The Neuroscientist · 2010. 2. 16. · 478 The Neuroscientist / Vol. 15, No. 5, October 2009 The...

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The Neuroscientist

DOI: 10.1177/1073858408327808 2009; 15; 477 originally published online Feb 17, 2009; Neuroscientist

Jorge Mendoza and Etienne Challet Brain Clocks: From the Suprachiasmatic Nuclei to a Cerebral Network

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477

Brain Clocks: From the Suprachiasmatic Nuclei to a Cerebral Network

Jorge Mendoza and Etienne Challet

Circadian timing affects almost all life’s processes. It not only dic-tates when we sleep, but also keeps every cell and tissue working under a tight temporal regimen. The daily variations of physiology and behavior are controlled by a highly complex system comprising of a master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus, extra-SCN cerebral clocks, and peripheral oscillators. Here are presented similarities and differences in the molecular mechanisms of the clock machinery between the primary SCN clock and extra-SCN brain clocks. Diversity of secondary clocks in the brain, their specific sensitivities to time-giving cues, as their differential

coupling to the master SCN clock, may allow more plasticity in the ability of the circadian timing system to integrate a wide range of temporal information. Furthermore, it raises the possibility that pathophysiological alterations of internal timing that are deleterious for health may result from internal desynchronization within the network of cerebral clocks.

Keywords: circadian rhythm; synchronization; light; food; chronotherapy

Everyday we experience daily changes in cerebral func-tion, the most obvious one being the sleep-wake cycle. Even if we are not necessarily conscious of

them, such a daily rhythmicity affects most of our physiolog-ical functions (e.g., hormonal secretion or body temperature) and behaviors (e.g., eating or drinking) as well. These daily variations clearly follow the 24-h light-dark cycle due to the daily rotation of the earth. It is now well established, however, that they are not passive responses to the changing outside world, but are driven by internal circadian (from the Latin circa and dies, meaning “about” “one day,” respectively) clocks. A unique property of the circadian timing system is thus to convert the passage of external time into synchronized internal timing. This function is achieved by endogenous circadian clocks that generate, via their outputs, an internal cyclic timing. The circadian clocks, identified in most living organisms from cyanobacteria to humans, can be synchro-nized to external cues, the most potent being the solar light signals (Fig. 1).

The Master Cerebral Clock: The Suprachiasmatic Nuclei

Central to the mammalian time-keeping system is the master clock, located in the suprachiasmatic nuclei (SCN) within the hypothalamic region of the brain (Fig. 2). Ablation of the

SCN abolishes circadian rhythmicity of the sleep-wake cycle whereas transplantation of fetal SCN can restore overt behav-ioral rhythmicity in constant environmental conditions (Ralph and others 1990), thus demonstrating the primary function of the SCN in creating internal rhythmicity. Like a conductor, the SCN clock beats time and conveys timing signals throughout the body. Circadian rhythms in the whole organ-ism are therefore coordinated in synchrony by the SCN (Herzog and Schwartz 2002; Ko and Takahashi 2006; Hastings and others 2007).

At the molecular level, circadian clocks use clock genes to generate self-sustained rhythmicity. Clock genes are expressed not only in the SCN, but also in extra-SCN brain regions as in most peripheral tissues. In part because of easiness and avail-ability of material compared with the small SCN, clockwork function has been studied in peripheral clocks, such as the liver and cultured fibroblasts. These investigations have allowed major breakthroughs in understanding the basic mechanisms underlying the molecular clockwork (Reppert and Weaver 2002; Ko and Takahashi 2006; Schibler 2006). Circadian oscillations rely on feedback loops in which two PAS domain helix-loop-helix proteins, CLOCK and BMAL1, can dimerize and then activate the transcription of three Period (Per1-3) and two Cryptochrome (Cry1-2) genes via E-Box sequences in their promoter (Fig. 2). PER-CRY dimers can translocate to the nucleus and interfere negatively with CLOCK/BMAL1-dependent transcription. CRYs impair phos-phorylation of CLOCK/BMAL1, reducing transcriptional activ-ity of this dimer. Transcription of nuclear orphan receptor genes, such as Rev-erbα, Rev-erbβ, Rorα, and Rorβ is activated by CLOCK/BMAL1 dimers and produces REV-ERBs and RORs with negative and positive regulatory effects on Bmal1 transcription, respectively. DEC1 and DEC2 are other circa-dian components capable in the SCN of reducing E-box–mediated transcription (Rossner and others 2008).

