limited effect of three types of daily stress on rat free-running locomotor rhythms
TRANSCRIPT
Chronohiology Inlernarional Vol. 10, No. 6, pp. 410-419 0 1993 International Society of Chronobiology
Limited Effect of Three Types of Daily Stress on Rat Free-Running Locomotor Rhythms
Julie Barrington, *Helen Jarvis, *Jennifer R. Redman, and Stuart Maxwell Armstrong
Psjrhology Drparlmml, La Trdw Univrrsilj: Bimdooru, and *Department of P.sjuholo*qj*. Monash Univer.yitj: Clayton. Victoria Australia
Summary: The effects of three types of stress/arousal on rat free-running circadian locomotor rhythms in constant darkness were investigated over a 93-day treat- ment period. Rats were subjected to 30-min daily immobilisation stress or 30-min novelty or to brief handling (n = IO/group). Seven of the 30 rats exhibited some changes in circadian parameters. Three rats (two immobilised, one handling) showed entrainment, three rats (one from each group) showed a change in T , and one rat (novelty) showed a phase advance. Thus, in total, 30% immobilisation, 20% percent novelty, and 20% handled rats showed circadian changes. These group changes paralleled changes in faecal boli and body weight, which were taken as indirect indices of the level of stress. Five of the seven changes took place when the end of the active phase (a ) , i.e., subjective dawn, coincided with the time of treatment and the other two when the onset of u, i.e., subjective dusk, coincided. Rat circadian locomotor rhythms appear much less susceptible to stress/arousal than those reported for hamsters. Key Words: Circadian rhythm-Pacemaker- Rat-Hamster-Stress-Period-Phase shift-Entrainment.
For several decades it was thought that the mammalian circadian pacemaker was impervious to stress and arousal. The effects of 19-24 h of sleep deprivation (by forced swimming), restraint, and electric shock stressors on free-running, wheel- running locomotor activity rhythms have long been evaluated in both wild and labo- ratory rats ( 1 ). While the behavioural manifestation of running in the wheel was often interrupted or disturbed for several days, no substantial change in periodicity or phase of free-running rhythms was reported. Similar results were obtained for a wide variety of physiological stressors such as anoxia, convulsions, anaesthesia, intoxica- tion, deep sleep induction, deep hypothermia, catalepsy, and analgesia (1 ) . Taken together, these results were all indicative of the immunity of the circadian pacemaker to stressful stimuli, an idea that was reinforced by other findings, such as the lack of
Received August 3, 1992: accepted with revisions December 15, 1992. Address correspondence and reprint requests to Dr. S. M. Armstrong, Psychology Department, La
Trohe University, Bundoora, Victoria, 3083. Australia.
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STRESS EFFECT ON RAT FREE-RUNNING RHYTHM 411
effect of 30-min immobilisation stress daily on male C57BL mice free-running in constant darkness (DD) (2). As with the previously cited work on rats, this strain of mice sometimes showed interference of the behavioural manifestations of running but no change in periodicity. Enforced exercise or restricted daytime feeding before or after a phase shift of the light-dark (LD) cycle has no effect on reentrainment rate of mice (3), while social interaction appears not to influence the free-running period ( T ) of rats, although occasional effects are found in mice (4).
In contrast to the situation in rats and mice, Syrian hamsters have recently been shown to be susceptible to arousal or what Aschoff originally termed alterations in “level of excitement” ( 5 ) . Phase shifts, entrainment, and accelerated reentrainment have all been induced by social interactions, cage changing, novelty-induced wheel- running, and simple access to running in a wheel (6,7). Further, it has been suggested that all these manipulations point to a nonspecific influence on the circadian pace- maker (7), which might explain other findings that have hitherto been thought to be due to specific inputs. For example, entrainment of rat free-running activity rhythms to daily melatonin injections (8) could be mediated through some modification of general processes controlling alertness and arousal (7). Independently, a similar pro- posal has been put forward (lo), which turned out to be correct for phase shifting and entrainment effects of another chemical, Triazolam (9). It is the activity induced in hamsters by Triazolam that produces phase shifts rather than a direct effect of the drug on the pacemaker (1 1). In addition to explaining drug effects, entrainment and anticipatory activity to daily periodic food presentation have also been suggested to be due to a nonspecific, general arousal process (7).
Since adult male Long-Evans rats in this laboratory have been shown to entrain to daily melatonin injections (8) and to anticipate daily periodic food presentation ( 12), it was deemed an appropriate strain with which to investigate the periodic influence of arousal and stress on free-running locomotor rhythms in DD. As it is possible that the circadian pacemaker is protected against severe stress but is influenced by mild arousal, three types of stress were employed in the following experiment. Such a distinction in types of arousal/stress could explain the difference between early ( 1) and more recent (6,lO) findings, which at present appear to reflect species differences in susceptibility between rats and mice versus hamsters.
