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Life Sciences 68 (2001) 2645–2656

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Circadian rhythms of body temperature and motor activity in rodents Their relationships with the light-dark cycle C. Benstaali, A. Mailloux, A. Bogdan, A. Auzéby, Y. Touitou* Faculté de Médecine Pitié-Salpêtrière, Service de Biochimie Médicale, 91 boulevard de l’Hôpital, 75 634 Paris Cedex 13, France Received 20 March 2000; accepted 20 July 2000

Abstract In rodents, the alternation of light and dark is the main synchronizer of circadian rhythms. The entrainment abilities of the LD cycle could be estimated by experimental modifications of the photoperiod and by following the subsequent temporal distribution of a circadian rhythm. The rate of reentrainment of a rhythm is determined by the nature of the studied variable, by the direction (advance or delay) and the magnitude (or value) of the phase shift. In rodents, core body temperature and motor activity are known to be well synchronized with each other under L:D 12:12 and under constant conditions (LL or DD). There are clear evidences that the circadian pattern of motor activity is generated by two oscillators, one from dusk signal and the other from dawn signal. Whether the circadian rhythms of body temperature and motor activity are generated by a common circadian mechanism or controlled by separate ones still remains unknown. The purpose of this review is to summarize the results obtained on the circadian rhythms of body temperature and motor activity throughout the daily cycle in order to clarify the relationships between these two functions. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Body temperature; Motor activity; Circadian; Desynchronization

Introduction Most living beings, animals or plants change their behavior on a daily basis (24-h), with rhythmicity, a fundamental property of living matter. Biological rhythms are characterized by their ability to be entrained by external environmental cues, mostly consequences of the earth’s revolution around its axis (day/night cycle). Many biological functions show circadian rhythms, i. e. their temporal variation may be considered as a cyclic function with a pe* Corresponding author. Tel.: (33) 1 40 77 96 63; fax: (33) 1 40 77 96 65. E-mail address: [email protected] (Y. Touitou) 0024-3205/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 0 2 4 - 3 2 0 5 ( 0 1 )0 1 0 8 1 -5

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riodicity ranging between 20 and 28-h. The persistence of a circadian rhythmicity in an environment without any known external time cues suggest that there is an internal time-keeping system (biological “clock”). A number of studies found that, in Mammals, the suprachiasmatic nuclei (SCN), located in the anterior hypothalamus, are responsible of many aspects of the circadian rhythmicity [1 – 3]. Since light is the primary entraining agent for the circadian rhythms in animals and plants, numerous studies try to understand the neuronal and chemical pathways by which the biological clock is entrained by the solar cycle. The purpose of these studies is to document the transduction processes responsible for the transmission of the photic information to the circadian oscillators [4]. Many results suggest an important role of hormones and neurotransmitters [5] in the regulation of circadian rhythms, possibly by the adjustment of coupling relationships between oscillatory units of the circadian system [review in 6]. In particular, the pineal melatonin may act to adjust the circadian phase in order to synchronize biological rhythms [7], thanks to its photoperiod-dependent circadian release. A wide range of measures of biochemical and physiological circadian functions (glucose utilization, body temperature, motor activity, blood pressure, sleep/wake cycle, heart rate . . .) are available for chronobiological studies, thanks to radio-telemetry or other non-invasive methods. This review summarizes the results obtained on the circadian rhythms of body temperature and locomotor activity in rodents throughout the daily cycle. A very close temporal and metabolic relation was found between these two functions. However, in humans [8] and in mice [9], it is well established that these two functions reach their circadian and adult patterns at different times of life. Whether these two rhythms are generated by a common circadian mechanism or controlled by separate ones still remains unknown. Influence of the light-dark cycle Several authors have studied the influence of the most potent known synchronizer: the alternance of day and night (Light/Dark cycle or L:D cycle), also called photoperiodism. For living organisms, the L:D cycle is transposed in biological representations, the circadian rhythms, genuine mirrors of an adaptation feature to a surrounding in constant evolution. Circadian rhythms are known to be entrained under natural conditions of the day-night alternance, to a 24-h periodicity, identical to that of the entraining agent (i.e. definition of the “entrainment state”). Influence of the light-dark cycle 12:12, the reference photoperiod In laboratory studies, the alternance of 12-hours of light and 12-hours of dark (L:D 12:12) is commonly used as standard lighting conditions and represents a reference photoperiod. Under these conditions, the circadian phase relation, i. e. the temporal distribution of a rhythm with reference to the entraining agent, is different among mammals. In diurnal species (human beings), the acrophase (time of day at which the peak occurs) of body temperature and activity occurs during daytime. In nocturnal animals (rats, hamsters), the acrophase of these two rhythms occurs at night. In rats kept in L:D 12:12, the circadian and nocturnal variations of body temperature and locomotor activity are synchronous. Ultradian oscillations in locomotor activity are also ob-