From the Institute of Cellular and Integrative Neurosciences, Centre National dela Recherche Scientifique, University Louis Pasteur, Strasbourg, France.

We thank Dr. A. Malan and Dr. P. Pévet for valuable comments and support.

Address correspondence to: Etienne Challet, Institut de Neurosciences Cellulaires et Intégratives, UMR7168, CNRS et Université Louis Pasteur, 5 rue Blaise Pascal, 67084 Strasbourg, France; e-mail: [email protected].

The NeuroscientistVolume 15 Number 5

October 2009 477-488© 2009 The Author(s)

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478 The Neuroscientist / Vol. 15, No. 5, October 2009

The clockwork is thought to be built so that most clock components do not cycle at the same time, which allows precise temporal regulation for a given gene and possible fine-tuning of circadian oscillations. Accordingly, most of these genes in the SCN display specific temporal patterns of expression over 24 h. For instance, the clock gene Per1 in the SCN peaks around midday (Albrecht and others 1997; Fig. 3). Therefore, the daily profiles of clock gene expression can be used as clock hands of the molecular clockwork. Moreover, a number of clock-controlled genes are considered as outputs of the circadian clocks that will distribute locally circadian signals. In the SCN, Vasopressin and D-site albumin binding protein (DBP) are clock-controlled factors thought to be regulated by the same interlocked feedback loops as those described above for core clock genes (Lopez-Molina and oth-ers 1997; Jin and others 1999).

Circadian signals from the suprachiasmatic clock are known to be distributed via neuronal outputs and diffusible/humoral messages (Kalsbeek and others 2006; Pévet and oth-ers 2006; Silver and LeSauter 2008). Therefore, coupling between the SCN and the extra-SCN brain clocks can be achieved by nervous and/or neurohormonal routes.

Cerebral Clocks outside the SCN

Numerous, But Not Ubiquitous: What For?

Several, but not all, brain areas outside the SCN express clock genes. This observation, however, does not imply that these cerebral regions harbor endogenous clocks. At least two struc-tures outside the SCN, the retina and olfactory bulbs (Tosini

Figure 1. Our physiological functions (e.g., body temperature, melatonin released from the pineal gland, glucorticoids secreted by the adre-nal glands) and behaviors (e.g., motor activity, alertness, working memory) show daily variations that are in phase with the 24-h sleep-wake cycle. These variations are not passive responses to the changing outside world (i.e., the 24-h light-dark cycle due to the daily rotation of the earth), but are driven by an internal circadian timing system that is mainly synchronized by light perceived by the retina.



Brain Clocks / Mendoza, Challet 479

and Menaker 1996; Herzog 2007), fulfill the criteria for endogenous “primary” clocks, including elaboration of self-sustained oscillations and distribution of rhythmic messages to other structures. Other brain areas can be damped circadian oscillators that express rhythmically the core clock genes iden-tified as necessary for circadian rhythms generation, some of them even showing rhythmicity for a few days when isolated in vitro (Abe and others 2002). Because their rhythmicity in vivo is either triggered by inputs (in particular, from the SCN) or not robust (i.e., it cannot be maintained for more than few cycles in vitro), these structures will be called “secondary clocks” below (Fig. 4). The functional differences between true self-sustaining oscillations of the primary clocks and the damped oscillations of secondary clocks are not fully under-stood yet (Guilding and Piggins 2007). At least cell coupling

appears critical for genesis of self-sustained circadian rhythms within the SCN (Aton and Herzog 2005). A third case con-cerns hourglass-like structures whose daily oscillations are only driven by rhythmic inputs to them (see below).

Although the SCN is important for keeping circadian time, it seems that the extra-SCN clocks are individual watches that could be reset periodically, eventually without gating (i.e., without specific temporal windows of sensitivity to synchronizers). We propose that outside-SCN brain clocks are useful for timing behavioral and physiological tasks to underlie specific activities during the 24 h, such as sleep, vigilance, learning, motivation, vision, or olfaction. Depending on the strength of their coupling to the SCN clock, some of the extra-SCN cerebral clocks may also simply fine-tune tim-ing of rhythms controlled by the SCN.

Figure 2. The suprachiasmatic nuclei (SCN) of the hypothalamus contain the master circadian clock in mammals. This main clock is com-posed of a molecular machinery in which the expression of several clock genes, and their protein products, are forming feedback (positive, Clock and Bmal1; negative, Per, Cry, and Dec) and feedforward (Rev-erbα, β and Ror α, β) loops for the genesis of circadian oscillations. This autoregulatory cycle takes around 24 h. Information of these circadian oscillations is thought to be distributed via cyclic expression of output clock genes (Avp, Dbp). CK = CLOCK; BM = BMAL1; Avp = Vasopressin; Dbp = D-site albumin binding protein.




