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The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions
Neuroscience Letters, 42 (1983) 49-54
49
Elsevier Scientific Publishers Ireland Ltd.
THE EFFECT OF SLEEP DEPRIVATION ON SLEEP IN RATS WITH SUPRACHIASMATIC LESIONS
1. TOBLER l, A.A. BORBI~LY l and G. GROOS 2
~Institute of Pharmacology, University of Ziirich, Gloriastrasse 32, CH-8006 Ziirich (Switzerland) and ZDepartment of Physiology and Physiological Physics, University of Leiden, Leiden (The Netherlands) (Received August 26th, 1983; Revised version received and accepted September 9th, 1983)
Key words: sleep deprivation - sleep - suprachiasmatic lesion - circadian rhythm - sleep regulation
The effect of 24-h sleep deprivation on sleep was investigated in rats whose circadian rest-activity rhythms were extensively disrupted by bilateral lesions of the suprachiasmatic nuclei (SCN). Sleep deprivation caused an increase in total sleep, REM sleep and the slow wave sleep fraction of non-REM sleep. It is concluded that the homeostatic component of sleep regulation is morphologically and functionally distinct from the circadian component.
Sleep regulation has a homeostatic and a circadian component [1]. Sleep homeostasis is evident from sleep deprivation experiments where sleep loss gives rise to an increase in rapid eye movement (REM) sleep as well as in the slow wave sleep (SWS) fraction of non-REM sleep [2]. The observation that sleep deprivation affects neither the phase nor the period of the circadian rest-activity rhythm reflects the powerful influence of circadian mechanisms on sleep regulation [5]. In recent years extensive evidence has accumulated demonstrating that the circadian sleep-wake cycle in rodents is cor,~rolled by the suprachiasmatic nuclei (SCN) of the anterior hypothalamus [7]. Complete bilateral lesions of the SCN have been Shown to permanently abolish the circadian sleep-wake rhythm as well as the associated rest-activity rhythm in rats [7, 8, 13]. These findings, together with other lines of evidence [7], have led to the conclusion that the SCN contain a pacemaker driving the circadian sleep-wake and rest-activity rhythms. In contrast, the neural substrate of the homeostatic facet of sleep regulation is still obscure. In the present study we investigated whether SCN lesions abolish sleep homeostasis concomitantly with the disruption of the circadian sleep-wake rhythm, or if these two aspects of sleep regulation are controlled by separate mechanisms. Twenty-five adult, male Wistar rats (TNO Zeist) served as experimental animals. When they had reached a body weight of ca. 300 g, bilateral ocular enucleation was carried out under deep anesthesia to ensure that the sleep-wake rhythm would not be affected by the sleep-promoting effect of light [3]. After an interval of at least 0304-3940/83/$ 03.00 © 1983 Elsevier Scientific Publishers Ireland Ltd.
50
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3 weeks the rats were anesthetized a n d subjected to bilateral lesions of the SCN. Insect pin type electrodes (insulated except for ca. 0.3 mm at the tip) were aimed at the SCN (adjusted coordinates according to Pellegrino and Cushman [11]: A 7.2, L 0.8, U 9.2 mm at an angle of 5 ° from the vertical), and a constant anodal current of 0.75 m A was applied for 15-20 sec once on each side of the brain. In a sep~ate group of animals, the electrodes were aimed at the SCN, but no current was applied (sham lesion). At least 3 weeks of recovery were allowed before activity recordings were started. Motor activity was recorded by mechano-electric transducers under the cage [14] for a period of 13-38 days. The animals were then anesthetized and implanted with chronic cortical and neck muscle electrodes. After a recovery period of at least 4 days sleep recordings were started. The techniques for recording the EEG by telemetry, and for the automatic identification of the vigilance states have been described previously [10, 12]. The zero-crossing rate (ZCR) of the EEG served as the measure of the dominant EEG frequency [2]. Slow wave sleep (SWS) was defined as the fraction of non-REM sleep with the lowest 30% of ZCR values in the baseline day [4]. After baseline recordings for at least one day, the rats were sleepdeprived for 24 h by forced locomotion [2]. Then sleep and the EEG were recorded for two recovery days. Finally, the activity recordings were continued for a further period of 21-40 days. Throughout the experiments