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Endocrinology Vol. 148, No. 12 5648-5655
Copyright © 2007 by The Endocrine Society

Minireview: Entrainment of the Suprachiasmatic Clockwork in Diurnal and Nocturnal Mammals

Etienne Challet

Department of Neurobiology of Rhythms, Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 7168/LC2), University Louis Pasteur, 67084 Strasbourg, France

Address all correspondence and requests for reprints to: Etienne Challet, Department of Neurobiology of Rhythms, Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 7168/LC2), University Louis Pasteur, 5 rue Blaise Pascal, 67084 Strasbourg, France. E-mail: challet{at}neurochem.u-strasbg.fr.


   Abstract
Top
 Abstract
Introduction
 Molecular SCN Clockwork in...
 External Synchronizing Cues
 Internal Feedback (Arousal...
 Conclusion
 References
 
Daily rhythmicity, including timing of wakefulness and hormone secretion, is mainly controlled by a master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN clockwork involves various clock genes, with specific temporal patterns of expression that are similar in nocturnal and diurnal species (e.g. the clock gene Per1 in the SCN peaks at midday in both categories). Timing of sensitivity to light is roughly similar, during nighttime, in diurnal and nocturnal species. Molecular mechanisms of photic resetting are also comparable in both species categories. By contrast, in animals housed in constant light, exposure to darkness can reset the SCN clock, mostly during the resting period, i.e. at opposite circadian times between diurnal and nocturnal species. Nonphotic stimuli, such as scheduled voluntary exercise, food shortage, exogenous melatonin, or serotonergic receptor activation, are also capable of shifting the master clock and/or modulating photic synchronization. Comparison between day- and night-active species allows classifications of nonphotic cues in two, arousal-independent and arousal-dependent, families of factors. Arousal-independent factors, such as melatonin (always secreted during nighttime, independently of daily activity pattern) or {gamma}-aminobutyric acid (GABA), have shifting effects at the same circadian times in both nocturnal and diurnal rodents. By contrast, arousal-dependent factors, such as serotonin (its cerebral levels follow activity pattern), induce phase shifts only during resting and have opposite modulating effects on photic resetting between diurnal and nocturnal species. Contrary to light and arousal-independent nonphotic cues, arousal-dependent nonphotic stimuli provide synchronizing feedback signals to the SCN clock in circadian antiphase between nocturnal and diurnal animals.


   Introduction
Top
 Abstract
 Introduction
Molecular SCN Clockwork in...
 External Synchronizing Cues
 Internal Feedback (Arousal...
 Conclusion
 References
 
MOST ANIMAL SPECIES display predictable daily rhythmicity in neuroendocrine function and most behaviors as well. The basic rest-activity or sleep-wake cycles are usually consistent for a given species (but see Refs. 1 and 2 for plasticity in daily activity) and vary from night-active animals, those mostly active at dawn and dusk (i.e. crepuscular), to day-active species. Crepuscular and/or day-active species, such as Arvicanthis, Octodon, and Spermophilus, will be referred to here as diurnal species because they share common features, such as minimum of core body temperature occurring in the middle of the night, that are opposed in phase to those of nocturnal animals (with minimum of body temperature around midday) (Fig. 1Go). Compared with nocturnal rodents, diurnal species have been studied much less often with regard to entraining properties, especially for synchronizing factors other than light. Keeping in mind that generalization from the few studies made in diurnal rodents might be premature, the present minireview will attempt to compare when synchronizing cues reach the main circadian clock and how they affect it in nocturnal and diurnal rodents.


Figure 1
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  		FIG. 1. Differential temporal organization of daily rhythms between nocturnal and diurnal mammals (red lines). Whereas the sleep period (shaded areas), body temperature (brown curves), and hypothalamic content of serotonin (green curves) are oppositely phased between the two categories, melatonin synthesis by the pineal gland (purple curves) always occurs during nighttime. Vertical blue or red bars on the x-axis represent the daily period of activity in nocturnal and diurnal animals, respectively. Daytime and nighttime are indicated on the x-axis by horizontal white and black bars, respectively.