Functional differences in the molecular clock machinery have been evidenced between the SCN and peripheral tis-sues, like muscle, kidney, thymus, or liver (Guillaumond and others 2005; DeBruyne and others 2007). As detailed in the next paragraphs, it becomes more and more likely that even within the brain, secondary clocks do not function exactly in the same way as the SCN in terms of circadian components or synchronizing properties (Feillet and others 2008; Rossner and others 2008).

Cerebral Clockworks outside the SCN

Individual brain regions such as the hypothalamus, the stria-tum, the olfactory bulbs, and the cortices contain their own circadian oscillators and are capable of generating circadian rhythms when isolated from the organism and cultured in vitro (Abe and others 2002; Herzog 2007). The molecular

loops that generate circadian oscillations within cells of the brain clocks, however, have been only partially characterized yet. Molecular clockwork among extra-SCN clocks can share most clock genes (Fig. 4), but minor differences may change the strength of the feedback loops.

For example, among the core clock genes participating in the oscillations in the SCN clock, those constituting the positive loop, Clock and Bmal1, have been reported to be expressed in the piriform cortex, the olfactory bulbs, the hip-pocampus, the striatum, and the cerebellum (Namihira and others 1999). A day-night variation of Bmal1 expression, similar in phase to that in the SCN, is found in these struc-tures (Abe and others 1998; Honma and others 1998). By contrast, whereas the expression of Clock is not rhythmic in rodent SCN, a day-night difference is observed in forebrain regions and the cerebellum (Namihira and others 1999). Functionally, whether the genes Clock and Bma11 play a

Figure 3. Clock genes such as Per1 display specific temporal patterns of expression in the suprachiasmatic nuclei (SCN) over 24 h. Transcription of Per1 in the SCN peaks around midday and the rhythm of PER1 protein expression is phase-delayed by about 6 h (i.e., it peaks in early night). This phase relationship is in accordance with a negative feedback control of Per1 transcription because mRNA levels start to decline when PER1 levels are rising and vice versa. Scale bar = 500 µm.




critical role in the molecular mechanism of the secondary clocks is still unknown.

Furthermore, molecular oscillations of forebrain regions where Clock is not expressed could depend on another gene: Npas2 (neuronal PAS domain protein 2), an analogue of Clock, whose protein can dimerize with BMAL1 to transacti-vate the Per and Cry genes (Reick and others 2001). Npas2 is expressed in few forebrain regions, such as the striatum, cor-tex, and hippocampus. Like Clock mutant mice, Npas2-deficient mice have specific circadian alterations, which affect sleep, locomotor activity, and feeding behavior. These alterations indicate that NPAS2 in the forebrain can influence circadian behaviors (Dudley and others 2003). The lack of Npas2 expression prevents day-night variations of other clock genes in the somatosensory cortex of Npas2 mutant mice (Reick and others 2001), suggesting that the secondary clock in that fore-brain structure involves NPAS2 as a clock component. In some forebrain regions (e.g., piriform cortex), both CLOCK and NPAS2 are clearly expressed concomitantly, although they are supposed to do the same work (i.e., to dimerize with BMAL1 and allow E-box transactivation of other clock genes). What is the relevance for this redundancy? This is not clearly known yet, but adds another level of modulation. Interestingly,

in the SCN of wild-type animals, NPAS2 is expressed at very low levels (i.e., hardly detectable by in situ hybridization). In CLOCK-deficient mice, the low expression of NPAS2 can still maintain a functional SCN clock (DeBruyne and others 2006). By contrast, although both CLOCK and NPAS2 are normally expressed in the liver, NPAS2 alone cannot maintain circadian oscillations when CLOCK is missing (DeBruyne and others 2007), highlighting a major difference between the SCN and hepatic clockworks (i.e., NPAS2 cannot always sub-stitute for CLOCK in the clock machinery). Further experi-ments are thus needed for better delineating the precise role of NPAS2 in extra-SCN clocks.

