Biomedical subjects
Publications and source records attributed to N Mrosovsky.
Golden hamsters, Mesocricetus auratus, ran more in wheels with the floor covered by a plastic mesh than in wheels with the usual rods. This preference was evident both in tests with a single wheel and in tests when the animals were offered a choice between two wheels. Phase shifts following a 3h confinement to a novel wheel were greater if the novel wheel had the plastic cover.
It is known that mice homozygous for the retinal degeneration (rd) mutation are able to synchronize their circadian rhythms to light-dark cycles. In the present experiments mice were given a choice of a dark or an illuminated living and nesting area. C3H, CBA and C57 rd/rd mice spent more time in the dark than in the illuminated area. Also, they spent as much time in the dark area as did wildtype controls. This shows that, despite advanced retinal degeneration, light can be used to control behaviour in space as well as in time. This was true of mutant mice over a year old, when retinal degeneration is very severe, and also of a transgenic strain of mice whose rods are destroyed as they begin to develop in the first few weeks after birth.
Phase shifts resulting from nonphotic events can be accompanied by sizable changes in the free-running period. This study examined the relationship between tau changes and phase shifts produced by confining Syrian hamsters to a novel running wheel in the mid-subjective day. Both phase shifting and tau lengthening were higher in animals that made a high number of wheel turns in the 3 h in the novel wheel. Hamsters that ran little during the activity pulse, and did not subsequently exhibit either phase shifts or tau lengthening, had low baseline activity and long taus before the pulse. However, long taus did not preclude hamsters from running in a novel wheel and subsequently phase shifting. This was demonstrated by finding the phase shifts after activity pulses in animals whose tau had already been lengthened by previous activity pulses in novel wheels. The possibility is discussed that feedback from locomotor activity influences the period of the clock in hamsters, but it is concluded that, in addition, there must be other mechanisms accounting for the relationships between activity and tau.
A synopsis of the effects of exercise on the circadian system in nocturnal rodents is followed by a review of the few studies investigating the influence of exercise on the human circadian system. It is premature to make specific recommendations about using exercise to promote synchronization in people because of the lack of information on the best times of exercise, the amounts required, and interactions between nonphotic and photic zeitgebers.
Serotonin-containing fibres (5-HT) project from the raphe complex to the suprachiasmatic nucleus (SCN). Previous studies have suggested that this pathway may be involved in nonphotic resetting of the circadian clock. For example, 5-HT agonists are capable of phase shifting the biological clock both in vivo and in vitro, producing phase response curves (PRCs) similar in shape to those of other nonphotic stimuli. Therefore we studied the role of the serotonergic projection to the SCN in nonphotic phase shifts by bilateral injection of the selective 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) onto the SCN of hamsters. About 50 days after the administration of the neurotoxin, the 5-HT and 5-HIAA (5-hydroxyindole acetic acid) levels were severely depleted in the SCN, as revealed by high performance liquid chromatography (HPLC), and immunocytochemistry (ICC). The average level of 5-HT depletion was 88% in Experiment 1 and 95% in Experiment 2. This treatment had no effect on the magnitude of phase shifts produced by 3 h of novelty-induced wheel-running starting at circadian time (CT) 4, the peak of the advance region of the PRC to this stimulus. The effect of 5-HT depletion on shifts produced by running at CT 22 were inconclusive because of changes in the behavior of control animals. No changes in the phase angle of entrainment of animals in a 14:10 light:dark (LD) cycle were detected in depleted animals. The results suggest that the 5-HT projection from the raphe to the SCN is not essential for activity-induced phase shifts in hamsters.
