first comprehensive time-dependent analysis of the effects of the commonly administered inhalational anaesthetic, isoflurane, on the murine circadian clock, by analysing its effects on (a) behavioural locomotor rhythms and (b) PER2::LUC expression in the suprachiasmatic nuclei (SCN) of the mouse brain. Behavioural phase shifts elicited by exposure of mice (n = 80) to six hours of GA (2% isoflurane) were determined by recording wheel-running rhythms in constant conditions (DD). Phase shifts in PER2::LUC expression were determined by recording bioluminescence in organotypic SCN slices (n = 38) prior to and following GA exposure (2% isoflurane). Full phase response curves for the effects of GA on behaviour and PER2::LUC rhythms were constructed, which show that the effects of GA are highly time-dependent. Shifts in SCN PER2 expression were much larger than those of behaviour (c. 0.7 h behaviour vs. 7.5 h PER2::LUC). We discuss the implications of this work for understanding how GA affects the clock, and how it may inform the development of chronotherapeutic strategies to reduce GA-induced phase-shifting in patients.

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Ionic Currents of Isolated Retinal Pacemaker Neurons: Projected Daily Phase Differences and Selective Enhancement by a Phase-Shifting Neurotransmitter

Journal of Neurophysiology ◽

10.1152/jn.1997.77.6.3075 ◽

1997 ◽

Vol 77 (6) ◽

pp. 3075-3084 ◽

Cited By ~ 18

Author(s):

Steven Barnes ◽

Jon W. Jacklet

Keyword(s):

Circadian Rhythm ◽

Circadian Clock ◽

Primary Culture ◽

Voltage Clamp ◽

Ionic Currents ◽

Phase Shifts ◽

Phase Shifting ◽

Pacemaker Neurons ◽

Selective Enhancement ◽

Phase Differences

Barnes, Steven and Jon W. Jacklet. Ionic currents of isolated retinal pacemaker neurons: projected daily phase differences and selective enhancement by a phase-shifting neurotransmitter. J. Neurophysiol. 77: 3075–3084, 1997. The eye of Aplysia expresses a robust circadian rhythm of neuronal activity. We dissociated the retinal cells in primary culture and studied isolated pacemaker neurons to identify ionic currents that may have roles in the circadian clock mechanism. Individual neurons were studied with perforated-patch whole cell recording techniques in current- and voltage-clamp modes. Pacemaker neurons had resting potentials near −40 mV and, if neurites had grown out, produced spontaneous action potentials in darkness at <1 Hz. Depolarizing current injections increased the rate of action potential firing. Hyperpolarizing current injections were followed by slowly decaying (1–3 s) afterhyperpolarizations. Four ionic currents were characterized under voltage-clamp, including a Ca current ( I Ca), a voltage-gated potassium current ( I KV), an A current ( I A), and a hyperpolarization-activated Cl current ( I Cl). I Cl was only seen using Cl−-filled electrodes when high concentrations of Cl− diffused from the electrode and is therefore unlikely to be important under physiological conditions. The magnitude of I KV was significantly larger during the projected zeitgeber predawn phase than during the postdawn phase, whereas the magnitude of I A was constant at these circadian phases, suggesting that only I KV is controlled by the circadian clock. Serotonin increased I KV by 29%, consistent with reports that serotonin suppresses optic nerve activity and phase shifts the circadian rhythm recorded from the intact eye. The enhancement of I KV likely contributes to membrane hyperpolarization, and it may be required for phase shifting. The phase-dependent changes in I KV provide evidence that each retinal pacemaker neuron contains a circadian clock, but confirmation must await further recordings made from individual pacemaker neurons that are isolated completely from all other cells in primary culture. From the present experiments, it appears that I KV is controlled by the circadian clock, in part, and it may be a required element in the pathway that is activated during serotonin-induced phase shifts.

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The cholinergic forebrain arousal system acts directly on the circadian pacemaker

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610342113 ◽

2016 ◽

Vol 113 (47) ◽

pp. 13498-13503 ◽

Cited By ~ 15

Author(s):

Glenn R. Yamakawa ◽

Priyoneel Basu ◽

Filomeno Cortese ◽

Johanna MacDonnell ◽

Danica Whalley ◽

...

Keyword(s):

Circadian Clock ◽

Basal Forebrain ◽

Temporal Structure ◽

Phase Shifts ◽

Phase Shifting ◽

Suprachiasmatic Nuclei ◽

Functional Link ◽

Substantia Innominata ◽

Arousal System ◽

Important System

Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7- to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system.

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The Effects of General Anaesthesia and Light on Behavioural Rhythms and GABAA Receptor Subunit Expression in the Mouse SCN

Clocks & Sleep ◽

10.3390/clockssleep3030034 ◽

2021 ◽

Vol 3 (3) ◽

pp. 482-494

Author(s):

Janelle Chong ◽

James Frederick Cheeseman ◽

Matthew D. M. Pawley ◽

Andrea Kwakowsky ◽

Guy R. Warman

Keyword(s):

