The SCN of the anterior hypothalamus are the site of the circadian pacemaker in mammals.7) Like any timing system, the circadian clock is made up of three components9– 11): an input pathway adjusting the time, a central oscillator generating the circadian signal, and an output pathway manifesting itself in circadian physiology and behavior. The daily changes in light intensities are thought to be the major environmental cue involved in circadian entrainment. Light signals are perceived by photoreceptor cells in the retina and transmitted to neurons of the SCN via the retinohypothalamic tract.9) A great deal of research shows that the inherited period of the human pacemaker clock is not precisely 24 hr. In fact, in most people, it is somewhat longer, closer to 25 hr. Environmental time cues, termed synchronizers or zeitgebers, the strongest one being the daily light-dark cycle occurring in conjunction with the wake-sleep routine, set the inherited pacemaker circadian timekeeping systems to 24 hr each day. Clock genes are the genes that control the circadian rhythms in physiology and behavior.8) Three mammalian clock genes (Per1, Per2 and Per3) are rhythmically expressed in the SCN. Per1 and Per2 are induced in response to light.12) In particular, Per1 induction is considered to be an initial event in light-induced resetting and entrainment of the circadian biological clock9). The transcriptional machinery of the core clockwork regulates a clock-controlled output rhythm as shown in Fig. 1.5) Namely, CLOCK-BMAL1 heterodimers act through an E box enhancer to activate the transcription of Pers, vasopressin and Dbp mRNA showing a speciˆc output function from the SCN to periphery.10,11,13) This activation can be inhibited by the PER and CRY proteins.14) A circadian rhythm of Pers mRNA expression is discovered not only in the SCN but also in other tissues.15) The circadian rhythm in the periphery is governed by that in the SCN, since the circadian rhythm in physiological function and Pers mRNA expression are abolished in SCN-lesioned rats15) and Clock mutant mice.10) Such a cascade of clock genes may contribute to the organization of biological rhythms in the whole body; however, the mechanisms employed by circadian output pathways are poorly understood but are likely to involve both nervous and humoral signals.16,17) Plasma glucocorticoid levels show a circadian rhythm via the hypothalamus-pituitaryadrenal (HPA) axis under the control of the SCN. Glucocorticoids regulate various physiological responses and developmental processes by binding to and modulating the transcriptional activity of their cognate nuclear receptor.18,19) A transit induction of Per1 and Dbp mRNA levels is observed by a single administration of dexamethasone.19) Glucocorticoid hormones are particularly attractive candidates, since they are endogenous substances and play an important role in the entrainment of peripheral oscillators but not SCN.19) The regulatory system of biological rhythm should be clariˆed in detail from the viewpoint of clock genes.
Answers to all your Biology Questions