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served, corresponding temporally to small increases in temperature amplitude [10–12]. In L:D 12:12, the literature reports either a phase advance of temperature on activity in the Sprague-Dawley rat [10] or a phase delay of temperature on activity in the Wistar rat [13]. These results suggest either a difference in experimental conditions on these functions or a species-related difference. Possibly, it cannot be ruled out that computing a group acrophase with the data gathered from all the animals may mask the real relationships between body temperature and activity recorded in individuals. The parallel temporal evolution of these two rhythms, both in circadian and ultradian frequency ranges, allows assuming the existence of either a common mechanism or two discrete but tightly coupled mechanisms generating the circadian rhythms of body temperature and locomotor activity. Constant conditions or free-running state Studies on the circadian rhythms in animals maintained under constant conditions lead to address several hypothesis on the functional organization of the biological clock. In an environment without time cues, the circadian rhythms persist with a period close but different from exactly 24-h: these are called “free-running” rhythms. These results are strong evidence in favor of an endogenous origin of the circadian rhythms. These constant conditions represent models of suppression of the day/night synchronizer. Two cases are usually used: 1) constant darkness or DD (dark/dark), 2) constant light or LL (light/light). 1- Animals maintained under constant darkness (DD) Species differences are observed in the free-running periods but most nocturnal rodents exhibit a free-running circadian period of approximately 25-h when they are housed in constant darkness [10, 14]. In particular, tau hamsters, displaying for locomotor activity a freerunning period of 20-h in DD, have been identified. Transplantation experiments showed that the SCN of tau hamsters confers 20-h periods to wild-type animals [15]. These results underline the endogenous component of the biological rhythmicity, generated by the suprachiasmatic nuclei. 2- Animals maintained under constant light (LL) In rat, the circadian rhythms of temperature, plasma corticosterone, locomotor activity, pineal N-acetyl transferase activity and sexual cycles were abolished when the animals were transferred from L:D 12:12 to prolonged continuous light [16]. Ultradian oscillations of these biological variables took the place of the circadian variations [10]. In the rat, the synchronism between ultradian components suggests a single mechanism, which does not disagree with the hypothesis of tightly coupled multiple oscillatory units [10, 17]. Thus, the ultradian rhythmicity could be a fundamental component of the circadian rhythm, also controlled by the same clock [13]. However, studies pointing out the biological function of the ultradian rhythmicity are scarce. After the shift from L:D 12:12 to light/light, the circadian rhythmicity of the rat plasma melatonin level was maintained in prolonged continuous light, whereas the circadian rhythms of temperature and locomotor activity turned aperiodic. Presence of a maintained melatonin’s