General Anaesthesia ◽

Phase Shifts ◽

Phase Shifting ◽

Response Curves ◽

Inhalational Anaesthetic ◽

Subunit Expression ◽

Locomotor Rhythms ◽

Wheel Activity ◽

Effect Of Light ◽

Gabaar Subunit

General anaesthesia (GA) is known to affect the circadian clock. However, the mechanisms that underlie GA-induced shifting of the clock are less well understood. Activation of γ-aminobutyric acid (GABA)-type A receptors (GABAAR) in the suprachiasmatic nucleus (SCN) can phase shift the clock and thus GABA and its receptors represent a putative pathway via which GA exerts its effect on the clock. Here, we investigated the concurrent effects of the inhalational anaesthetic, isoflurane, and light, on mouse behavioural locomotor rhythms and on α1, β3, and γ2 GABAAR subunit expression in the SCN of the mouse brain. Behavioural phase shifts elicited by exposure of mice to four hours of GA (2% isoflurane) and light (400 lux) (n = 60) were determined by recording running wheel activity rhythms in constant conditions (DD). Full phase response curves for the effects of GA + light on behavioural rhythms show that phase shifts persist in anaesthetized mice exposed to light. Daily variation was detected in all three GABAAR subunits in LD 12:12. The γ2 subunit expression was significantly increased following GA in DD (compared to light alone) at times of large behavioural phase delays. We conclude that the phase shifting effect of light on the mouse clock is not blocked by GA administration, and that γ2 may potentially be involved in the phase shifting effect of GA on the clock. Further analysis of GABAAR subunit expression in the SCN will be necessary to confirm its role.

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Feeding melatonin enhances the phase shifting response to triazolam in both young and old golden hamsters

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00362.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. R1382-R1388 ◽

Cited By ~ 7

Author(s):

Daniel E. Kolker ◽

Susan Losee Olson ◽

Jeanette Dutton-Boilek ◽

Katherine M. Bennett ◽

Edward P. Wallen ◽

...

Keyword(s):

Circadian Clock ◽

Activity Rhythm ◽

Age Groups ◽

Phase Shifting ◽

Melatonin Secretion ◽

Melatonin Treatment ◽

Age Related ◽

Circadian Time ◽

Timing System ◽

Circadian Timing System

Aging alters many aspects of circadian rhythmicity, including responsivity to phase-shifting stimuli and the amplitude of the rhythm of melatonin secretion. As melatonin is both an output from and an input to the circadian clock, we hypothesized that the decreased melatonin levels exhibited by old hamsters may adversely impact the circadian system as a whole. We enhanced the diurnal rhythm of melatonin by feeding melatonin to young and old hamsters. Animals of both age groups on the melatonin diet showed larger phase shifts than control-fed animals in response to an injection with the benzodiazepine triazolam at a circadian time known to induce phase advances in the activity rhythm of young animals. Thus melatonin treatment can increase the sensitivity of the circadian timing system of young animals to a nonphotic stimulus, and the ability to increase this sensitivity persists into old age, indicating exogenous melatonin might be useful in reversing at least some age-related changes in circadian clock function.

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Temperature dependence of the hamster circadian pacemaker

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1983.244.5.r607 ◽

1983 ◽

Vol 244 (5) ◽

pp. R607-R610 ◽

Cited By ~ 2

Author(s):

F. P. Gibbs

Keyword(s):

Locomotor Activity ◽

Temperature Dependence ◽

Circadian Pacemaker ◽

Dark Cycle ◽

Running Wheel ◽

Ether Anesthesia ◽

Method Of Calculation ◽

Circadian Time ◽

Activity Onset ◽

Reduced Rate

Blind male hamsters were maintained in running-wheel cages in a LD 12:12 light-dark cycle. After regular running patterns were established hypothermia was induced by ether anesthesia, wetting of the fur with ethanol, and cooling with ice. The hamsters were kept hypothermic for 3-24 h at colonic temperatures from 10 to 20 degrees C. Following hypothermia the animals were rewarmed and replaced in their home cages. Examination of the locomotor activity records showed phase shifts (delays) in activity onset that were correlated with the temperature and duration of the hypothermia but not with the circadian time at which the hypothermia was administered. The data were interpreted to mean that the circadian pacemaker was running at a reduced rate during the hypothermic bout. Calculation of the Q10 for the rate of the clock during hypothermia produced a range from 1.08 to 1.34 depending on the method of calculation. When compared with earlier data gathered from rats under similar conditions, the hamsters circadian pacemaker appears to be better temperature compensated.

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Cycloheximide-induced phase shifting of circadian clock of Neurospora

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1981.241.1.r31 ◽

1981 ◽

Vol 241 (1) ◽

pp. R31-R35 ◽

Cited By ~ 1

Author(s):

H. Nakashima ◽

J. Perlman ◽

J. F. Feldman

Keyword(s):

Protein Synthesis ◽

Circadian Clock ◽

Response Curve ◽

Phase Response Curve ◽

Phase Shifts ◽

Phase Shifting ◽

Normal Operation ◽

Circadian Cycle ◽

Response Curves ◽

Inhibition Of Protein Synthesis

Cycloheximide (CHX), an inhibitor of cytosolic (80S) protein synthesis in eucaryotes, causes phase shifts of the circadian clock of Neurospora crassa when administered as 4-h pulses to cultures in liquid medium. Differential effects of the pulses at different phases of the circadian cycle were observed and plotted as a phase-response curve (PRC). Nearly all phase shifts observed were phase advances, with maximum sensitivity in the middle of the subjective day. Inhibition of protein synthesis by CHX was the same at both phases of the cycle. The PRC was the same at 20 and 25 degrees C. Dose-response curves for the effects of CHX on phase shifting and inhibition of protein synthesis were determined and showed a striking parallel in the responses of these two phenomena to CHX. These results support the view that synthesis of one or more proteins at specific phases of the circadian cycle is necessary for the normal operation of the circadian clock of Neurospora.

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