the animals were kept in individual cages at an ambient temperature of ca. 22°C. At the end of the experiments the animals were deeply anesthetized and perfused intracardially with a 10e/0 formaline solution. The brain was removed and 25 #m paraffin sections were prepared at the level of the anterior and medial hypothalamus. The extent of the lesions was documented on the basis of cresyl violet and Luxol fast blue stained sections. The activity records of 3 animals showed a complete loss of the circadian rhythm which was confirmed by a periodogram analysis [6] (Fig. 1: SCN 1, 2, 4), whereas in 2 others the circadian rhythm was extensively disrupted, but still detectable (SCN 3,5). Histology revealed extensive or complete bilateral destruction of the SCN. The loss of the circadian rest-activity rhythm was paralleled by an aperiodic'sleep-wake rhythm (Figs. 1 and 2). Distinct free-running circadian rhythms were present in the sham-lesioned rats (Fig. 1). After 24-h sleep deprivation, total sleep (TS), SWS per non-REM sleep, and REM sleep (REMS), were significantly enhanced during the first hours of recovery day
.,q,-_
Fig. 1. Effect of lesions of the suprachiasmatic nuclei (SCN) on the circadian rest-activity and sleep-wake rhythms. Top: motor activity is plotted on a 48-h time base (standard double-plot method) for one sham-lesioned and 5 SCN-lesioned rats. Horizontal bars represent suptathreshold activity. The gaps in the records are due to the telemetric sleep recordings which were carried out in a separate setup. Bottom: vigilance states (W, waking; NREM, non-REM sleep; REM, REM sleep) and motor activity (arbitrary units) recorded on the baseline day of rat SCN 4.
52
1 (Fig. 2) (mean values in percent +_ S.E.M.: Baseline day, TS 56.0 + 2.0, SWS/ NREMS 29.4 :l: 0.4, REMS 6.9 + 0.4; Recovery day 1, TS 65.7 + 1.0, SWS/ NREMS 39.2 :!: 3.4, REMS 11.0 +_ 1.1). For every one of the 5 lesioned animals, the 24-h value of these three sleep parameters was higher on recovery day 1 than
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in the baseline day preceding sleep deprivation ( P < 0.05; one-sided Wilcoxon matched pairs signed ranks test). On recovery day 2 the values were again close to baseline (Fig. 2). This response to sleep deprivation is comparable to that obtained previously in intact rats [2]. When evaluating the present results it should be kept in mind that we attempted to induce focal SCN lesions which do not encroach upon adjacent forebrain structures where sleep regulating mechanisms may be located (see ref. 9). Consequently the number of successfully lesioned arrhythmic animals was small. Nevertheless, the results of the study demonstrate unambiguously that homeostatic regulation of sleep still occurs in SCN-lesioned rats in which the circadian rest-activity rhythm has been disrupted. Thus the homeostatic component of sleep regulation is morphologically and functionally distinct from the circadian component. The authors i;ratefully acknowledge the help of Ms Karin Schwarz and Mr. J. den Hoed. The study was supported by the Swiss National Foundation, Grant 3.171-0-81. I Borb~ly, A.A., Sleep regulation: circadian rhythm and homeostasis. In D. Ganten and D. Pfaff (Eds.), Sleep. Clinical and Experimental Aspects, Current Topics in Neuroendocrinology, Vol. 1, Springer-Verlag, Berlin, 1982, pp. 83-103. 2 Borb~ly, A.A. attd Neuhaus, H.U., Sleep-deprivation: effects on sleep and EEG in the rat, J. comp. Physiol., 133 (1979) 71-87. 3 Borb~ly, A.A., Huston, J.P. and Waser, P.G., Control of sleep states in the rat by short light-dark cycles, Brain Rcs., 95 (1975) 89-101. 4 Borb~ly, A.A., Neuhaus, H.U. and Tobler, i., Effect of p-chlorophenylalanine and tryptophan on sleep, EEG and motor activity in the rat, Behav. Brain Res., 2 (1981) 1-22. 5 Borb~ly, A.A., Tobler, !. and Groos, G., Sleep homeostasis and the circadian sleep-wake rhythm. In M.H. Chase and E.D. Weitzman (Eds.), Sleep Disorders: Basic and Clinical Research, Spectrum, Jamaica, NJ., 1983, pp. 227-243. 6 Doerrscheidt, G.J. and Beck, L., Advanced method for evaluating characteristic parameters (~-,oe,Q) of circadian rhythms, J. Math. Biol., 2 (1975) 107-121. 7 Groos, G., Regulation of the circadian sleep-wake cycle, in W.P. Koella (Ed.), Sleep 1982, Karger, Basel, 1983, p p 19-29. 8 lbuka, N. lnouye, S.T. and Kawamura, H., Analysis of sleep-wakefulness rhythms in male rats after suprachiasmatic nucleus lesions and ocular enucleation, Brain Res., 122 (1977) 33-47.