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circadian rhythm and of ultradian rhythms of temperature and activity would suggest existence of three different oscillators (10). In rats exposed to continuous light, the coupling of the melatonin circadian secretion to the clock would be more robust than that of locomotor activity and body temperature [17]. Thus, in nocturnal rodents maintained under continuous light, the circadian profiles were severely disrupted or even abolished, compared to their patterns under L:D 12:12. Two phenomenons were observed: 1) a spontaneous or transient internal desynchronization, 2) a dissociation of a circadian rhythm into two components (“splitting”). Internal desynchronization. The shift from L:D 12:12 to prolonged continuous light results in a loss of many aspects of the circadian rhythmicity of body temperature and activity in rats. The temporal analysis of the disruption showed an alteration in the usual phase relationships between body temperature and motor activity, which moved with different frequencies [10]. After a certain number of transient cycles, depending on species, individuals and studied functions, normal phase relations were restored in the ultradian field, i. e. the rhythms were resynchronized with each other and with the new lighting schedule. This phenomenon, also called transient internal desynchronization, has been also observed in non-human primates, after a single shift in L:D cycle [18]. In human subjects, the internal desynchronization seems to be a common phenomenon in shift work as well as in jet lag sufferers or in affective disorders [19]. The sleep/wake cycle and the circadian rhythm of temperature become desynchronized in subjects placed in a constant environment without known synchronizer. In this case, this phenomenon is called spontaneous internal desynchronization [20]. Other physiological functions are also implicated: some follow the circadian periodicity of the body temperature (plasma cortisol, REM sleep), others follow the infradian period of the rest/wake cycle (slow-wave sleep, plasma growth hormone GH). These results suggest the existence of two mechanisms: a strong oscillator that rules the circadian rhythms of body temperature, cortisol . . . and a weaker oscillator for sleep, GH . . . In rodents, the organization of the circadian system seems to follow the same model of two oscillators. However, the distinction strong/weaker is less obvious since such a spontaneous desynchronization has not been reported in small mammals. Some experiments showed that the circadian rhythm of body temperature was quite more robust than the activity rhythm in animals submitted to modifications in free-running conditions [10, 21]. The difference in robustness, i. e. a circadian rhythm is more resistant to a modification in synchronizing agents, could be explained by different sensitivities of the efferent pathways from the clock. Splitting of a circadian profile. In hamsters placed from L:D 12:12 to prolonged continuous light, the circadian rhythm of locomotor activity often dissociates into two distinct components, so that the unimodal pattern becomes bimodal [22, 23]. The two components evolve with respectively short and long periods, until reaching a stable antiphase state: the activity rhythm period of these hamsters was of 12-h (2 bouts of activity per day). The two components often merged into one to restore an unimodal profile. Sometimes, this dissociation persists and the components free-run. Subsequent reexposition to constant darkness restores a single daily activity pattern, which shows the reversibility of the “splitting” phenomenon. According to Pittendrigh [22], these components would provide from two bouts of the


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rhythm: 1) one from the activity onset, called dusk or evening component, 2) the other from the activity offset, called dawn or morning component. Each split component being able to respond independently to dark pulses [24], two distinct mechanisms are likely responsible for the generation of the circadian rhythm of locomotor activity. While such a phenomenon has been observed in rats [25] and for other rhythms than activity (drink uptake, food uptake, body temperature [26, 27]), it is worth to note differences in the emergence conditions of splitting (light intensity, sexual cycle, sex, species . . .). Besides, the splitting occurs only in 50 % of Golden hamsters. Splitting of a rhythm strongly suggests the expression of two oscillators that could have different phase relationships depending on the external lighting conditions. Until now, the splitting of the activity pattern is known to be the most dramatic evidence of the existence of a multioscillatory system. 3- Light and dark pulses Studying how a free-running rhythm behaves after a brief modification in lighting conditions is an interesting aspect concerning the formal properties of the circadian system. Because the circadian rhythmicity is generally free-running in constant conditions, the notion of subjective day (subjective night) is commonly used to describe the light phase (dark phase) during which the animal has been exposed. These experiments consist in maintaining animals under constant conditions (LL or DD). At different times of the circadian cycle, the animals were exposed to dark or bright light pulses. The graphic representation of the phase shift induced by this pulse, depending on the time at which it was applied, is called phase response curve or PRC [28] (Fig. 1). The following conclusions can be drawn: 1. The circadian clock possesses its own calendar, allowing the organism to keep its circadian rhythmicity. This is the reason why bright light pulses have little or no effect during the subjective day (corresponding with the “dead zone” of the curve) [29, 30]. 2. Two circadian oscillators would be responsible for the generation of the circadian rhythm of activity: the oscillator, sensitive to dark onset, responsible for the phase advance observed when the animal is exposed to dark pulses during light phase: oscillator E (as evening), and the second oscillator sensitive to light onset: oscillator M (as morning). 3. Pinealectomy has no effect on the responses of the animals to these brief perturbations [29]. However, in humans, giving melatonin after the start of a light exposure during the night, has been shown to antagonize the phase shifts of body temperature, cortisol and melatonin rhythms. This result supposed that the suppression of the circadian rhythm of melatonin release is necessary for the adaptation of circadian rhythms to a perturbation in the lighting cycle, at least in humans [31]. 4. Other central structures modulate the entrainment ability of the NSC. For example, the injection of antiserum against NPY in ventral NSC potentialized the light-induced phase advances in the circadian rhythm of wheel-running in hamsters maintained under DD [32], while a local micro-injection of NPY was able to attenuate the phase advances induced by light pulses. The hypothesis of a NPY/serotonin interaction in the photic modulation is sustainable because of the anatomical relations between the fibers

