Endocrinology Vol. 148, No. 11 5162-5164
Copyright © 2007 by The Endocrine Society
Corticosterone and Activity: The Long Arms of the Clock Talk Back
Ruud M. Buijs and
Carolina Escobar
Departamento de Biología Celular y Fisiología (R.M.B.) Instituto de Investigaciones Biomédicas and Departamento de Anatomía Facultad de Medicina (C.E.) Universidad Nacional Autónoma de México México City 04510, México; and Netherlands Institute for Neuroscience (R.M.B.) 1105 BA Amsterdam, The Netherlands
Address all correspondence and requests for reprints to: Ruud M. Buijs, Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México, México City 04510, México. E-mail: ruudbuijs{at}gmail.com.
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Introduction
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Our daily lives are dominated by the activity and inactivity cycles that are synchronized by the eternal cycle of sunrise and sunset. To help us to adapt to this daily changing cycle of activity and inactivity, in the mammalian brain, a paired structure, the suprachiasmatic nucleus (SCN), has evolved that helps us to anticipate the approaching period of (in)activity. The consequence is that within every 24-h period, our physiology changes gracefully from a state that supports sleep and rest to one that supports an active state. Separate from the research about how the SCN is able to synchronize this rhythmicity, recently it has been asked what happens if this clockwork fails to function properly? Studies have shown that when we persistently ignore the signals of our clock and eat or are active at the wrong time of the day, and thus at the wrong time of our physiological rhythm, we have a greater chance of developing diseases like depression, obesity, or hypertension (1, 2, 3). Consequently, research on how the SCN imposes its rhythm onto us has received much greater attention (4, 5). In this issue of Endocrinology, a remarkable study by Malek et al. (6) provides insight into how two completely different rhythms, those of activity and corticosterone, induce the rhythm in serotonin production. This is significant not only because it gives an interesting insight into how the SCN can use locomotor activity and corticosterone to drive indirectly the activity of a transmitter system of the brain, but also because it may provide an important explanation of how changes in serotonin metabolism can alter some behaviors. The latter may be of great relevance for the interpretation of possible mechanisms behind seasonal depression in which both the circadian and serotonin systems seem to be involved (7, 8).
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Our Biological Clock
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Insight into how the biological clock is able to impose its rhythmicity onto our bodies has progressed enormously in the last 30 yr. The breakthrough in the search for the master clock was the finding that, in addition to the lateral geniculate nucleus, a small cell group in the hypothalamus, the SCN, was a direct target for retinal fibers (9). Specific lesions of the SCN resulted in complete disappearance of all circadian rhythms: the "Master Clock" had been found (10). After this finding, a series of fundamental functions and properties of this clock was established. SCN neurons contain an internal pacemaker that induces an endogenous rhythm in electrical activity with high activity during the subjective daytime (11). Vasopressin secretion, one of the peptide transmitters of the SCN, follows the general pattern of electrical and metabolic activity of the SCN neurons in both rats and monkeys (12, 13). SCN activity, therefore, signals inactivity in nocturnal rats and mice and activity in diurnal mammals, i.e. humans. The final evidence for the SCN as a master clock was provided by transplanting the SCN of a mutant hamster with a fast free-running rhythm (i.e. 
20 h) into the hypothalamus of a wild-type, SCN-lesioned hamster; this resulted in an animal with a faster free-running rhythm than the normal approximately 24 h (14).
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The Long Arms of the Clock
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Since the discovery of the SCN as the master clock, further insight has accrued about how the SCN may transmit its rhythmic message to the brain and body. Initially it was assumed that direct synaptic transmission of its transmitter molecules would suffice to transmit its message into the rest of the brain. However, because SCN transplantation restores locomotor activity patterns in SCN-lesioned animals and SCN transplants generally lack outgrowth of fibers, the question arose whether the output of the SCN needs to be directed to specific targets in the central nervous system or whether diffusion of molecules released by the graft might be sufficient to transfer its message. The answer is that both forms of signaling are used (15, 16). The SCN produces molecules that in addition to being transported by synaptic transmission also can reach their target by diffusion (17); in addition, the SCN also produces glutamate and 
-aminobutyric acid that reach their targets in brain only by direct synaptic release (18). The SCN specifically uses at least four different types of neuronal targets in the hypothalamus to transmit its circadian signal; these range from neuroendocrine neurons to preautonomic neurons (4). Perhaps the most important aspect of this is that in addition to direct control of hypothalamic hormone secretion, the SCN also controls the sensitivity of the target organs for these hormones by affecting the autonomic output of the brain (19). These are the tools the SCN uses to control sleep-wake cycles and the daily surges in corticosterone and melatonin.