 
Irrespective of the regular temporal niche used in the laboratory or in the natural environment, daily rhythmicity under a light-dark cycle is controlled by an endogenous clock (3) and possibly modulated by direct, clock-independent responses to light, the so-called masking (4, 5).

Comparative analysis between mammalian species shows that a number of daily rhythms are oppositely phased with respect to the light-dark cycle in diurnal compared with nocturnal animals. For instance, daily body temperature peaks during daytime and nighttime in diurnal and nocturnal rodents, respectively (6, 7) (Fig. 1Go). Another example is the daily variations in plasma corticosteroid that display maximal values at dusk in nocturnal rats (8, 9) and at dawn in diurnal rhesus monkeys (10). By contrast, a few daily rhythms are equally phased with respect to the light-dark cycle, regardless of diurnality/nocturnality. Melatonin perfectly matches this phase-locked feature in that its secretion by the pineal gland always occurs during the night in both diurnal and nocturnal mammals (11, 12, 13) (Fig. 1Go).


   Molecular SCN Clockwork in Diurnal and Nocturnal Species
Top
 Abstract
 Introduction
 Molecular SCN Clockwork in...
External Synchronizing Cues
 Internal Feedback (Arousal...
 Conclusion
 References
 
In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus harbors the master circadian clock that coordinates most aspects of behavior and physiology (14, 15). Lesion of the SCN abolishes circadian rhythmicity of sleep-wake states and hormone secretion (16, 17). To generate circadian signals, the SCN clockwork relies on feedback loops in which the CLOCK/BMAL1 heterodimers activate the transcription of three Period (Per1–3) and two Cryptochrome (Cry1–2) genes. PER-CRY dimers act as negative regulators of CLOCK/BMAL1 (18, 19). CRY1 and CRY2 impair phosphorylation of CLOCK/BMAL1, reducing transcriptional activity of this heterodimer (20). Some nuclear orphan receptor genes, such as Rev-erb{alpha}, Rev-erbß, Ror{alpha}, and Rorß are activated by CLOCK/BMAL1 heterodimers and produce protein products that differentially modulate Bmal1 transcription (21, 22, 23). Clock-controlled genes like Vasopressin are thought to be regulated by the same interlocked feedback loops (24).

In the SCN, most of these genes display specific temporal patterns of expression over 24 h. Of note, the expression patterns of most clock genes are similar in nocturnal and diurnal species. For instance, the clock gene Per1 in the SCN peaks at midday in both categories of animals (25, 26, 27, 28, 29, 30, 31). Levels of Clock mRNA and protein are generally constitutively expressed in the SCN (32, 33, 34), whereas they oscillate in sheep (diurnal) under both long and short photoperiods (28) and Syrian hamsters (nocturnal) kept in short photoperiods (30). Furthermore, both Per1 and Per2 are markedly expressed in the dorsomedial part of the SCN (i.e. the region containing vasopressin neurons), contrasting with their low expression in the ventrolateral part of the SCN (i.e. the region containing vasoactive intestinal peptide and gastrin-releasing peptide neurons). This compartmentalization is found not only in nocturnal rodents (35, 36, 37) but also in diurnal species (35).


   External Synchronizing Cues
Top
 Abstract
 Introduction
 Molecular SCN Clockwork in...
 External Synchronizing Cues
Internal Feedback (Arousal...
 Conclusion
 References
 
Light
Light is the most powerful synchronizer of the SCN clock. Photic (i.e. nonvisual irradiance) information from the environment is detected by a subset of retinal ganglion cells by means of a specific photopigment, melanopsin. These photosensitive ganglion cells then signal photic cues to the SCN directly via retinohypothalamic fibers (38, 39, 40, 41) and indirectly via projections from a thalamic relay structure, the intergeniculate leaflet (IGL) (42). Considering that mice knockout for melanopsin can switch partially their activity from nighttime to daytime (43), it cannot be fully excluded that some functional differences at the retinal level between diurnal and nocturnal species may participate in the regulation of diurnality/nocturnality. Moreover, it should be mentioned that different neurophysiological responses to light have been found between the diurnal Octodon and the nocturnal rat (44).