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Fig. 1. Phase response curve. On the top, are represented the free-running actogramms of a nocturnal animal, the corresponding time of the light stimulation and the subsequent result of the brief perturbation on the activity rhythm. According to the time of the light stimulation, it is possible to note: in A (during the day) no effect on the phase; in B and C (respectively end of the day and dark onset) phase delay; in D and E (end of the night), phase advance. On the bottom, the obtained phase response curve informs on the direction and the amplitude of the phase shift (according to Moore-Ede et al., 1982).

of the geniculohypothalamic tract releasing NPY and the serotoninergic fibers from mesencephalic raphe nuclei [5]. Moreover, local injection of muscimol, a GABAA receptor agonist, changed the phase of wheel-running circadian rhythm of hamsters, with PRC similar to those obtained with dark pulses, while bicuculline, a GABAA receptor antagonist, blocked the light-induced phase shift [33]. These results suggest a part played by biochemical and/or hormonal mechanisms in supporting the generation and the control of a coherent circadian rhythmicity [34]. Shifts and modifications in the light-dark cycle Effects of phase shifting the reference photoperiod The entrainment ability of the circadian system to the light/dark cycle can be experimentally evaluated by shifting L:D cycle of several hours and following the subsequent effects on rhythmic biological functions. For instance, after a 6-hours advance in L:D 12:12 cycle, the circadian activity rhythm in a diurnal rodent was reported to be reentrained within 4 days [35] (Fig. 2). Effects of a photoperiodic modification The period of the solar cycle is constantly of 24-h, but both duration and intensity of light phase vary with seasons. Thus, changing photoperiod can help to investigate the influence of


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Fig. 2. Actogramms of a diurnal rodent. In A: entrainment with L:D 12:12 for 8 days. In B: 6-hour advance of the L:D 12:12. The activity pattern reentrained within 4 days, with gradual changes in activity onset and offset (according to Servière and Lavialle 1996).

seasons on the circadian rhythms and the mechanisms allowing the internal clock to adjust the seasonal variations. Keeping with the hypothesis of two oscillators respectively sensitive to dusk and dawn, different photoperiodic modifications are possible: symmetric (changing the dark onset and offset) or asymmetric (changing the dark onset or offset). Symmetric photoperiodic modification When Wistar rats are submitted to a transition from L:D 12:12 to short days cycle (L:D 8:16) by a 2-hours advance and delay, respectively in dark onset and offset, the photoperiodic shift induces a 1-hour phase-delay of the activity rhythm, and significant amplitude and mesor decrease [36]. Asymmetric photoperiodic modification In Wistar rat, the shift from L:D 12:12 to a short photoperiod L:D 8:16, by a 4-hours advance in dark onset, resulted in a 1-hour advance of the acrophase and a decrease in the circadian mesor of the activity rhythm [36]. Syrian hamsters maintained under long days (L:D 16:8) show a compressed duration of the active phase, i. e. the animals are active during a shorter night. After 4 weeks, the photoperiod is asymmetrically reduced by a dark onset advance (L:D 8:16). Although the dark offset remained unchanged, a gradual but asymmetric advance in activity onset and offset was observed, until the activity onset was in phase with the new dark onset [37]. Thus, the active phase expanded, since the activity onset and offset are asymmetrically shifted as shown in Fig. 3.