Stimuli that make hamsters active, such as dark pulses or triazolam administration, also phase shift their circadian clocks, producing phase advances during the subjective day and phase delays during the subjective night. Activity or its correlate appears to be important in producing the shifts because preventing locomotion blocks the phase shifts associated with these stimuli. The physiological basis of clock resetting induced by activity is not fully understood. The serotonergic (5-HT) projection from the raphe to the suprachiasmatic nucleus (SCN) is a possible route by which nonphotic information could reach the pacemaker. Administration of 8-HYDROXY-2-(DI-N-PROPYLAMINO) TETRALIN HYDROBROMIDE (8-OH-DPAT), a 5-HT1A and 5-HT7 receptor agonist, at circadian time (CT) 8 produces phase advances in the circadian rhythms of hamsters. Before concluding that 5-HT mediates the effect of activity on the pacemaker, it must be shown that 5-HT agonist do not produce shifts simply because they make animals more active. Therefore, we investigated the contribution of activity to 8-OH-DPAT-produced shifts. Preventing hamsters from moving around after administering 8-OH-DPAT did not abolish phase shifts. Moreover, higher doses of 8-OH-DPAT diminished activity on the day of injection but did not affect the amplitude of phase shifts. Suprisingly, quipazine (a non specific 5-HT agonist), when injected in the middle of subjective day did not phase shift the activity rhythm of hamsters, as it has been reported to do in rats.
Some of the main themes in this review are as follows. 1. The notion that non-photic zeitgebers are weak needs re-examining. Phase-shifts to some non-photic manipulations can be as large as those to light pulses. 2. As well as being able to phase-shift and entrain free-running rhythms, non-photic events have a number of other effects: these include after-effects of entrainment, period changes, and promotion of splitting. 3. The critical variable for non-photic shifting is unknown. Locomotor activity is more likely to be an index of some other necessary state rather than being causal itself. This index may be better when tendencies to move are channelled into easily measured behaviours like wheel-running. 4. Given ignorance about the critical variable, quantification of activity may be the best presently available measure of zeitgeber intensity. Therefore, the behaviour during non-photic manipulations must be examined as carefully as the shifts themselves. When no phase-shifting follows manipulations such as IGL lesions or serotonin depletion, if the animals are inactive, then little can be inferred. 5. Lack of information on the critical variable(s) for non-photic shifting makes it problematic to compare data from studies using different non-photic manipulations. However, the presence of locomotor activity (or its correlate) does appear to be necessary for triazolam to produce shifts. 6. Novelty-induced wheel-running in hamsters depends on the NPY projection from the IGL to SCN. It remains to be determined how important NPY is in other species or in clock-resetting by other manipulations, but methods are now available to study this. 7. Interactions between photic and non-photic zeitgebers remain virtually unexplored, but it is evident that photic and non-photic stimuli can attenuate the phase-shifting effects of each other. Interactions are not purely additive or predictable from PRCs. 8. The circadian system does more than synchronize free-running rhythms to the solar day. Its non-photic functions and their interactions with photic inputs probably account for some of the anatomical complexity of circadian circuitry.
Neuropeptide Y (NPY)-containing fibers project from the intergeniculate leaflet to the suprachiasmatic nucleus. NPY has been shown to phase shift the circadian locomotor activity rhythm of wildtype hamsters, producing large phase advances in the subjective day and small delays in the subjective night. Previous studies have implicated this pathway in the mediation of activity-induced resetting of the circadian clock. Homozygous tau mutant and wildtype hamsters respond very differently to pulses of activity. Not only is the amplitude of the phase response curve exaggerated in the mutants with shifts of up to 7 h, but the stimuli are effective at different times during the cycle. Homozygous tau mutant hamsters and wildtype controls were implanted with guide cannulas aimed at the suprachiasmatic nucleus and injected with NPY at various times during the circadian cycle. The responses of homozygous tau mutant hamsters to NPY resembled their responses to nonphotic stimuli in both timing and direction of phase shift. This finding provides correlational evidence that NPY is involved in the effects of nonphotic behavioral events on the circadian system.