The phase-shifting responses of the SCN clock to light depend on the time of the day when light is applied, as demonstrated by resetting properties of discrete light pulses in animals housed in constant darkness. Light-induced phase shifts of the SCN mainly occur during nighttime (i.e. the active and resting period in nocturnal and diurnal species, respectively), regardless of the timing of activity, as investigated in a large range of night-active (3, 45, 46) and day-active mammalian species (29, 45, 47, 48, 49, 50, 51). In the daytime, there is a period during which light has no resetting effect, defining a dead zone in between the circadian windows of sensitivity to light (3, 46) (see arrow in Fig. 2Go). Comparison of the phase-response curves in the studies cited just above reveals that the duration of photic insensitivity is usually longer in nocturnal than in diurnal mammals, and it could even be absent in humans (52).


Figure 2
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  		FIG. 2. Phase-response curves to light (A; yellow), exogenous melatonin (B; purple), and serotonergic receptor activation (C; green) in nocturnal (blue lines) and diurnal (red lines) mammals. Hatched areas indicate the circadian windows of sensitivity to these synchronizing cues. Subjective day and night in constant darkness are indicated on the x-axis by gray and black bars, respectively. The black arrow indicates the dead zone in the phase-response curve to light (A).

 
In response to photic stimulation of melanopsinergic ganglion cells in the retina, glutamate is released from retinohypothalamic terminals and activates SCN cells via N-methyl-D-aspartate (NMDA) and metabotropic receptors to mediate photic resetting (53). In vivo injections of NMDA in the SCN of both nocturnal and diurnal species during nighttime induce photic-like behavioral phase shifts (54, 55).

Light stimuli at night are known to trigger FOS expression in the SCN of both nocturnal (56, 57) and diurnal species (50, 58). Synchronization of the SCN clock to light cues has been further associated with transcriptional mechanisms involving up-regulation of clock gene expression. In keeping with the nocturnal windows of sensitivity to light, light exposure induces expression of Per1 and Per2 mRNA and proteins during the night in the SCN of both nocturnal (25, 59, 60) and diurnal mammals (29). The involvement of Per1 and Per2 in the synchronization of the SCN clock to photic signals has been further demonstrated by the fact that intracerebroventricular injections of antisense oligodeoxynucleotides to Per1 and/or Per2 reduce light-induced phase delays in mice (61, 62). Also, mice carrying a mutated Per1 gene show no light-induced phase advances, whereas Per2 mutant mice display no light-induced phase delays (63). In nocturnal rodents exposed to a light pulse at night, Per1 expression is triggered in the ventrolateral, gastrin-releasing peptide-containing SCN cells and spreads to the dorsomedial, vasopressin region of the SCN (64, 65), whereas Per2 expression is increased throughout the SCN (64).

Therefore, under laboratory conditions, shifting mechanisms of synchronization to light are closely similar in nocturnal and diurnal mammals (but see also Ref. 66 for differential regulation of Per1 and Per2 in the SCN between diurnal and nocturnal individuals of blind mole rats). In the natural environment, however, diurnal species are exposed to much more light in duration and intensity than nocturnal ones are. In that context, Daan (67) reviewed the concept developed by J. Aschoff that light may have tonic effects on the master circadian clock that would lead to a tight control of its endogenous period. This hypothesis has recently regained some appeal with the discovery that diurnal ground squirrels in the field start to be active more than 3 h after civil twilight at dawn and go back to their burrow 2–3 h before civil twilight at dusk (68). In that species, synchronization to light may thus result from resetting effects of light during late morning/early afternoon and/or from adjustment of their endogenous period to daytime light (68).

Nevertheless, to summarize, the circadian responses to light at both behavioral and molecular levels are not basically different between day-active and night-active species (Table 1Go).