MATERIALS AND METHODS Animals and Housing
Thirty male hooded Long-Evans rats, 1 18 days old, were housed in individual wire cages equipped with running wheels in a temperature-controlled room (20 -t 1 “C), as described previously ( 1 3). Cages were arranged six per row in a five-tiered, 30-cage rack. Food and water were continuously available. For the initial LD cycle, light was provided by four fluorescent tubes, giving an illumination level across all cages of -280 lux. In DD conditions the room was illuminated by two 25-W red light globes (< I .O lux at cage level).
Data Acquisition and Analysis Wheel-running activity and drinking (licks of the water spout) were sampled every
15 min by a real-time data acquisition and control computer situated in an adjacent
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412 J. BARRINGTON ET AL.
room. Data were saved, stored, and then plotted in the form of actograms. To aid visual inspection of rhythms, data were double-plotted over a 48-h time scale using a 30-min resolution. Periodicity was calculated by drawing lines eye-fitted along the onset and the end of activity for at least 10 days of data. Periodicity of the activity rhythm was calculated by two experienced independent judges who were blind to the treatment condition. Pearson correlation coefficients for interrater reliability be- tween the two judges were high, ranging from r = 0.78 to r = 0.95, p < 0.005.
Apparatus
Ten clear Perspex tubes were utilised for the immobilisation procedure. Each tube was 24 cm long and 7.5 cm in diameter. Two circular rubber stoppers attached with screws were used to block each end ofthe tube. Holes in the stoppers were designed to accommodate the nose and tail. The stopper at the head end was permanently fixed and that at the tail end was adjustable to suit the size of the animal.
Experimental Procedure
The rats were maintained in a 12: 12 LD cycle for 14 days and were then placed in DD for 14 days to establish free-running rhythms. Each animal was then assigned to one of the three treatment conditions: immobilisation, novelty, or handling. Animals were allocated so that (a) the length of the free-running period and (b) the level of the daily wheel-running activity were balanced across conditions. No more than two animals in adjacent cages (horizontally or vertically) received the same treatment. The following treatment procedures were performed at the same time each day, between 11:OO and 12:OO h.
Immobilisation (n = 10)
Each animal was placed head first into a Perspex restraint tube and the tail passed through the hole in the rear rubber stopper. The stopper was then positioned firmly behind the animal, creating a tight fit, and screwed into place. After 30 min the tail stopper was released and the animal was gently removed from the tube and returned to its home cage. This form of immobilisation stress has been shown to elicit large corticosterone responses (K. T. Ng et al., unpublished data).
Novelty (n = 10)
Animals were placed for 30 min each day in wire-topped plastic boxes lined with sawdust that were situated on the floor of the treatment room. Novelty stress has been shown to be a potent experimental stressor as evidenced by corticosterone re- lease (14).
Handling (n = 10)
Animals were carried into the treatment room and placed momentarily on the bench before being camed back to their home cages. The entire handling procedure was performed within 1 min.
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STRESS EFFECT ON RAT FREE-RUNNING RHYTHM 413
TABLE 1. Summary of circadian changes observed in rats in three treatment conditions and uhase ut which chanxes took dace relative to treatment
Period Phase Total Treatment (n ) Entrainment change advance change
3
2
- lmmobilisation (10) 2 (MI 1 (M) Novelty (10) - 103 2 1 (MI Handling (10) 1 (MI 1 (El Total changes 3 3 1 7
-
(E). when treatment coincided with activity onset (subjective evening, dusk): (M), when treatment coincided with activity end (subjective morning, dawn). Seventeen animals were tested throughout entire circadian cycle, and 28 animals at activity onset and end.
Daily treatments were continued until each animal had been exposed to the treat- ment at all phases of the activity cycle or until entrainment occurred (93 days). To assess posttreatment free-running rhythms, animals were left undisturbed for a fur- ther 28 days after the cessation of treatment.
Measurements
Body weight measures were made on treatment days 1,28,56,84, and 93, and also 28 days after treatment ceased. Faecal boli counts were used as an indicator of emo- tionality and hence an index of the severity of stress. Due to interindividual variabil- ity, the number of boli produced by each rat was averaged over 10 consecutive days at three time intervals during treatment and for one block of 3 consecutive days post treatment (see Fig. 3).
RESULTS
Circadian Changes
Overall, 7 of the 30 rats exhibited either phase shifts, changes in 7, or entrainment. Table I shows these circadian changes in terms of the treatment group to which the animal belonged and the phase of the circadian cycle at which the changes occurred either at the onset (subjective dusk) or at the end (subjective dawn) of a. Examples of the different circadian changes that occurred and an example of a rhythm unaffected by the treatment are shown in Figs. 1-3.