The Per genes, members of the main negative feedback loop in clock machinery, are widely present in many, but not all, brain regions outside the SCN. Per mRNA and proteins are rhythmically expressed in most structures mentioned before (hippocampus, striatum, piriform cortex, and cerebel-lum) and in many more regions implicated in other physiolog-ical functions (Abe and others 2002; Yamamoto and others 2001; Feillet and others 2008). Interestingly, a closer analysis indicates that PER1 and PER2 are not equally expressed within the forebrain, suggesting that these secondary clocks do not need the two PER proteins to run and may tick with

Figure 4. In the brain outside the main clock in the suprachiasmatic nuclei (SCN), diverse nuclei are considered as circadian clocks. Some of them contain self-sustained oscillators (i.e., primary clocks), and others are damped circadian oscillators (i.e., secondary clocks) with overt rhyth-micity triggered or enhanced by rhythmic inputs (in particular, from the SCN). In these extra-SCN clocks, there is a rhythmic expression of clock genes as Per, Cry, Clock, Bmal1, Npas2. Not all of these clocks use the same clock components to tick. Brain clocks are coupled with each other (blue arrows) and with the SCN master clock, forming a circadian network to maintain an oscillatory synchrony in the whole organism.




different clock genes, or clock hands, compared with the SCN clock. Altered patterns of other clock genes in forebrain structures of Per1 or Per2 mutant mice give support to this assumption (Feillet and others 2008).

DEC1 and DEC2 are other examples of the same clock components showing different roles in and outside the SCN. Whereas they are thought to repress circadian transcription in the SCN, they can activate E-box–mediated transcription in the frontal cortex (Rossner and others 2008).

It is also probable that clock-controlled genes are not always the same between SCN and extra-SCN clocks. For instance, Dbp which is heavily expressed in the SCN, is also abundant throughout specific brain regions, including cerebral cortex, piriform cortex, striatum, hippocampus, hypothalamus an cerebellum, where it may play the role of a clock-controlled gene (Yan and others 2000). By contrast, besides basal fore-brain (bed nucleus of the stria terminalis), Vasopressin is only expressed in three hypothalamic nuclei (i.e., SCN, paraven-tricular and supraoptic nuclei). Because its daily pattern of expression is rhythmic only in the SCN, Vasopressin appears to be a clock-controlled gene specific to the SCN clock.

The Olfactory Bulbs: A Primary Cerebral Clock outside the SCN

The olfactory bulbs have been recently identified as an endog-enous circadian clock, which does not need the SCN pace-maker to track time in a cyclic manner (Granados-Fuentes and others 2004; Herzog 2007). As soon as Clock and Bmal1 mRNA were studied in different brain sites outside the SCN, the olfactory bulbs were shown as a key site for a strongly rhythmic expression of these genes (Abe and others 1998; Honma and others 1998). Per1 was thereafter reported to be also rhythmic in the olfactory bulbs (Abe and others 2002; Abraham and others 2005). Cells in the olfactory bulbs keep 24-h time and are normally highly synchronized to each other similarly to the individual SCN clock cells (Herzog 2007). Unlike the SCN, the olfactory bulb clock does not participate in the daily rhythm of locomotor activity (Granados-Fuentes and others 2004). Rather, the olfactory bulb clock, whose activity (electrical, molecular, and cellular) is higher at night (i.e., during the active period in mice), regulates the timing of olfactory responsivity (Granados-Fuentes and others 2006; Herzog 2007). Thus, when one realizes how important olfaction is for events of daily life, especially for rodents, we can see that olfactory sensitivity in mammals has high physiological rele-vance to find food or mates.

Secondary Cerebral Clocks outside the SCN: The Amygdala Complex and the Hippocampus

As mentioned earlier, the outside-SCN brain clocks may play a role in timing specific physiological or behavioral tasks. Within the brain, some regions are implicated in the control of emotional state and motivated behaviors: the amygdala complex, constituted by functionally and anatomically differ-ent nuclei, such as the basolateral and central nuclei. Another region tightly connected to the amydgala is the hippocampus, a key structure for learning and spatial memory. All these limbic structures show circadian expression of different clock genes (Abe and others 1998; Honma and others 1998;

Lamont and others 2005; Feillet and others 2008). The role of these circadian oscillations in cognitive performance is not fully understood yet, although they probably participate to the well-known propensity of improved performance at certain times of the day.

It is noteworthy that two temporally distinct patterns of PER2 expression can be observed between the basolateral and central amygdala, and hippocampus. Indeed, PER2 expression in rats peaks in the night (i.e., during the active period) in the central amygdala, and in the morning in both the basolateral amygdala and the hippocampus (Lamont and others 2005). Thus, the same clock component, PER2, is used at different times of the day, or rather, these secondary clocks are not phased at the same time. Because day-night variations in PER2 expression disappear in SCN-lesioned animals, this suggests that these clocks are not self-sustained but driven by the SCN. A peculiarity evidenced for the central amygdala is that daily oscillations in clock gene expression can be driven by the SCN-controlled rhythm of corticoster-one secretion from the adrenal glands (Lamont and others 2005; see below), suggesting hourglass-like mechanisms for these oscillations. Instead, the basolateral amygdala and the hippocampus appear to involve secondary clocks, whose cou-pling with the SCN could involve neuronal connections.