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  		TABLE 1. Circadian windows of sensitivity to resetting cues in nocturnal and diurnal species

 
Dark
In animals housed in constant light, the SCN clock can be more or less reset by dark exposure lasting from several minutes to hours (69, 70). In nocturnal species, long dark pulses have been shown to produce phase advances during most of the subjective day and early night and phase delays during the late subjective night and early day (69, 70, 71, 72). In view of this phase-response curve, dark pulses appear to be complex stimuli, with both antiphotic and nonphotic features. The antiphotic features are defined by the observations that dark pulses in hamsters have opposite windows of sensitivity compared with light (71, 73). The so-called nonphotic properties (see below for details) result from the fact that, at least during the subjective day, part of resetting properties of dark exposure can be due to dark-induced hyperactivity and behavioral activation (70, 72), whereas the remaining part of dark resetting can be attributed to exposure to darkness per se (74, 75). Comparative studies between nocturnal and diurnal species demonstrate that resetting to dark pulses mostly occurs during resting, irrespective of the timing of locomotor activity pattern (75, 76) (Table 1Go). Thus, the circadian sensitivity to dark exposure differs largely between nocturnal (Syrian hamster) and diurnal species (Arvicanthis).

At the molecular level, dark pulses during the subjective day have been shown to down-regulate FOS expression in the SCN of hamsters (77), but this molecular response remains to be investigated in diurnal species. Moreover, exposure to dark can transiently down-regulate Per1 and Per2 expression in the SCN of hamsters (74). Similar molecular changes of Per expression in the SCN have been detected after exposure of Arvicanthis to dark pulses (75). Despite different circadian windows of sensitivity between hamsters and Arvicanthis, this apparent similarity of dark-induced molecular effects may be due partly to constant light-induced changes in Per1 and Per2 expression, the mRNA levels of which are still high during early subjective night in the SCN of Arvicanthis but not in that of hamsters (75). Furthermore, dark-induced shifts at subjective dusk are specifically associated with a transient down-regulation of Rev-erb{alpha} in the SCN of diurnal Arvicanthis but not in nocturnal hamsters.

To summarize, the circadian window of sensitivity to dark determined at the behavioral level is clearly different between day-active and night-active rodents, because it occurs essentially during the resting period (Table 1Go). By contrast, at the molecular level, dark pulses produce comparable (nonphotic-like) changes of Per expression.


   Internal Feedback (Arousal Independent) Cues
Top
 Abstract
 Introduction
 Molecular SCN Clockwork in...
 External Synchronizing Cues
 Internal Feedback (Arousal...
Conclusion
 References
 
Melatonin
Nonphotic stimuli, such as scheduled voluntary exercise, exogenous melatonin or serotonergic activation, are also capable of shifting the master clock. New comparative results between day- and night-active species allow categorization of at least two (i.e. arousal-independent and arousal-dependent) families of nonphotic cues. Such classification is comparable to a previous distinction between activity-independent and activity-related circadian rhythms, the former showing similar acrophases in all mammals and the latter showing different timing in connection with the daily pattern of activity (78).

Melatonin is a hormone always secreted at night by the pineal gland, independently of the locomotor activity pattern (11, 12, 13) (Fig. 1Go). For that reason, melatonin can be considered as an arousal-independent factor. Because the SCN control the circadian rhythmicity of pineal synthesis of melatonin and also express high-affinity melatonin receptors, this hormone is thought to play a feedback role on the SCN (79). It is noteworthy that pharmacological doses of melatonin can produce behavioral phase advances when injected at subjective dusk in mice (80). Moreover, a daily infusion of melatonin entrains the circadian rhythms of rats housed in constant darkness when the infusion coincides with activity onset (i.e. subjective dusk) (81). Of interest, melatonin shifting effects occur exactly at the same circadian time in diurnal rodents, that is, when melatonin infusion coincides with activity offset (i.e. subjective dusk) (82) (Fig. 2Go). Because pineal melatonin is synthesized and secreted only at night in both diurnal and nocturnal mammals, exogenous melatonin thus has phase-advancing effects when endogenous melatonin is supposed to be not synthesized/secreted by the pineal gland. This melatonin-induced phase advance of the SCN clock would permit readjustment of a hypothetical delay of the SCN clock compared with the temporal signals provided by melatonin secreted by the pineal gland.