All rats free-ran initially with a 7 of >24 h. A change in 7 (three cases) was said to have occurred when the posttreatment period was either longer or shorter than the pretreatment 7. Changes in 7 were in all three cases shorter but the sizes were not substantial or large enough to merit the term “relative coordination.” Sizes of reduc- tions in 7 were from 24 h 7 rnin to 24 h 4 rnin (immobilisation), 24 h 9 rnin to 24 h 4 rnin (novelty), and 24 h 9 rnin to 24 h 4 rnin (handling, e.g., rat no. 2 1 in Fig. 1A).
Entrainment to daily treatment was said to have occurred when 7 shortened to 24 h for a minimum period of 20 days. Three rats showed entrainment (two immobilisa- tion, one handling) and in all cases this occurred when the end of the active phase (a, subjective dawn) coincided with the time of day of treatment ( e g , rat no. 22 in Fig.
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B Rat No. 21
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t heel-running activity rhythms. A: Rat that PIC.. I. uoume-piottea computer-generatea actograms or
showed a reduction in 7 due to < I -min daily handling (H). Reduction in T to closer to 24 h occurred when onset of activity coincided with time of day of handling treatment at approximately day 83. 9: Phase advance due to 30 rnin of novelty (N) stress. Advance occurred when activity onset coincided with time of day of novelty treatment at approximately day 75. m, missing data: LD, light-dark; DD, complete dark- ness. Vertical arrow indicates time of day of treatment. Horizontal arrows indicate start and finish of daily treatment.
2A). No entrainment was found at the onset of a. Of the two immobilisation-treated rats that entrained, the T of one was very close to 24 h and this may have facilitated entrainment (rat no. 12 in Fig. 2B).
Irregularities exhibited at the onset of activity, and the fact that activity was plotted every I5 min, meant that judges were inconsistent in their estimation of phase shifts
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Rat No. 22
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FIG. 2. A: Actogram of wheel-running activity for a rat subjected to brief daily handling (H), which entrained when the end of a (activity) coincided with daily handling treatment on approximately day 36. This was followed until day 65 by either a compression of a or masking. Entrainment was sustained for the remaining 65 days. Following cessation of treatment. a expanded or became unmasked at subjective dawn, but no further change in periodicity occurred before the end of the experiment. B: Drinking actogram showing entrainment to 30 min of daily immobilisation (I). It is unknown why a return to T exhibited before treatment did not occur in either of these rats. m, missing data; LD. light-dark; DD, complete darkness.
of under 15 min. One phase advance was found for a rat in the novelty condition that showed a phase shift of -75 min; this occurred when the onset of a crossed the time of day of immobilisation (rat no. 1 1 in Fig. 1B). Although only seven rats showed circadian changes, entrainment and other alterations appeared to be unrelated to the
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A Rat No. 17
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FIG. 3. A: Actogram of drinking activity of rat, showing no effect of 30-min daily immobilisation (I). A small degree of positive masking appears when daily treatment coincides with the end of a at approxi- mately day 48. B Actogram ofwheel-running activity of rat, showing no effect of30-min daily immobilisa- tion. This is an example of a large degree of positive masking when daily treatment coincides on approxi-
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STRESS EFFECT O N R A T FREE-RUNNING R H Y T H M 417
length of the initial 7; i.e., it was not the case that rats with 7 closest to 24 h entrained while those with longer 7 did not. However, since 7 varied only from 24 h 4 min to 24 h 1 1 min, this lack of covariation may not be meaningful. Circadian changes also appeared to be unrelated to the amount of daily wheel-running activity and the level of treatment-associated activity (i.e., intensification of activity immediately before or after treatment). An example of a rat (no. 17) unaffected by treatments is shown in Fig. 3A. Positive masking appeared in several rats when immobilisation stress coin- cided with the end of (Y (Fig. 3B, rat no. 14), indicating that in these individuals increased activity induced by stress did not result in phase shifts.
Body Weight Changes
Percentage body weight gain was calculated for each rat by computing differences between body weight measured on the first treatment day and body weight measured at intervals during and after the treatment regimen. Means and standard deviations for each treatment group appear in Fig. 3C. Weight increases occurred in all three groups, but the overall increase in the immobilisation group was retarded in compari- son with the other two groups [F(2,27) = 9.1, p < 0.011. There were no significant treatment effects at 28 days [F(2,27) = 1.53, p > 0.11, but there were significant treatment effects found at 56 [F(2,27) = 11.2, p < 0.0011, 84 [F(2,27) = 10.5, p <0.001], and 93 [F(2,27) = 10.5, p < 0.001] days. Assessment of posttreatment weight gains in the three groups showed that there was a significantly greater rate of percentage body weight increase in the immobilised group posttreatment than there was in the other two treatment groups [F(2,27) = 6.36, p < 0.011.
