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mise à jour du 31 août 2002
Nature Reviews Neuroscience
2001; 2; 521- 525
sur le site Nature Reviews Neuroscience
Hypothalamic integration of central
and peripheral clocks
Ruud M. Buijs and Andries Kalsbeek
Netherlands Institute for Brain Research, Amsterdam
The neurobiology of sleep: genetics, cellular physiology and subcortical networks Pace-Schott, Hobson
Circadian variation of yawning behavior Anias J et al
Apomorphine induced yawning in the rat : influence of fasting and time of day Naselo A
During sleep, our biological clock prepares us for the forthcoming period of activity by controlling the release of hormones and the activity of the autonomic nervous system.
Here, we review the history of the study of circadian rhythms and highlight recent observations indicating that the same mechanisms that govern our central clock might be at work in the cells of peripheral organs. Peripheral clocks are proposed to synchronize the activity of the organ, enhancing the functional message of the central clock. We speculate that peripheral visceral information is then fed back to the same brain areas that are directly controlled by the central clock. Both clock mechanisms are proposed to have a complementary function in the organization of behaviour and hormone secretion. The rotation of the earth exposes all organisms to a daily change in light intensity. From algae to mammals, nearly all organisms have adapted their lifestyle to cycles of 24 hours.

Sunlight penetration has resulted in the development of cellular mechanisms that are sensitive to light and that allow the anticipation of regular changes in the environment; the evolutionary selection pressure has been so strong that this property has been retained in most species - from fungi to mammals. Although most cells of all organisms (including mammals) still have a molecular mechanism able to drive a cellular clock, the coupling of this mechanism to a biochemical system capable of receiving and transducing light has been retained in only a few tissues. So, until recently, a common idea was that, from lower invertebrates to mammals, the crucial circadian clock elements had moved to the central nervous system (CNS) and had become concentrated close to or within the light-transducing parts of the CNS. In mammals, for example, the light signal can only reach the CNS through glutamate secretion from retinal terminals. However, recent findings have refocused our attention on the circadian rhythms of peripheral organ- organs that were thought to have lost their rhythmic activity.

As a result of this shift in our thinking, molecular clock mechanisms have been uncovered in several peripheral organs. Together with the older literature on the rhythmic functions of such organs, these data indicate a preservation of circadian functions outside the CNS. Here, we review some of the earlier literature on central and peripheral circadian rhythms, and try to provide a tentative functional link between central and peripheral clocks. First, we describe some of the experiments that led to the identification of the suprachiasmatic nucleus (SCN) as the central clock.We then consider the anatomical and physiological evidence for the control that the SCN exerts on peripheral-organ clocks and on the autonomic nervous system. We conclude by proposing a mechanism by which peripheral clocks can feed back their circadian messageto the brain, and point to some possible future directions in this field. [...]

SCN and the autonomic nervous system : The SCN-mediated control of the melatonin surge indicates that autonomic control is at least one important aspect of SCN function. Early data showed a pronounced circadian change in the sensitivity of the adrenal cortex to ACTH. Transneuronal tracing and physiological experiments provided proof that, in addition to the classical neuroendocrine control of the adrenal cortex by the release of CRH from the PVN, and the subsequent release of ACTH, an important neuronal SCNÐPVNÐsympathetic nervous systemÐadrenal cortex axis also determinesthe final levels of corticosterone secretion from the adrenal gland. So, the SCN uses a dual mechanism to provide an optimum secretion of corticosterone: direct control of the hypothalamic neuroendocrine neurons and of neurons of the autonomic nervous system.We propose that this is a general principle that might hold, not only for endocrine glands but for other organs as well. For example, recent evidence indicates that, just before the onset of activity, the SCN increases insulin sensitivity, resulting in a physiologically relevant increase in glucose uptake in muscle, and simultaneously causes increased hepatic glucose production. [...]

Peripheral and central clocks meet : Despite the fact that cells of many organs have the ability to retain a rhythmic function for a few days, this property disappears without daily enforcement (that is,without the SCN) . It is interesting that soon after the SCN was identified as the site of the biological clock, other studies showed the capacity of an animal to respond to a 24-hour rhythm of food availability without an SCN. Although many attempts were made to pinpoint the mechanism of the observed anticipatory behaviour and accompanying changes in hormone secretion, it has remained enigmatic.However,we would like to propose that peripheral clocks of different organs, most notably of the liver, are essential for this anticipatory behaviour.These peripheral clocks, which lose their rhythm without the SCN, can be entrained with food or hormone stimulation.They are coupled to the metabolism of the cell and, consequently, their synchronized activity could send an important signal to the brain. This hypothesis is supported by several observations in relation to the entrainment of behaviour in intact and SCN-lesioned animals. One of the entrainment properties of the SCN by light is that the clock responds within certain limits, that is, a 22Ð28-hour period. If peripheral clocks have a molecular mechanism similar to the central clock, one might expect a similar limit of entrainment as well. Interestingly, Stephan showed more than 20 years ago that entrainment to restricted feeding showed similar limits in SCN-lesioned animals, an observation that led this investigator to propose a multi-oscillatory clock model in mammals. However, some differences in the properties of central and peripheral clocks exist. For example, in contrast to the SCN, peripheral oscillators do not seem to have a 'dead zone' for entrainment; phase shifts can be induced at any time of the lightÐdark cycle. On the basis of these observations,we would like to suggest a role for peripheral oscillators in synchronizing the metabolic activity of the organ by their signalling to the brain, mainly to the hypothalamus.Visceral information could enter the hypothalamus directly through hormones and/or through axons from the nucleus of the solitary tract (NTS), and indirectly through projections from the parabrachial nucleus.As one might expect, lesions of the vagus nerve or the parabrachial nucleus lead to impaired entrainment to feeding schedules. In this regard, it is worth noting that the NTS and parabrachial nucleus heavily target the same hypothalamic structures that are innervated by the SCN.These observations indicate a common ground for the functioning of clock systems. In our view, peripheralperipheral clocks, like the central clock, control hypothalamic nuclei to maintain a balance between body and brain.

Conclusions and future prospects

Although peripheral organs were first shown to have a rhythm about 100 years ago, attention quickly moved to the study of circadian rhythms controlled by the CNS.Now the pendulum swings back as we try to understand the interaction between the central and peripheral clocks. Evolution has equipped our organs with the capacity to anticipate and adapt their activity in relation to the activity pattern of the whole organism.With hindsight, it is easy to see why the function of the period (per) gene in the circadian clock of Drosophila initially confused scientists. As homogenates of the whole body were used to detect circadian changes in per mRNA concentrations, the rhythms of the individual organs were masked by the conspicuous noncycling nature of this transcript in the female ovary. Similarly,we can now begin to explain why clock rhythms in different mammalian organs have a different momentum, and how they relate to the pace of the central biological clock. Organisms have to anticipate and adapt to a changing external and internal environment. Information from these two environments is picked up by sensory and endogenous systems that evolution has connected to cellular circadian pacemakers. Information between these different systems is constantly exchanged; in mammals, this exchange takes place mainly within the hypothalamus.Here, the physiological state of the whole body is evaluated and the appropriate hormonal and autonomic output is selected. This idea is supported by several reports of circadian rhythm disturbances in humans suffering from chronic diseases - disturbances that are manifest even before the onset of other symptoms. Furthermore, these observations are bolstered by correlated changes in the anatomical integrity of the human SCN.We hope that these insights will help to bridge the gap, not only between body and brain, but also between neurology and internal medicine.