At the molecular level, exogenous melatonin in rats does not acutely modulate Per mRNA levels (83), as do light pulses in constant dark and dark pulses in constant light (see above). Melatonin, however, has been shown to modulate the expression of two nuclear orphan receptors present in the SCN; it leads to a phase advance of the rhythmic expression of Rev-erb{alpha} and to a prolonged up-regulation of Rorß mRNA levels (84).

Taken together, these data indicate that pharmacological injections of melatonin produce phase advances at the same circadian time (dusk) in both nocturnal and diurnal species independently of activity patterns (Fig. 2Go). This observation is in accordance with the hypothesis that melatonin may provide internal feedback cues to the SCN but only at a certain circadian time (subjective dusk; Table 1Go), irrespective of the behavioral state of the animals. Furthermore, melatonin treatment affects expression of Rev-erb{alpha} and Rorß, but not of Per, in the SCN. Until now, this molecular approach has been investigated only in a nocturnal species, the rat. Considering that in nocturnal and diurnal species, melatonin acts at the same circadian time (i.e. at the same cycling state of the molecular SCN clockwork), this raises the possibility that transcriptional changes similar to those obtained in the rat likely occur in diurnal species treated with exogenous melatonin.

{gamma}-Aminobutyric acid (GABA)
GABA has long been recognized as an important neurotransmitter of the circadian timing system. Nearly all neurons of the SCN as well as those of the IGL contain GABA (85). More recently, GABA has been shown to play a key role in coupling between the ventral and dorsal parts of the SCN (86) and among SCN neurons as well (87, 88).

When applied during the middle of the subjective day, activation of GABAA receptors (e.g. with muscimol) produces phase advances in nocturnal rodents, such as hamsters (89). This treatment administered in diurnal Arvicanthis at the same circadian times also has significant shifting effects, albeit opposite in direction (i.e. phase delays instead of advances) (90). It is noteworthy here that the phase-shifting effects in response to GABAA receptor activation occur at the same circadian times in diurnal and nocturnal rodents, that is, independently of the daily pattern of locomotor activity. This is why GABA activation can be classified as an arousal-independent stimulus for the SCN clock (Table 1Go). Such phase shifts induced by GABAA activation during the mid-subjective day have been associated with a down-regulation of both Per1 and Per2 in the SCN of hamsters (91) and only of Per2 in the SCN of Arvicanthis (92).

During the subjective night, a GABAergic stimulation, via GABAA receptors with muscimol or GABAB receptors with baclofen, has been shown to reduce light-induced phase shifts in nocturnal rodents, such as hamsters (93). Interestingly, similar microinjections of muscimol or baclofen in the SCN of diurnal Arvicanthis also lead to decreased shifting to light (90, 94), suggesting comparable GABAergic modulation of photic resetting in diurnal and nocturnal species.

Serotonin
Serotonin [5-hydroxytryptamine (5-HT)] is another important neurotransmitter within the circadian timing system. Both the SCN and IGL receive differential serotonergic projections from the midbrain raphe nuclei (95). Serotonergic receptor activation can be defined as an arousal-dependent factor because activity of serotonergic neurons is closely correlated with the level of behavioral arousal (96). Consistent with this, 5-HT levels in the SCN region follow the daily pattern of locomotor activity in nocturnal rats (97, 98) and diurnal Arvicanthis (Cuesta, M., J. Mendoza, P. Pevet, and E. Challet, manuscript submitted) (Fig. 1Go).