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Nonphotic and photic stimuli that phase shift circadian rhythms were presented to hamsters, Mesocricetus auratus. The nonphotic stimulus was a 3-h pulse of novelty-induced wheel running starting at circadian time 4-5. The photic stimulus used was a 0.5 h light pulse starting at circadian time 18. Double immunocytochemistry was used to determine the neurochemical phenotype of cells in the intergeniculate leaflet that were activated by these stimuli. Both the nonphotic and the photic phase-shifting stimuli induced the expression of c-fos in the intergeniculate leaflet compared to unstimulated controls. However, after nonphotic stimulation, Fos-like immunoreactivity was common in neurons that also were NPY positive. Such colocalization of Fos and NPY after photic stimuli was rare. These findings suggest that the NPY pathway from the intergeniculate leaflet to the suprachiasmatic nucleus carries information about nonphotic events.
Previous studies have indicated that the neuropeptide Y input from the intergeniculate leaflet of the lateral geniculate nucleus to the suprachiasmatic nucleus is the final part of a non-photic phase shifting pathway to pacemakers in hamsters, or that neuropeptide Y is necessary for other pathways to be effective. Experiments in which two stimuli are presented during the same circadian cycle have shown that phase shifts in response to at least two non-photic stimuli are attenuated by a subsequent light pulse during the subjective day. This study was conducted to investigate the neural site of the blocking effect of light on non-photic stimuli. Experiment 1 showed that phase shifts in response to induced wheel-running during the subjective day are greatly attenuated by a subsequent light pulse. Experiment 2 showed that phase shifts in response to injections of neuropeptide Y in the middle of the subjective day were also greatly reduced by a subsequent light pulse. These results provide some insight about the site of the blocking action of light on non-photic phase shifts. Because there is evidence indicating that neuropeptide Y may mediate phase shifts in response to induced activity, and because light was able to block phase shifts produced by neuropeptide Y, we conclude that, in blocking activity-induced shifts, light must act downstream from the release of neuropeptide Y into the suprachiasmatic nucleus.
This paper considers the neural mechanisms underlying a particular kind of non-photic phase shifting, that produced by novelty-induced wheel running in the hamster. The projection from the intergeniculate leaflet (IGL) to the suprachiasmatic nucleus (SCN) appears to be an important part of the mechanism mediating such phase shifts. A number of experiments support this view. First, expression of immediate-early genes in the IGL is induced by non-photic phase-shifting stimuli. Second, Fos-like immunoreactivity in the IGL co-localizes with neuropeptide Y (NPY) immunoreactivity. Third, direct application of NPY to the SCN produces phase shifts which do not depend on the hamsters becoming active following the injections. Fourth, blocking the normal actions of NPY at the SCN blocks or greatly attenuates the phase shifting that is normally produced by novelty-induced wheel running. Progress on the physiological basis of phase shifts associated with activity, or a correlate, depends on understanding the behavioural aspects of this phenomenon. The activity-shift response curve is especially useful.
The aim of this work was to assess the effect of lesions of the intergeniculate leaflet on nonphotic phase shifts produced by confining hamsters to novel running wheels for 3 h in the middle of the subjective day. In intact hamsters this procedure produces large phase advances provided that the hamsters maintain high levels of wheel running during the confinement. Intergeniculate leaflet lesions blocked or reduced phase shifts after confinement to a novel wheel. However, for most animals these lesions also reduced both the amount of activity during the 3 h pulse in the novel wheel and the amount of daily wheel running in the home cage. To boost activity of lesioned hamsters to levels associated with large phase shifts, the animals were confined to novel wheels at low ambient temperature. The lesioned hamsters still failed to show large phase shifts. The benzodiazepine triazolam also failed to induce phase shifts in lesioned animals, but it induced less activity in lesioned animals as compared to sham-operated controls. The data support the hypothesis that the intergeniculate leaflet conveys information about nonphotic phase-shifting to the circadian pacemaker in the suprachiasmatic nucleus. They also raise the possibility that some effects of intergeniculate leaflet lesions previously interpreted as having a photic basis, might be due to the activity-lowering effect of the lesions.