Faecal Boli
The mean number of faecal deposits for each rat for each of the three 10-day blocks during treatment and the 3-day block 28 days post treatment were averaged for each group and are presented in Fig. 3D. Immobilised rats produced significantly greater numbers of boli than those in novelty and handling conditions [F(2,27) 9.5, p < 0.005], and this difference was sustained throughout the treatment span, i.e., no indication of tolerance to immobilisation stress. Further analysis revealed a signifi- cant group effect during treatment [F(2,27) = 9.50, p < 0.0051 but no significant group effect 28 days post treatment.
DISCUSSION
Changes in circadian rhythmicity were found in 7 ofthe 30 rats tested (23%), with a 30% incidence in the immobilisation group but only 20% in each of the handling and novelty groups. This difference between the immobilisation group and the other two
mately day 37. C Mean percentage body weight increases during treatment (days 28, 56, 84, and 93) and 28 days after cessation of treatment. Daily immobilisation stress significantly reduced the rate of body weight growth relative to the novelty and handled group. D Means and SD of the number of faecal boli deposited during 30 min of immobilisation, novelty, and handling during and after treatment. Boli were collected and weighed over blocks of 10 days at three times during treatment and over a block of 3 days starting 28 days posttreatment. lmmobilisation significantly increased faecal deposits during treatment relative to novelty and handling. m, missing data; LD, light-dark; DD, complete darkness.
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groups is reflected in the changes in body weight and faecal boli used as indices of level of stress. From Table 1 it is clear that the end of a, subjective dawn, is the circadian phase at which the rat pacemaker is most likely to be influenced by stress- ors. The finding that exposure to daily stressors of the type and intensity used in the present experiment produced no substantial circadian changes in the majority of rats free-running in DD conditions supports previous research findings in rats and mice (1,2). A more recent study of the effects of treadmill running on rat free-running rhythms also proved negative unless T was very close to 24 h (1 5,16); negative results of enforced activity on rate of reentrainment after a phase shift of the zeitgeber have also been reported (3). These findings are in contrast to recent reports of major alterations in hamster circadian rhythms in response to immobilisation ( 10) and apparently stressful “social interactions” involving antagonistic encounters between male hamsters (6,7).
The circadian changes that occurred appeared to be specific to the experimental manipulations, because the observed changes occurred when the stimulus coincided with either activity onset (subjective dusk) or the end of the activity period (subjective dawn). The fact that the majority of changes occurred at subjective dawn (five of seven) indicates why such changes have not been seen in previous experimentation in this laboratory. In the studies investigating entrainment of free-running rhythms to daily melatonin injections, entrainment takes place at subjective dusk and thus sub- jective dawn is rarely tested; i.e., rats entrain at subjective dusk to daily injections and then injections are ceased for observation of the subsequent free-run (e.g., 8). When single melatonin injections were given at all circadian phases ( 17), no signs of phase shifts to either vehicle or melatonin injections at subjective dawn were found. It is concluded that experiments reporting entrainment to melatonin (8,18,19) are not parsimoniously interpretable in terms of a nonspecific input to the circadian pace- maker as suggested by others (7,20). The fact that daily handling per se produced no phase shifts, only one case of entrainment, and one case of period change indicates that melatonin administration effects shown in previous studies cannot be attributed to the handling procedure, a suggestion that has been made on the basis of saline injections exerting phase advances in hamsters (20).
The possibility that the results were confounded by habituation to repeated stress was not supported by evidence from body weight and faecal bolus measures. Growth rate was retarded and faecal bolus deposits were significantly elevated in immobilised rats compared with the novelty and handling groups during the treatment regimen, but not 28 days post treatment, indicating that immobilisation continued to be a potent stressor even after 93 days (Fig. 3C and D). Absence of habituation to chronic stress has been previously reported in rats subjected to daily cold stress for 3 months (2 1). In the latter study, chronically stressed rats exhibited growth retardation during treatment similar to that in the present experiment.
It appears from this experiment and previous findings ( 1-4,15,16) that, in contrast to Syrian hamsters (6,7,10,11,20), the murine circadian pacemaker system is well protected from stress/arousal. The sensitivity of hamsters to even saline injections (20) indicates that they are an unsuitable animal model for investigating the effects of putative chronobiotic agents on circadian locomotor activity rhythms. Furthermore,
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this species difference should be recognized when generalising to humans from ro- dents on the effects of arousal and stress on circadian rhythmicity.
Acknowledgment: This research was supported by an Australian Research Council grant (A789 30858).
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