An in vivo serotonergic activation, as induced by systemic or intracerebroventricular injections of 5-HT agonists [e.g. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A/7 receptor agonist], is capable of phase advancing the SCN clock of nocturnal rodents during the mid-subjective day, with very low or even no shifting effects at other circadian times (i.e. during the subjective night) (100, 101, 102). Similar circadian windows of sensitivity to serotonergic cues have been shown in vitro on SCN slices of hamsters or rats (103, 104, 105). By contrast, in the diurnal Arvicanthis, serotonergic receptor activation produces phase advances essentially during the subjective night but not during the mid-subjective day (Cuesta, M., J. Mendoza, P. Pevet, and E. Challet, manuscript submitted). Therefore, shifting effects of serotonergic stimulation take place in opposite circadian windows of sensitivity (i.e. during subjective day and night, respectively) between nocturnal and diurnal animals, but this always corresponds to the resting period (Fig. 2Go and Table 1Go). At least two previous studies have investigated the effects of nonphotic activity-inducing locomotor activity in two diurnal species, the European ground squirrel (106) and the Common marmoset (107). Because small phase advances in ground squirrels can occur after nonphotic stimulation in late subjective day, the authors concluded that in this diurnal species, the responses of the SCN clock to nonphotic cues were similar to those previously described in nocturnal rodents. It should be noted, however, that this conclusion was obtained after studying phase angle of entrainment, instead of phase-response curve to single nonphotic stimuli as determined with serotonergic activation in a diurnal rodent, Arvicanthis (Cuesta, M., J. Mendoza, P. Pevet, and E. Challet, manuscript submitted). Based on these data, the circadian phase of sensitivity to serotonergic cues starts in late subjective day instead of ending at that time point as in nocturnal rodents. Thus, it is possible that synchronization of the circadian rhythms by a nonphotic activity-inducing factor (also supposed to activate the serotonergic system) can occur at the subjective day-night transition in the diurnal ground squirrel (106).

Resetting of the SCN clock in nocturnal animals after acute hyperactivity or serotonergic receptor activation during the mid-subjective day has been associated with transient down-regulation of Per expression (107, 108, 109) (Fig. 3Go). Moreover, intracerebroventricular injections of antisense oligodeoxynucleotides to Per1 in the Syrian hamster mimic the effects of behavioral or serotonergic activation; that is, they produce large behavioral phase advances when administered during the subjective day (110). The molecular mechanisms mediating serotonergic resetting in diurnal species are still unknown. The available data indicate at least that the expression of Per1, Per2, Rev-erb{alpha}, and -ß, and Ror{alpha} and -ß mRNA is not modified by a serotonergic activation within the SCN of Arvicanthis (Cuesta, M., J. Mendoza, P. Pevet, and E. Challet, manuscript submitted) (Fig. 3Go). Nevertheless, it is not surprising that the molecular changes induced by serotonergic cues are different between diurnal and nocturnal species, because they occur at opposite circadian times. Besides the transcriptional hypothesis, it is quite possible that in diurnal rodents, serotonergic stimulation during nighttime modulates translation or post-translation of clock proteins.


Figure 3
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  		FIG. 3. Changes in mRNA levels of the clock genes Period within the suprachiasmatic clockwork after light (yellow) or serotonin stimulation (green) in nocturnal (blue lines) and diurnal (red lines) mammals. Hatched areas indicate the circadian windows of sensitivity to these synchronizing cues. Subjective day and night in constant darkness are indicated on the x-axis by horizontal gray and black bars, respectively.

 
Moreover, serotonergic activation modulates photic synchronization in both nocturnal and diurnal species. Interestingly, in nocturnal animals, serotonergic activation reduces both light-induced phase shifts and activation of Per transcription (111, 112), whereas in diurnal ones, it potentiates light-induced phase shifts (Fig. 4Go) and differentially affects transcription of Per1–2 and of the nuclear orphan receptors, Rev-erb{alpha} and Rorß (Cuesta, M., J. Mendoza, P. Pevet, and E. Challet, manuscript submitted).


Figure 4
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  		FIG. 4. Modulation of photic resetting (yellow) by serotonergic stimulation (green) in diurnal and nocturnal rodents. Serotonergic stimulation (5-HT {Sigma}; hatched histograms) reduces light-induced phase delays and advances in the nocturnal hamsters (left panel), whereas it potentiates light-induced phase shifts in the diurnal Arvicanthis (right panel). Vertical blue or red bars on the x-axis represent the daily period of activity in nocturnal and diurnal animals, respectively.