Syrian hamsters entrained to a light-dark (LD) cycle of 14:10 h were given the opportunity to run in novel wheels for 3 h in the middle of the light phase. This manipulation transiently altered the phase angle of entrainment to the LD cycle: activity onset was significantly advanced (by about 0.5 h) on the day after the pulse and gradually drifted back toward its prepulse time. When animals were held in LD 11.5:12.5 h, a photoperiod in which onset time occurs later relative to the time of lights-off, they again advanced about 0.5 h in response to the pulse of wheel running, but many animals retained an advanced phase angle for at least 7 days, and some for more than 21 days. Individual changes in phase angle were highly correlated with the prepulse phase angle: the more negative the phase angle, the greater the advance subsequent to the novel wheel pulse. These results show that a single, short-duration, nonphotic manipulation can produce long-lasting alterations in the phase angle of entrainment to a LD cycle.
Neuropeptide Y-containing fibers project from the intergeniculate leaflet of the lateral geniculate nucleus to the suprachiasmatic nucleus. Previous studies have indicated that this pathway may be involved in non-photic resetting of the circadian clock. Therefore, we investigated the possibility that neuropeptide Y mediates phase shifts induced by a particular non-photic stimulus, a pulse of running in a novel wheel. Confining hamsters to a small nest box failed to block phase shifts induced by neuropeptide Y given at zeitgeber time 4; this indicates that increased locomotor activity is not necessary for the observed shifts. Antiserum raised against neuropeptide Y or normal serum was administered at circadian time 5 through a cannula aimed at the suprachiasmatic nucleus. The hamsters were then removed from their cages and placed in a novel wheel for 3 h. Hamsters that received normal serum and ran > 5000 revolutions in the novel wheel advanced their rhythms (mean shift 2.55 h +/- 0.22 S.E.M.) by amounts similar to those of unoperated hamsters. Administration of neuropeptide Y antiserum attenuated the shift normally associated with running in a novel wheel (mean shift 0.21 h +/- 0.14 S.E.M.). These studies indicate that the neuropeptide Y input from the lateral geniculate nucleus to the biological clock is involved in the phase shifts seen in response to novelty-induced wheel running. It also provides another example of the ability of antisera to alter behavior. This may be a useful approach in manipulations of neurochemical activity when antagonists are not yet available or poorly defined.
Chronotypic effects of rubidium (Rb) were examined in hamsters whose circadian activity rhythms had split into two components while they were housed in bright constant light. Seven of 12 hamsters receiving RbCl in drinking water for 10 weeks showed fusing of the components into an intact rhythm compared with none of 7 control hamsters (p = 0.016). Rb may modify coupling between circadian oscillators via reduced photic input to the suprachiasmatic nuclei. Alternative mechanisms include changes in potassium metabolism or endocrine function or behavioral changes that in turn alter circadian function. This normalization of a circadian anomaly by a putative antidepressant suggests that Rb may be valuable in strengthening coupling between oscillators in cases of human chronopathology, including those implicated in the etiology of some affective disorders.
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When confined to novel running wheels or when given injections of triazolam in their home cages, old hamsters do not become as active as young hamsters. Therefore, lack of nonphotic phase shifting following such manipulations may stem from insufficient activity or arousal. Phase advances can be obtained in some 10-month-old animals when wheel running during the pulse is increased by the presence of females in estrous condition and in most 18-month-old hamsters by combining confinement to a novel wheel with triazolam injections. These data suggest that there is relatively little if anything wrong in aging hamsters with the nonphotic phase-shifting mechanism itself. The reason why in certain situations old hamsters do not shift appears to be because the nonphotic inputs to these shifting mechanisms are not strong enough. However, when running in novel wheels is increased by carrying out the tests at cold temperatures, most old animals did not show subsequent phase shifts. Evidently it is not running per se that is critical for phase shifts, but probably the motivational context for such running.