It has long been assumed that corticosterone and melatonin form essential links in the chain from the SCN leading to the adaptation of the body to periods of activity and inactivity. Up till now, only melatonin receptors in the SCN have been demonstrated (20), and these provide the basis for its feedback to the SCN (21). Through this means, melatonin emphasizes the night signal of the SCN, a function to which melatonin owes its fame as a sleep-inducing substance in humans. For the adrenal corticosteroids, corticosterone in rats, cortisol in us, a direct feedback function to the SCN has never been demonstrated, probably because there are no corticosteroid receptors in the SCN. In the study by Malek et al. (6), the Strasbourg group has shown for the first time how corticosterone feeds back to the SCN, not directly but indirectly via a change in serotonin production. Such a change in serotonin production can be very meaningful for the function of the SCN because serotonin has an important role in regulating the sensitivity of the SCN to light and may even shift the phase of the SCN when applied during the daytime (22).
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Feedback to the SCN
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Despite the fact that the SCN is mainly involved in organizing the sleep-wake cycle and all associated physiology of the body, little is known about how the information from the body is signaled back to the SCN. Only recently, a study was published in Endocrinology indicating how substances present in the general circulation may, via the circumventricular organs, provide feedback information to the SCN (23). Most studies that relate to the input of the SCN have mainly focused on the phase-shifting properties of different stimuli but have not examined directly their effects on the output of the SCN. In this way also, the phase-shifting effect of locomotor activity has been investigated, and it was shown that activity can indeed alter the phase of the SCN via the geniculate nucleus (24). Additionally, anatomical studies on the input to the SCN relate mainly to those brain regions that provide input to the SCN, of which, for example, the Raphe nucleus is known to provide the serotonergic input to the ventral part of the SCN (22). The Strasbourg group had reported previously that the synthesis of serotonin and its release in the SCN exhibited a circadian pattern (25). Up until now it remained uncertain how the SCN was able to impose that rhythm; the novel finding in the study of Malek et al. (6) is that two output components of the SCN were shown to influence the serotonin synthesis of the Raphe nucleus profoundly. It is remarkable that in addition to corticosterone, locomotor activity is also strongly able to affect serotonin synthesis. Unfortunately, the Malek study does not provide any clue or suggestion as to what systems might be involved in transmitting this locomotor information to the serotonin system. The fact that corticosterone induces an increase in serotonin synthesis is easily explained by the fact that the Raphe nuclei contain a high density of glucocorticoid receptors that are present in the serotonin neurons (6). In line with the function attributed to corticosterone to help the body to anticipate activity, both corticosterone and activity increase the synthesis of serotonin. Because serotonin is also known to support the active state, this finding provokes the suggestion that the increase of serotonergic activity in the brain will also support such function, and this SCN-corticosterone-serotonin-SCN circuit may form a feed-forward circuit promoting activity.
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During the Wake Phase, Locomotion Functions as a Feed-Forward Signal to the SCN
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It is well known that serotonin from the Raphe nucleus may influence and inhibit the activity of the SCN (26). It is interesting that the study of Malek et al. (6) provides further insight into the origin of the circadian rhythm in serotonin synthesis, and we now may infer a possible function for this serotonergic input to the SCN and its subsequent rhythmic secretion into the brain. Serotonin, in general, makes the SCN less sensitive to light, although in line with its inhibitory role only in the light phase, it may induce a phase shift in SCN activity (22). In view of the findings of Malek et al. (6), it seems logical to propose that locomotor activity and increased corticosterone give, through increased secretion of serotonin, the signal to the SCN for increased activity. This may explain why serotonin (and locomotor activity!) in rodents renders the SCN less sensitive to light (22), because light is the signal to the SCN for inactivity (Fig. 1
). Interestingly seasonal depression in humans is associated with a lower drive for activity and decreased serotonin metabolism in the brain. In line with these considerations, we can find the rationale for treating seasonal depression successfully in humans with approaches that affect both the SCN (light therapy) and the serotonergic system (serotonin reuptake inhibitors) or both (agomelatine) (27). In addition, it also gives for the first time a logical explanation for why exercise is a natural treatment for seasonal depression (28).
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FIG. 1. The feed-forward mechanisms of activity and corticosterone. Illustrates the interaction between the Suprachiasmatic nucleus and the Raphe nucleus based on the paper of Malek et al. (6 ). Electrical activity-inactivity of neurons or excitatory or inhibitory action of terminals is indicated with + or –. The clock mechanism of the SCN is indicated by a moving arrow that induces the secretion of corticosterone or melatonin or induces activity. Both activity and corticosterone affect the synthesis and release, respectively, of serotonin in the Raphe nucleus and respective terminals, which has an inhibitory action on the firing of SCN neurons, enforcing the night phase of the SCN. Light stimulates the release of glutamate from the retinal terminals and activates neurons in the SCN, an action which is inhibited by serotonin. In addition the release of serotonin by its terminals in other brain regions supports the wakefulness of the animal.
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Footnotes
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Disclosure Statement: The authors have no conflict of interest to declare.
Abbreviation: SCN, Suprachiasmatic nucleus.
Received July 9, 2007.
Accepted for publication July 26, 2007.
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Introduction
Our Biological Clock