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Fig. 3. Actogramms of a male Syrian hamster kept under L:D 16:8 for 10 days [in A], and placed under L:D 8:16 by asymmetric modification [in B]. A gradual “decompression” is achieved within 3 weeks, with asymmetric advance of activity onset and offset (according to Hastings et al. 1987).

Similarly, the effects of a photoperiodic reduction on melatonin release have been investigated [37]. Melatonin nocturnal secretion is considered as a photoperiodic mediator [38, 39]. Indeed, the profile of the melatonin secretion in hamsters changed with the day length: in short days, the duration of the nocturnal secretion is longer while in long days, the duration


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of the secretion is compressed. Thus, in nocturnal rodents, the duration of the active phase and of the melatonin secretion is determined by day length. However, the two rhythms are expressed independently since the decompression of the active phase was not affected by pinealectomy [37]. According to these experiments, the pineal gland would not be a critical factor in the photoperiodic regulation of rodent’s activity rhythm. It is well established that pinealectomy has no effect on the expression of activity circadian rhythms in animals both placed in constant darkness and submitted to a modification of photoperiod [40 – 43]. However, melatonin would play an important role in the entrainment of the circadian rhythms in rodents [44]. Several experimental evidences favor this hypothesis. The daily administration of exogenous melatonin at precise times is able: 1) to entrain the circadian rhythms with a precise 24-h period in rats housed under free-running conditions [7]; 2) to prevent the internal desynchronization between temperature and activity in SpragueDawley rat under prolonged continuous light [45]. The metabolically and electrical activities of the SCN are affected by exogenous melatonin both in vivo and in vitro, in a phase- and dose-dependent manner [46 – 48]. In the SCN of several mammalian species (e.g. rat and hamster), receptors with high affinity for melatonin have been found, suggesting a feedback control of the pineal hormone on the putative circadian clock [49]. Thus, the pineal could play a double role in 1) the modulation of light sensitivity (pinealectomized animals perceive differently the ambient light), 2) the coupling relationships inside the circadian system. However, results from the literature are very heterogeneous depending on the studied animal species. Conclusion The daily rhythmicity is the result of the combined action of the endogenous biological clock(s) and environmental time cues [21]. Synchronizers do not create the biological rhythmicity but only modulate its parameters in order to help the organism to adapt and anticipate environmental variations [50]. The circadian rhythms, like that of locomotor activity, must adapt to modifications of the photoperiod. During transient period of adjustment to new lighting conditions, it is possible to observe gradual changes in the activity onset and offset, phase shifts, and sometimes, changes in the period of the rhythm. The asymmetrical reentrainment of the activity onset and offset indicates the expression of two different but tightly coupled oscillators [51]. Depending on the external lighting conditions, the phase relation between these two oscillators varies, determines the photoperiodic response and induces a modulation in the activity and melatonin patterns. Thus, it is worth to note that according to the symmetrical or asymmetrical character of the experimentally imposed modification, the photoperiodic response will be different. In rodents, two oscillators are mutually coupled: “E” for evening, entrained by dusk and “M” for morning, entrained by dawn. In constant darkness, the internal coupling would be very tight, inducing a common periodicity; in constant light, the internal coupling would be disrupted, each oscillator expressing its own periodicity [52]. The ultradian components may well be the expression of a restructuration among the different circadian oscillatory units, until reaching stable mutual relationships, insofar as the coupling is photoperiod-modulated [14, 53, 54]. This model would be indicative of a hierarchy in the circadian oscillators, with