Synchronization of the Cerebral Clocks

The process of clock synchronization is critical because it allows the organisms and their internal cyclic timing to be in phase with external cues. Even if light is the most potent syn-chronizer of the SCN, this master clock can also integrate a wide range of temporal information from synchronizing cues (Challet and Pévet 2003; Mistlberger and Skene 2004). In addition to environmental factors, we will see that internal signals can also feedback to the cerebral clocks to provide them with modulatory temporal cues. Compared with the SCN clock, how extra-SCN brain clocks are synchronized has started to be investigated only recently. Nevertheless, some interesting dif-ferences have been already found among them (Lamont and others 2005; Feillet and others 2008).

Light

Solar light signals are the most powerful synchronizer of the SCN clock (Fig. 5). Photic information from the environment is detected by a subset of retinal ganglion cells expressing a specific photopigment, melanopsin (Fig. 1). These photosensitive gan-glion cells project to the SCN directly via the retinohypotha-lamic tract and indirectly via a thalamic relay structure, the intergeniculate leaflet (Meijer and Schwartz 2003). Light-induced phase shifts of the SCN clock to light depend on the time of the day when light is applied, as shown by using dis-crete light pulses in animals housed in constant darkness. Light-induced phase shifts mainly occur at night (i.e., the active and resting period in nocturnal and diurnal species, respectively). Retinal illumination leads to glutamate release from retinohypothalamic terminals, activation of N-methyl-D-aspartate receptor and Ca2+ influx in ventral cells of the SCN. Then phosphorylation of cAMP response element binding protein (CREB) and its binding to cAMP response element




(CRE) present on the promoters of target genes, including Per genes (Reppert and Weaver 2002; Fig. 3). Therefore, light exposure at night triggers an acute transcription of Per1 and Per2 genes in the SCN, when their circadian levels are the low-est (Albrecht and others 1997). Concomitantly, acute expres-sion of c-FOS, the phosphoprotein product of the immediate early gene c-fos, can be induced in the SCN in response to light pulses at night (Kornhauser and others 1990). Concerning the localization of transcriptional changes within the SCN, it is interesting that light-induced transcription of Per1 and c-fos in the SCN occurs specifically in the ventral cells (Fig. 6), whereas photic induction of Per2 occurs in the whole SCN (Kornhauser and others 1990; Dardente and others 2002; Karatsoreos and others 2004; Mendoza and others 2007). In vivo alterations of Per transcription and studies in Per mutants indicate a causal role of Per1 and Per2 genes in mediating light-induced resetting of the SCN (Albrecht and others 2001). Light exposure at night also triggers expression of AVP (i.e., a clock-controlled component) in the SCN (Mendoza and others 2007).

Furthermore, daytime light exposure can increase Per1 and Per2 oscillations, thereby increasing the amplitude of the SCN clockwork (Yan and others 1999; Challet and others 2003). This photic effect on the circadian amplitude could be relevant for improving the efficiency of light synchronization.

Feeding Cues

Periodic food availability, provided by scheduled restricted feeding, is the dominant synchronizer for peripheral clocks, such as the liver (Damiola and others 2000), whereas the SCN are usually considered impervious to any effect of meal timing (Mendoza 2007). Nevertheless, nutritional cues associ-ated with chronic conditions of calorie restriction can feed-back on the SCN clock and modulate its synchronization to light, also involving Per1 and Per2 genes (Mendoza, Graff, and others 2005; Feillet and others 2006; Mendoza and others 2007). Furthermore, a timed palatable food, in addition or not to chow pellets available ad libitum, can synchronize the SCN and affect its gene expression (Mendoza, Angeles-Castellanos, and others 2005; Fig. 5).