Fig. 2. Effect of sleep deprivation on sleep states and EEG zero-crossing rate (ZCR). Top: mean values (3-h sliding averages of hourly values) of total sleep and REM sleep (percent of recording time) and slow wave sleep (percent of non-REM sleep) for the baseline day preceding sleep deprivation (dashed line; n - 5), recovery day i (thick continuous line; n - 5) and recovery day 2 (thin continuous line; n - 3; not plotted for SWS due to extensive data loss). Asterisks indicate significant differences from baseline (P< 0.05; one-sided Wilcoxon matched pairs signed ranks test). Bottom: 8-h records of baseline day and recovery day 1 (plot beginning immediately after sleep deprivation) for rat SCN 2, Vigilance states and motor activity are indicated as in Fig. 1. Marks on left of zero-crossing curves indicate 0, 64 and 128 ZCR per 10 sec. Note reduced ZCR values and rhythmic flucc.uation after sleep deprivation.
54 9 Moruzzi, G., The sleep-waking cycle, Ergebn. Physiol., 64 (1972) 1-165. 10 Neuhaus, 'H.U. and Borb~ly, A.A, Sleep telemetry in the rat: 11. Automatic identification and recording of vigilance states, Electroenceph. clin. Neurophysiol., 44 (1978) 115-119. ! 1 Pellegrino, L.J. and Cushman, A.J., A Stereotaxic Atlas of the Rat Brain, Meredith Publ., New York, 1967. 12 Ruedin, P., Bisang, J., Waser, P.G. and Borb~ly, A.A., Sleep telemetry in the rat: I. A. Miniaturized FM-AM transmitter for EEG and EMG, Electroenceph. clin. Neurophysiol., 44 (1978) 112-114. 13 Rusak, B. and Zucker, I., Neural regulation of circadian rhythms, Physiol. Rev., 59 (1979) 449-526. 14 Tobler, !. and Borb61y, A.A. Effect of delta sleep inducing peptide (DSIP) and arginine vasotocin (AVT) on sleep and motor activity in the rat, Waking and Sleeping, 4 (1980) 139-153.
49
Elsevier Scientific Publishers Ireland Ltd.
THE EFFECT OF SLEEP DEPRIVATION ON SLEEP IN RATS WITH SUPRACHIASMATIC LESIONS
1. TOBLER l, A.A. BORBI~LY l and G. GROOS 2
~Institute of Pharmacology, University of Ziirich, Gloriastrasse 32, CH-8006 Ziirich (Switzerland) and ZDepartment of Physiology and Physiological Physics, University of Leiden, Leiden (The Netherlands) (Received August 26th, 1983; Revised version received and accepted September 9th, 1983)
Key words: sleep deprivation - sleep - suprachiasmatic lesion - circadian rhythm - sleep regulation
The effect of 24-h sleep deprivation on sleep was investigated in rats whose circadian rest-activity rhythms were extensively disrupted by bilateral lesions of the suprachiasmatic nuclei (SCN). Sleep deprivation caused an increase in total sleep, REM sleep and the slow wave sleep fraction of non-REM sleep. It is concluded that the homeostatic component of sleep regulation is morphologically and functionally distinct from the circadian component.
Sleep regulation has a homeostatic and a circadian component [1]. Sleep homeostasis is evident from sleep deprivation experiments where sleep loss gives rise to an increase in rapid eye movement (REM) sleep as well as in the slow wave sleep (SWS) fraction of non-REM sleep [2]. The observation that sleep deprivation affects neither the phase nor the period of the circadian rest-activity rhythm reflects the powerful influence of circadian mechanisms on sleep regulation [5]. In recent years extensive evidence has accumulated demonstrating that the circadian sleep-wake cycle in rodents is cor,~rolled by the suprachiasmatic nuclei (SCN) of the anterior hypothalamus [7]. Complete bilateral lesions of the SCN have been Shown to permanently abolish the circadian sleep-wake rhythm as well as the associated rest-activity rhythm in rats [7, 8, 13]. These findings, together with other lines of evidence [7], have led to the conclusion that the SCN contain a pacemaker driving the circadian sleep-wake and rest-activity rhythms. In contrast, the neural substrate of the homeostatic facet of sleep regulation is still obscure. In the present study we investigated whether SCN lesions abolish sleep homeostasis concomitantly with the disruption of the circadian sleep-wake rhythm, or if these two aspects of sleep regulation are controlled by separate mechanisms. Twenty-five adult, male Wistar rats (TNO Zeist) served as experimental animals. When they had reached a body weight of ca. 300 g, bilateral ocular enucleation was carried out under deep anesthesia to ensure that the sleep-wake rhythm would not be affected by the sleep-promoting effect of light [3]. After an interval of at least 0304-3940/83/$ 03.00 © 1983 Elsevier Scientific Publishers Ireland Ltd.