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the idea of one and quite dominant mechanism that synchronizes a number of subordinated oscillators. In the absence of influence from the dominant oscillator (s), for example under continuous light, the oscillators would express their own periodicity independently [55]. When “E” and “M” are in phase with their own temporal signals, the organism is synchronized with the new environment. Despite extensive studies in several systems, the molecular basis of the coupling between the two sets of oscillators has not been yet demonstrated [56]. Therefore, throughout the year, in most mammals, the seasonal modifications in day length affect the expression of the circadian rhythms in hormones (melatonin), behavior (locomotor activity, sleep/wake) and physiological (temperature) parameters. Changes in the physiological status of the circadian system, i. e. the suprachiasmatic nuclei, could be the basis of the photoperiodic response [51]. Indeed, as sunset and sunrise are closer in summer, the phase relation between the two oscillators “E” and “M” is modified [22, 57]. However, during the critical transient period of adaptation to a new (natural or experimental) L:D cycle, the evolution of the temporal relation between the circadian rhythms of activity and temperature has been scarcely studied. These two functions are only known to evolve in synchrony in standard lighting conditions L:D 12:12 or in free-running conditions. The circadian clock seems to be a clock for all seasons, adjusting the behavioral and physiological circadian rhythms with the photoperiodic changes. The NSC and/or hormonal secretions (melatonin, gonadal hormones, thyroid hormones . . .) may modulate the degree of coupling between the oscillatory units and thus, the expression of the circadian rhythmicity. References 1. Fuller CA, Lydic R, Sulzman FM, Albers HE, Tepper B, Moore-Ede MC. Circadian rhythm of body temperature persists after suprachiasmatic lesions in the squirrel monkey. American Journal of Physiology 1981; 241 R385–R391. 2. Rusaz B, Zucker I. Neural regulation of circadian rhythms. Physiology Review 1979; 59 (3) 449–526. 3. Sehgal A, Ousley A, Hunter-Ensor M. Control of circadian rhythms by a two-component clock. Molecular and Cellular Neurosciences 1996; 7 165–172. 4. Campbell SS, Murphy PJ. Extraocular circadian phototransduction in humans. Science 1998; 279 386–388. 5. Weber TE, Rea MA. Neuropeptide Y blocks light-induced phase advances but not delays of the circadian activity rhythm in hamsters. Neurosciences Letters 1997; 231 159–162. 6. Touitou Y. Biological Clocks: Mechanisms and Applications, 584 pages, Excerpta Medica, Elsevier, Amsterdam. 7. Redman J, Armstrong S, Ng KT. Free-running activity rhythms in the rat : entrainment by melatonin. Science 1983; 29 1089–1091. 8. Weinert D, Sitka U, Minors D, Waterhouse J. The development of circadian rhythmicity in neonates. Early Human Development 1994; 36 117–126. 9. Weinert D, Schuh J. Frequency and phase correlations of biorhythms of some metabolic parameters during postnatal ontogenesis in mice. Bulletin of Experimental Biology and Medicine 1988; 12 1764–1767. 10. Deprès-Brummer P, Lévi F, Metzger G, Touitou Y. Light-induced suppression of the rat circadian system. American Journal of Physiology 1995; 268 R1111–R1116. 11. Honma K, Hiroshige T. Internal synchronization among several circadian rhythms in rats under constant light. American Journal of Physiology 1978; 235 R243–R249. 12. Refinetti R, Menaker M. The circadian rhythm of body temperature. Physiology and Behavior 1992; 51 613–637. 13. Honma K, Hiroshige T. Endogenous ultradian rhythms in rats exposed to prolonged continuous light. American Journal of Physiology 1978; 235 R250–R256. 14. Vilaplana J, Cambras T, Diez-Noguera A. Dissociation of motor activity circadian rhythm in rats after exposure to LD cycles of 4-h period. American Journal of Physiology 1997; 272 R95–R102.


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