In the brain, many extra-SCN clocks studied are mark-edly influenced by scheduled food access. This is can be evi-denced by phase advances of PER2 oscillations in a number of forebrain regions, such as central amygdala or hypotha-lamic ventromedial or paraventricular nuclei (Feillet and oth-ers 2008; Verwey and others 2007). By contrast, PER1 oscillations outside the SCN are not phase changed, but can display larger amplitude in response to scheduled food access. The dorsomedial hypothalamus has been proposed to host a clock inducible by timed feeding (Mieda and others

Figure 5. There are many cerebral clocks with diverse clockworks and synchronizers. Light is the major synchronizer for the SCN clock, leading to activation of transcription of Per genes. Other cues, such as food and melatonin, can also have synchronizing or modulating effects on the SCN clock. On the other hand, feeding cues are powerful synchronizers for most extra-SCN clocks via changes of Per and Npas2 expres-sion. Corticosterone (CORT) and other glucocorticoids secreted by the adrenal glands can affect the timing of brain oscillators expressing high density of glucocorticoid receptors like the amygdala or the hippocampus. Melatonin drives the rhythmic expression of clock genes in the pars tuberalis of the adenohypophysis.




2006; Gooley and others 2006), although some findings do not perfectly fit this assumption (e.g., Landry and others 2007; Feillet and others 2008).

Of interest, a few secondary clocks are hardly affected by meal timing, such as the basolateral amygdala or hippocam-pus (Waddington-Lamont and others 2007; Feillet and others 2008; Verwey and others 2008). This may be indicative of a strong coupling between the SCN and these two specific lim-bic structures, whereas the other forebrain clocks could become uncoupled from the SCN by meal timing. Based on this differential sensitivity to feeding cues, we can infer that chronic restricted feeding would thus lead to desynchroniza-tion within the network cerebral clocks.

Hormonal Signals: Melatonin

Melatonin is a hormone synthesized by the pineal gland. Its secretion occurs only at night in both diurnal and nocturnal mammals. In view of the fact that the SCN control the circa-dian rhythmicity in secretion of pineal melatonin and express high-affinity melatonin receptors, this hormone is believed to play a feedback role on the SCN (Pévet and others 2006). At pharmacological doses, it is well established that melatonin induces behavioral phase advances when injected at subjective dusk. At the molecular level, exogenous melatonin in rats does not acutely modulate Per mRNA levels, as do light pulses (Poirel and others 2003). By contrast, melatonin treatment modulates the expression of two nuclear orphan receptors present in the SCN, Rev-erbα (phase-advanced) and Rorβ (up-regulated; see Agez and others 2007; Fig. 5).

It is worth mentioning the case of the pars tuberalis of the adenohypophysis, an important structure for seasonal timing. First, it expresses melatonin receptors and clock genes. Second, its rhythmic oscillations of Cry1 and Per1 are driven by circulating melatonin (Dardente 2007), illustrating hourglass-like mechanisms. The involvement of melatonin

rhythm within the brain, as a synchronizer for self-sustained clocks or a timer for hourglass-like oscillators, has not been studied in detail. Nevertheless, all cerebral regions expressing melatonin receptors are potential targets and could be theo-retically sensitive to temporal cues mediated by the daily variations of circulating melatonin. This view, however, is mitigated by the fact that the SCN clock, a known target of the pineal hormone, is not phased by melatonin as are oscil-lations in the pars tuberalis, unless the SCN could actually be the exception to the rule.

Hormonal Signals: Glucocorticoids

Even if stressful events can disturb overt expression of circa-dian rhythms, evidence for marked effects of stress on the SCN clock is scarce (Meerlo and others 2002). At least one problem arises from a high interspecies difference in suscep-tibility of the SCN to stress/arousal in hamsters (very sensi-tive during resting period; Mistlberger and others 2003) compared with rats or mice (rather impervious; Barrington and others 1993). Moreover, acute stress and circulating glucocorticoids are capable of modulating synchronization of the SCN to light, even in mice and rats (Challet and others 2001; Sage and others 2004).

Concerning extra-SCN brain clocks, stress elevates Per1 mRNA levels in the PVN (Takahashi and others 2001). In keeping with this finding, Per1 transcription in peripheral organs can be regulated by plasma glucocorticoids via the glucocorticoid-responsive element in its promoter (Yamamoto and others 2005). In the central amygdala, oscillations of PER2 can be suppressed by adrenalectomy (Lamont and oth-ers 2005), demonstrating that the daily corticosterone rhythm normally generated by the adrenal glands can drive rhythmic-ity to brain structures expressing glucocorticoid receptors (Fig. 5). Similar timing mediated by circulating glucocorti-coids has been shown for the raphe nuclei, even if they do not express clock genes (Malek and others 2007). As melatonin does, circulating glucocorticoids may thus contribute to stabi-lize self-sustained cerebral clocks or drive daily rhythmicity in hourglass-like oscillatory structures such as the raphe.