50
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LESION
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3 weeks the rats were anesthetized a n d subjected to bilateral lesions of the SCN. Insect pin type electrodes (insulated except for ca. 0.3 mm at the tip) were aimed at the SCN (adjusted coordinates according to Pellegrino and Cushman [11]: A 7.2, L 0.8, U 9.2 mm at an angle of 5 ° from the vertical), and a constant anodal current of 0.75 m A was applied for 15-20 sec once on each side of the brain. In a sep~ate group of animals, the electrodes were aimed at the SCN, but no current was applied (sham lesion). At least 3 weeks of recovery were allowed before activity recordings were started. Motor activity was recorded by mechano-electric transducers under the cage [14] for a period of 13-38 days. The animals were then anesthetized and implanted with chronic cortical and neck muscle electrodes. After a recovery period of at least 4 days sleep recordings were started. The techniques for recording the EEG by telemetry, and for the automatic identification of the vigilance states have been described previously [10, 12]. The zero-crossing rate (ZCR) of the EEG served as the measure of the dominant EEG frequency [2]. Slow wave sleep (SWS) was defined as the fraction of non-REM sleep with the lowest 30% of ZCR values in the baseline day [4]. After baseline recordings for at least one day, the rats were sleepdeprived for 24 h by forced locomotion [2]. Then sleep and the EEG were recorded for two recovery days. Finally, the activity recordings were continued for a further period of 21-40 days. Throughout the experiments the animals were kept in individual cages at an ambient temperature of ca. 22°C. At the end of the experiments the animals were deeply anesthetized and perfused intracardially with a 10e/0 formaline solution. The brain was removed and 25 #m paraffin sections were prepared at the level of the anterior and medial hypothalamus. The extent of the lesions was documented on the basis of cresyl violet and Luxol fast blue stained sections. The activity records of 3 animals showed a complete loss of the circadian rhythm which was confirmed by a periodogram analysis [6] (Fig. 1: SCN 1, 2, 4), whereas in 2 others the circadian rhythm was extensively disrupted, but still detectable (SCN 3,5). Histology revealed extensive or complete bilateral destruction of the SCN. The loss of the circadian rest-activity rhythm was paralleled by an aperiodic'sleep-wake rhythm (Figs. 1 and 2). Distinct free-running circadian rhythms were present in the sham-lesioned rats (Fig. 1). After 24-h sleep deprivation, total sleep (TS), SWS per non-REM sleep, and REM sleep (REMS), were significantly enhanced during the first hours of recovery day
.,q,-_
Fig. 1. Effect of lesions of the suprachiasmatic nuclei (SCN) on the circadian rest-activity and sleep-wake rhythms. Top: motor activity is plotted on a 48-h time base (standard double-plot method) for one sham-lesioned and 5 SCN-lesioned rats. Horizontal bars represent suptathreshold activity. The gaps in the records are due to the telemetric sleep recordings which were carried out in a separate setup. Bottom: vigilance states (W, waking; NREM, non-REM sleep; REM, REM sleep) and motor activity (arbitrary units) recorded on the baseline day of rat SCN 4.
