Morphology and function of the circadian clock

As an introduction to the Leopoldina satellite symposium on Chronobiology, the morphology and function of the mammalian circadian clock are briefly summarized. The clock is epitomized as circadian (from circa diem) as its endogenous period length is not exactly, but close to 24h. The central master clock is of paramount importance as it regulates e.g. locomotor activity, the sleep-wake cycle and hormonal rhythms. Peripheral clocks will not be considered. The present review draws heavily on animal studies, because in humans the actual clock mechanisms are difficult to explore. The central master clock consists of two bilateral accumulations of small, inconspicuous nerve cells lying in the hypothalamus above the optic chiasm, called suprachiasmatic nuclei (SCN). That these nuclei are responsible for generating 24-h rhythmicity is illustrated by the fact that, in animals, removal of these nuclei leads to the cessation of locomotor and other rhythms, and that after reimplantation of the nuclei the rhythm is resumed. Electrophysiological single-cell recordings show that the master clock consists of thousands of clocks with circadian and other firing rhythms. In vivo, the clock cells are synchronized, and fire more strongly during day than night. In vitro, the cells show a lesser degree of synchrony. The 24-h rhythm of the SCN neurons is gene-driven. Expression of clock genes in the cell nuclei is followed by formation of clock proteins in the cytoplasm. Here the proteins are chemically modified and eventually imported into the nucleus where they feed back and inhibit clock gene expression, until a new 24-hr-cycle of gene expression starts. The circadian rhythm of gene expression is stabilized by concomitant interaction of cAMP. If, due to a genetic defect, casein kinase ε is dysfunctional, metabolism of clock proteins is compromized resulting in 21-h rhythmicity. As the term circadian indicates, the endogenous period is not excactly 24h. Precise 24-h rhythmicity is imposed onto the clockwork mainly by the ambient lighting. This information comes from the retina, reaching the SCN via the retinohypothalamic tract. In completely blind subjects, the master clock follows its own, near 24-h rhythm, resulting in an increasing deviation from the objective time, leading to desynchronisation with the enviroment and lack of wellbeing. The timing of the SCN is conveyed to other parts of the body by two ways mainly. 1. The longest known output is a multisynaptic pathway to the melatonin synthesizing pineal gland, involving the paraventricular nucleus, the brain stem, intermediolateral nucleus of the upper spinal cord, superior cervical ganglion and postganglionic sympathetic fibres innervating the pineal gland and stimulating melatonin synthesis at night. In tetraplegic subjects, this neuronal chain is interrupted leading to impairment of melatonin synthesis at night. 2. The way in which the SCN imparts its time cues on the neighbouring neurons regulating hormone sythesis, sleep and arousal etc., is only partly understood. In addition to synaptic processes, paracrine mechanisms play a role. The viscera are timed by fibres of the autonomic nervous system. Several studies dealing with shift workers reveal that perturbations of the circadian rhythms may represent a health hazard.