Taken together, these findings indicate that circadian timing in the brain relies on complex interactions between neural (direct) and hormonal (indirect) inputs from the mas-ter clock in the SCN and the extra-SCN cerebral clocks. These interactions are susceptible to be strongly modulated by light via SCN gating and by meal time, melatonin, or stress/glucocorticoids cues as well. Feeding at unusual times (e.g., during expected resting period) or stress will produce a daily state of cerebral desynchronization according to the various sensitivities of brain clocks to these cues.

Pathophysiological Perspectives

There is a huge impact of circadian biology on health (e.g., Knutsson 2003; Megdal and others 2005; Davidson and others 2006; Martino and others 2008). Alterations of circa-dian rhythms including disrupted sleep-wake cycle are com-monly observed in many diseases (e.g., depression, Huntington disease, or dementia) and also aging (Hofman and Swaab 2006; Gibson and others 2009). Rotating shift and night workers are exposed to conflicting synchronizing cues, leading

Figure 6. Synchronization of the suprachiasmatic clock has been associated with acute transcription of clock and clock-controlled genes. A light exposure at night also triggers c-FOS expression in the ventral region of suprachiasmatic nuclei. Scale bar = 500 µm.




to circadian disturbances considered as pathogenic on a long-term scale (Karlsson and others 2003; Knutsson 2003; Megdal and others 2005). In the next lines we will focus on the cogni-tive phenotypes of mice mutant for clock genes and on the consequences of dampened amplitude of circadian oscilla-tions or internal desynchronization on health (Fig. 7).

Neurobehavioral Phenotypes of Mice Mutant for Circadian Genes

Of interest, mice carrying a mutation of the gene Clock show altered behavioral phenotypes, including mania-like behavior (Roybal and others 2007) and they are more sensitive to the reward effects of cocaine consumption, which is accompanied by an up-regulated excitability in dopaminergic neurons from ventral tegmental area (McClung and others 2005). These mice exhibit hyperactivity, altered sleep patterns, and increased response to cocaine. Interestingly, mesolimbic, dopaminergic structures (ventral tegmental area, striatum) showing expres-sion of the Clock gene are implicated in the expression of many of these behaviors. Therefore, the role of the mesolimbic system as well as the association between circadian genes and drug addiction or psychiatry pathologies must be studied in depth.

Some abnormalities in addictive behavior are observed in mice carrying a mutation of the genes Per. Alterations in alcohol consumption, however, differ between Per1 and Per2 mutant mice. Indeed Per1 mutant animals drink a similar amount of alcohol and Per2 mutant mice consume more alco-hol than wild-type littermates (Zghoul and others 2007). Ethanol ingestive behavior in Per2 mutant mice has been related to enhanced extracellular levels of glutamate, as resulting from down-regulation of the glutamate transporter in some forebrain structures, like the nucleus accumbens (Spanagel and others 2005). This mechanism thus suggests that the gene Per2, but not Per1, can regulate glutamate in the brain.

Besides alcohol drinking behavior, the Per1 and Per2 genes influence cocaine-induced sensitization and reward in an oppo-site manner. The lack of the gene Per1 abolishes cocaine sensi-tization and reward. In Per2 mutant mice, by contrast, there is a hypersensitized response to cocaine (Abarca and others 2002). All these results taken together indicate that Per2 gene as a critical component not only in the molecular mechanism of circadian clocks, but also for the development of different drug addictions. Nowadays, drug addiction and alcohol consumption are not the only pathologies in ingestive behavior. Abnormal

Figure 7. A regular 24-h temporal organization is thought to be important for good health. Dampening in the amplitude of circadian oscilla-tions can affect the main SCN clock and/or some other brain clocks. Internal desynchronization can occur between brain oscillators and the SCN clock or between all of them. Dampened amplitude of circadian oscillations or internal desynchronization within the brain both lead to altered circadian organization that may have major impacts on health.




feeding behaviors and poor nutrition are becoming public health problems in modern societies, as major risks factors for develop-ing the metabolic syndrome, obesity, and cardiovascular dis-eases. Compulsive feeding behavior has been interpreted as an addictive behavior in which the central mechanisms are similar to those involved in drug addiction (mesolimbic, dopaminergic system). Therefore, it is possible that the gene Per2 (and perhaps Per1 as well) could also be implicated in addiction to food.