52
1 (Fig. 2) (mean values in percent +_ S.E.M.: Baseline day, TS 56.0 + 2.0, SWS/ NREMS 29.4 :l: 0.4, REMS 6.9 + 0.4; Recovery day 1, TS 65.7 + 1.0, SWS/ NREMS 39.2 :!: 3.4, REMS 11.0 +_ 1.1). For every one of the 5 lesioned animals, the 24-h value of these three sleep parameters was higher on recovery day 1 than
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in the baseline day preceding sleep deprivation ( P < 0.05; one-sided Wilcoxon matched pairs signed ranks test). On recovery day 2 the values were again close to baseline (Fig. 2). This response to sleep deprivation is comparable to that obtained previously in intact rats [2]. When evaluating the present results it should be kept in mind that we attempted to induce focal SCN lesions which do not encroach upon adjacent forebrain structures where sleep regulating mechanisms may be located (see ref. 9). Consequently the number of successfully lesioned arrhythmic animals was small. Nevertheless, the results of the study demonstrate unambiguously that homeostatic regulation of sleep still occurs in SCN-lesioned rats in which the circadian rest-activity rhythm has been disrupted. Thus the homeostatic component of sleep regulation is morphologically and functionally distinct from the circadian component. The authors i;ratefully acknowledge the help of Ms Karin Schwarz and Mr. J. den Hoed. The study was supported by the Swiss National Foundation, Grant 3.171-0-81. I Borb~ly, A.A., Sleep regulation: circadian rhythm and homeostasis. In D. Ganten and D. Pfaff (Eds.), Sleep. Clinical and Experimental Aspects, Current Topics in Neuroendocrinology, Vol. 1, Springer-Verlag, Berlin, 1982, pp. 83-103. 2 Borb~ly, A.A. attd Neuhaus, H.U., Sleep-deprivation: effects on sleep and EEG in the rat, J. comp. Physiol., 133 (1979) 71-87. 3 Borb~ly, A.A., Huston, J.P. and Waser, P.G., Control of sleep states in the rat by short light-dark cycles, Brain Rcs., 95 (1975) 89-101. 4 Borb~ly, A.A., Neuhaus, H.U. and Tobler, i., Effect of p-chlorophenylalanine and tryptophan on sleep, EEG and motor activity in the rat, Behav. Brain Res., 2 (1981) 1-22. 5 Borb~ly, A.A., Tobler, !. and Groos, G., Sleep homeostasis and the circadian sleep-wake rhythm. In M.H. Chase and E.D. Weitzman (Eds.), Sleep Disorders: Basic and Clinical Research, Spectrum, Jamaica, NJ., 1983, pp. 227-243. 6 Doerrscheidt, G.J. and Beck, L., Advanced method for evaluating characteristic parameters (~-,oe,Q) of circadian rhythms, J. Math. Biol., 2 (1975) 107-121. 7 Groos, G., Regulation of the circadian sleep-wake cycle, in W.P. Koella (Ed.), Sleep 1982, Karger, Basel, 1983, p p 19-29. 8 lbuka, N. lnouye, S.T. and Kawamura, H., Analysis of sleep-wakefulness rhythms in male rats after suprachiasmatic nucleus lesions and ocular enucleation, Brain Res., 122 (1977) 33-47.
Fig. 2. Effect of sleep deprivation on sleep states and EEG zero-crossing rate (ZCR). Top: mean values (3-h sliding averages of hourly values) of total sleep and REM sleep (percent of recording time) and slow wave sleep (percent of non-REM sleep) for the baseline day preceding sleep deprivation (dashed line; n - 5), recovery day i (thick continuous line; n - 5) and recovery day 2 (thin continuous line; n - 3; not plotted for SWS due to extensive data loss). Asterisks indicate significant differences from baseline (P< 0.05; one-sided Wilcoxon matched pairs signed ranks test). Bottom: 8-h records of baseline day and recovery day 1 (plot beginning immediately after sleep deprivation) for rat SCN 2, Vigilance states and motor activity are indicated as in Fig. 1. Marks on left of zero-crossing curves indicate 0, 64 and 128 ZCR per 10 sec. Note reduced ZCR values and rhythmic flucc.uation after sleep deprivation.
54 9 Moruzzi, G., The sleep-waking cycle, Ergebn. Physiol., 64 (1972) 1-165. 10 Neuhaus, 'H.U. and Borb~ly, A.A, Sleep telemetry in the rat: 11. Automatic identification and recording of vigilance states, Electroenceph. clin. Neurophysiol., 44 (1978) 115-119. ! 1 Pellegrino, L.J. and Cushman, A.J., A Stereotaxic Atlas of the Rat Brain, Meredith Publ., New York, 1967. 12 Ruedin, P., Bisang, J., Waser, P.G. and Borb~ly, A.A., Sleep telemetry in the rat: I. A. Miniaturized FM-AM transmitter for EEG and EMG, Electroenceph. clin. Neurophysiol., 44 (1978) 112-114. 13 Rusak, B. and Zucker, I., Neural regulation of circadian rhythms, Physiol. Rev., 59 (1979) 449-526. 14 Tobler, !. and Borb61y, A.A. Effect of delta sleep inducing peptide (DSIP) and arginine vasotocin (AVT) on sleep and motor activity in the rat, Waking and Sleeping, 4 (1980) 139-153.