 
Finally, another neuropeptide that deserves attention within the circadian timing system is neuropeptide Y (NPY) released in the SCN from projections originating in the IGL (42). NPY is thought to convey nonphotic cues to the SCN of nocturnal animals, as shown by behavioral (42, 113) and molecular changes induced by NPY treatment (114). Of interest, as for 5-HT, NPY injected at night can reduce photic responses in hamsters (99). Unfortunately, no information is yet available on the circadian role of NPY in diurnal species. Nevertheless, the data gathered in nocturnal species suggest that NPYergic cues belong to the family of arousal-dependent factors, providing internal feedback signals to the SCN (Table 1Go). Thus, it will be necessary to test this hypothesis in diurnal species and see whether NPYergic cues applied in diurnal rodents could produce shifts of the SCN at night and potentiate light-induced phase shifts.


   Conclusion
Top
 Abstract
 Introduction
 Molecular SCN Clockwork in...
 External Synchronizing Cues
 Internal Feedback (Arousal...
 Conclusion
References
 
Even if light is the most potent synchronizer of the SCN clock, several other nonphotic cues are also known to shift or synchronize this clock and, perhaps more importantly, to fine-tune its photic synchronization. Even if diurnal and nocturnal species are exposed to very different levels of light intensity on a daily basis, the synchronizing effects of light are mainly restricted to nighttime in both categories. Until recently, nonphotic factors have been classified as such, only because they differ in nature from light. Based on their resetting properties, especially the phase sensitivity, a comparative analysis between day- and night-active species allows classification of nonphotic cues in two families, arousal-independent and arousal-dependent. Arousal-independent factors, such as melatonin (always secreted during nighttime, independently of daily activity pattern) or GABA, have shifting effects at the same circadian times in both nocturnal and diurnal rodents. Moreover, GABA activation similarly modulates photic resetting during nighttime in both diurnal and nocturnal species. Conversely, arousal-dependent factors, such as serotonin, induce phase shifts only during resting, and they display opposite modulating effects on photic resetting between diurnal and nocturnal species.

As a general conclusion, it should be noted that photic and nonphotic cues in day- or night-active species usually have synchronizing effects when they are normally not present: during nighttime for light in both categories, at dusk for melatonin (as arousal-independent in both categories), and during daytime and nighttime for serotonin in nocturnal and diurnal species, respectively. Such a phase control may be important in real-life situations to keep or adjust the timing of the sleep-wake cycle and neuroendocrine functions to daily variations in the environment.

In view of the differences of circadian regulation between diurnal and nocturnal species described above, the data obtained in diurnal rodents, especially those concerning arousal-dependent cues, appear to be very relevant for understanding the circadian physiology in humans and for the design of appropriate chronobiotic treatments as well.


   Acknowledgments
 
I thank deeply Marc Cuesta and Dr. Jorge Mendoza for their critical help as well as Dr. Paul Pévet for his continuous support. I am also grateful to Dr. Jeffrey D. Blaustein, Dr. Françoise Eclancher, and Dr. Sophie Reibel-Foisset for helpful comments on the manuscript. I also thank Sylviane Gourmelen for excellent technical help.


   Footnotes
 
Disclosure Statement: E.C. has nothing to disclose.

First Published Online September 27, 2007

Based on talk given at the "From Molecular Clocks to Human Health" session at the Sixth International Congress of Neuroendocrinology, Pittsburgh, PA, June 2006.

Abbreviations: GABA, {gamma}-Aminobutyric acid; 5-HT, 5-hydroxytryptamine; IGL, intergeniculate leaflet; NMDA, N-methyl-D-aspartate; NPY, neuropeptide Y; SCN, suprachiasmatic nucleus.

Received June 15, 2007.

Accepted for publication September 11, 2007.


   References
Top
 Abstract
 Introduction
 Molecular SCN Clockwork in...
 External Synchronizing Cues
 Internal Feedback (Arousal...
 Conclusion
 References
 

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F. J. Valenzuela, C. Torres-Farfan, H. G. Richter, N. Mendez, C. Campino, F. Torrealba, G. J. Valenzuela, and M. Seron-Ferre
Clock Gene Expression in Adult Primate Suprachiasmatic Nuclei and Adrenal: Is the Adrenal a Peripheral Clock Responsive to Melatonin?
Endocrinology, April 1, 2008; 149(4): 1454 - 1461.
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