The Circadian Clock Is One of the Most Indispensable Biological Functions

Organisms populating the Earth are under the steady influence of daily and seasonal changes resulting from the planet's rotation and orbit around the sun. This periodic pattern is most prominently manifested by the light-dark cycle and has led to the establishment of endogenous circadian timing systems that synchronize biological functions to the environment. This is the basis of predictive homeostasis (Moore-Ede 1986), evolving as an adaptation to anticipate predictable changes in the environment, such as light and darkness, temperature, food availability or predator activity. Therefore, the circadian clock is one of the most indispensable biological functions for living organisms that acts like a multifunctional timer to adjust the homeostatic system, including sleep and wakefulness, hormonal secretions and various other bodily functions, to the 24-h cycle (Buijs, van Eden, Goncharuk, and Kalsbeek 2003; Collins and Blau 2006; Hastings, Reddy, and Maywood 2003). In mammals, the circadian system is composed of many individual, tissue-specific cellular clocks. To generate coherent physiological and behavioral responses, the phases of this multitude of cellular clocks are orchestrated by a master circadian pacemaker residing in the suprachiasmatic nuclei (SCN) of the hypothalamus.

At a molecular level, circadian clocks are based on clock genes, some of which encode proteins able to feedback and inhibit their own transcription. These cellular oscillators consist of interlocked transcriptional and posttranslational feedback loops that involve a small number of core clock genes (about 12 genes identified currently). The positive drive to the daily clock is constituted by two, basic helix— loop-helix, PAS-domain containing transcription factor genes, called Clock and Bmall. The protein products of these genes form heterodimeric complexes that control the transcription of other clock genes, notably three Period (Per1/Per2/Per3) genes and two Cryptochrome (Cry1/Cry2) genes, which in turn provide the negative feedback signal that shuts down the Clock/Bmal drive to complete the circadian cycle (Okamura 2003). Per and Cry messenger RNAs peak in the SCN in mid-to-late circadian day, regardless of whether an animal is nocturnal or diurnal. Other clock genes provide additional negative and positive transcriptional/translational feedback loops to form the rest of the core clockwork, which has been characterized in rodents by a transgenic gene deletion methodology. Clock gene expression oscillates because of the delay in the feedback loops, regulated in part by phosphorylation of the clock proteins that control their stability, nuclear reentry and transcription complex formation (Collins and Blau 2006; Lakin-Thomas 2006). Clock genes are expressed in a tissue-specific fashion, often with unknown function. Although a substantial number of genes are rhythmic (about 10% in the SCN or peripheral tissues), the rhythmic genes tend to be different in the different tissues. For example, in comparisons between heart and liver, or between the SCN and liver, only a 10% coincidence is seen (Okamura 2003). The phase of the peripheral clock oscillations is delayed by 3 to 9 h as compared to that of SCN cells, suggesting that the peripheral tissues might be receiving timing cues from the master SCN oscillator. Furthermore, oscillations in isolated peripheral tissues dampen rapidly, unlike the persistent rhythms in isolated SCN neurons (Albrecht and Eichele 2003; Buijs et al. 2003; Fukuhara and Tosini 2003; Hastings et al. 2003; Okamura 2003).

Sorting of the cycling transcripts into functional groups has revealed that the major classes of clock-regulated genes are implicated in processes specific to the tissue in which they are found. For example, many cycling transcripts in the liver are involved in nutrient metabolism. It is also of interest that many of the regulated transcripts correspond to rate limiting steps in their respective pathways, indicating that control is selective and very efficient. Indeed, about 10% of the genome is under control of the circadian clock (Ueda et al. 2005). As noted, the trillions of cellular clocks in primates are synchronized by a few thousand neurons located in the SCN. It is remarkable that such a small group of neurons display the properties of a central clock. Indeed, these "neuronal oligarchies," like the human ones, control trillions of cells in the body by (a) taking control of the major communication channels (the endocrine and autonomic nervous systems); (b) concentrating the relevant information in a private way (i.e., light information arriving via the retinohypothalamic tract). Thus, it is not surprising that anatomical studies have showed that the SCN projects to at least three different neuronal targets: endocrine neurons, autonomic neurons of the paraventricular nucleus (PVN) of the hypothalamus, and other hypothalamic structures that transmit the circadian signal to other brain regions (Buijs et al. 2003). The SCN projections are generally indirect, via the sub-PVN zone (Saper, Lu, Chou, and Gooley 2005). Through autonomic nervous system projections involving the superior cervical ganglia the SCN controls the release of a major internal synchronizer, the pineal substance melatonin (Cardinali 1981; Hardeland, Pandi-Perumal, and Cardinali 2006).

Recordings from single dispersed SCN neurons have demonstrated that the circadian mechanism is not an emergent property of the SCN neuronal network but it is expressed in each individual cell. Multisynaptic links of SCN through the hypothalamic sub-PVN zone outflow to the adrenocorticotropic and other neuroendocrine axes and to autonomic ganglia that innervate the viscera including all the immune system, whereas innervation of the dorsomedial hypothalamus contributes to circadian control of the orexin/hypocretin system, that participates in wakefulness (Buijs et al. 2003; Saper et al. 2005). By projecting to areas outside the hypothalamus, such as the lateral geniculate bodies and the paraventricular nucleus of the thalamus, the SCN neurons can synchronize hypothalamic-induced behavior (e.g., feeding) and locomotor activity. The circadian control of rest/activity cycles also involves SCN paracrine signaling, e.g., the secretion of transforming growth factor-a and prokineticin-2 (Hastings et al. 2003; Saper et al. 2005).

In the case of the immune system, our own work concentrated on the role of the autonomic nervous system (parasympathetic and sympathetic) to provide the anatomical basis for the circadian control of lymph node function (Cardinali and Esquifino 1998; Esquifino and Cardinali 1994). These studies were the continuation of our former studies on the role of sympathetic and parasympathetic nerves in thyroid follicular and C cell and parathyroid cell regulation (Cardinali and Romeo 1991; Cardinali and Stern 1994). The concept that autonomic nerves are a very efficient avenue to convey time of day information to the periphery has been since then generalized to tissues like the adrenal, pancreas, liver, ovaries and many other organs (Buijs et al. 2003). Although circadian rhythms are anchored genetically, they are synchronized by and maintain certain phase relationships to external factors (Murphy and Campbell 1996). These rhythms will persist with a period different from 24 h when external time cues are suppressed or removed, such as during complete social isolation or in constant light or darkness. Research in animals and humans has shown that only a few such environmental cues, like light-dark cycles, are effective entraining agents for the circadian oscillator ("Zeitgebers").

An entraining agent can actually reset, or phase shift, the internal clock. Depending on when an organism is exposed to such an entraining agent, circadian rhythms may be advanced, delayed, or not shifted at all. Therefore, involved in adjusting the daily activity pattern to the appropriate time of day is a rhythmic variation in the influence of the Zeitgeber as a resetting factor (Murphy and Campbell 1996). In humans, light exposure during the first part of the night delays the phase of the cycle; a comparable light change near the end of the night, advances it. At other times during the day light exposure has no phase-shifting influence (Lewy, Ahmed, and Sack 1996; Pandi-Perumal et al. in press). Melatonin, a chemical code of the night in most species, showed an opposite phase response curve to light, producing phase advances during the first half of the night and phase delays during the second (Lewy et al. 1996; Pandi-Perumal et al. in press).

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