Considering that NPAS2 is expressed in the hippoc-ampus, a structure essential for learning and memory proc-ess, this could be explain why NPAS2 mutant mice show alterations in some memory tasks (Garcia and others 2000). Recently, it has been reported that Cry double-knockout mice cannot manage a time-place learning task, even after numer-ous trials (Van der Zee and others 2008). As for Npas2, Cry genes are highly expressed in the hippocampus. These data thus suggest the clock proteins CRYs and NPAS2 per se could be implicated in the modulation of learning and memory. Alternatively, these cognitive impairments in clock mutants could be due to altered timing within the hippocampal clock machinery. Furthermore, it cannot be excluded that these impairments result indirectly from circadian desynchroniza-tion between cerebral clocks. The latter hypothesis is sup-ported by the fact that circadian disruption is a contributing factor for altered learning and memory performance (Devan and others 2001).

Altered Temporal Organization due to Dampened Amplitude

Timing abnormalities could be the consequence of a dampen-ing in clock gene oscillation, either in the main SCN clock or in some other brain clocks (Fig. 7). Huntington’s disease is a neurodegenerative disorder characterized by motor deficits, cognitive impairment, and sleep disturbances. Huntington’s disease patients are awake frequently during the period of nocturnal sleep. In a mouse model of Huntington’s disease (R6/2 mice), showing similar behavioral and sleep distur-bances as in humans, the rhythmic expression of Per and Bma11 is dampened not only in the SCN, but also in the striatum and the cortex. Consequently, the disruption of rest-activity cycle in R6/2 mice can arise from impaired SCN function (Morton and others 2005). However, it cannot be excluded that the reduced amplitude of extra-SCN circadian oscillations (due to neurodegeneration rather than altered amplitude from the SCN?) plays a role in the disruption of the sleep-wake cycle.

Disorganized circadian rhythms of rest/activity are also present in patients suffering dementia. In these patients, however, other daily rhythms such as salivary cortisol are not altered. This is why the disruptions of the rest-activity rhythm in these patients have been interpreted as alterations in the outputs of the SCN controlling behavioral rhythms, and not in the SCN clock itself (Hatfield and others 2004). It is also possible that an extra-SCN brain oscillator controlling or modulating the rest-activity rhythm (see Masubichi and oth-ers 2000) is affected.

Almost all overt rhythms (behavioral, hormonal, tem-perature) show reduced amplitudes in aged humans and animals compared with young controls (Gibson and others 2008). Moreover the amplitude of the electrical activity and

rhythmic expression of the clock gene and AVP as well are decreased by aging in the SCN. These dampened circadian rhythms in both aged humans and animals thus suggest a reduction in the amplitude of the SCN clock with aging (Hofman and Swaab 2006). Possible changes in other brain circadian clocks of the old brain remain to be investigated.

Altered Temporal Organization due to Internal Desynchronization

Epidemiologic studies in shift and night workers have sug-gested an increase in the incidence of pathologies such as cancer, cardiovascular disease, and metabolic syndrome (Karlsson and others 2003; Knutsson 2003; Megdal and oth-ers 2005). The primary cause may be due to the misalign-ment of the main circadian clock in the SCN with the unusual light-dark cycles shift workers and night workers are exposed to. Experimental studies also indicate that repeated phase shifts of the light-dark cycle have negative effects on health. As already proposed in this review, the recent charac-terization of intermediate, extra-SCN brain clocks adds another level of targeted dysfunction. Indeed, the complex network of various cerebral clocks with specific synchroniz-ers described above raises the possibility that pathophysio-logical alterations of internal timing may result, in part, from internal desynchronization between these clocks (Fig. 7). Conflicting synchronizers, like jet-lag and rotational shift work, could differentially affect the cerebral clocks depending on the clocks sensitivities to synchronizing cues. Consequently, these conflicting conditions would also lead to a state of internal desynchronization. If correct, this hypothesis suggests that new pharmacological should target appropriate chronobiotic drugs or treatments able to recouple the network of the brain clocks. In this view, one of the most powerful synchronizers able to affect almost all the brain oscillators—including the SCN clock under certain conditions—is food (Mendoza 2007). Nonetheless, it remains to determine the appropriate quality and quantity of food and the phase (i.e., meal time) at which circadian clocks could be synchronized and set in phase between them.

Concluding Remarks

Circadian and noncircadian pathologies could be associated with different alterations of circadian clocks: either in the SCN clock itself (reduced amplitude of oscillations) or in the other brain circadian clocks, or in a desynchronization between brain oscillators and the SCN clock, or between all of them (Fig. 7).

Understanding further how extra-SCN brain clocks tick, how they are reset by specific cues, and how they talk to each other could provide new tools not only to improve treatments of psychopathological diseases, like depression, but also to better manage circadian disorders due to societal constraints, such as rotational shift and jet-lag.

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