CLOCK suprachiasmatic nucleus

Figure 22.1 Pathways projecting to and from the suprachiasmatic nucleus (SCN). Inputs from photoreceptors in the retina help to reset the circadian clock in response to changes in the light cycle. Other inputs derive from the lateral geniculate complex and the serotonergic, Raphe nuclei and help to reset the SCN in response to non-photic stimuli. Neurons in the SCN project to the hypothalamus, which has a key role in the regulation of the reproductive cycle, mood and the sleep-waking cycle. These neurons also project to the pineal gland which shows rhythmic changes in the rate of synthesis and release of the hormone, melatonin...

Glass, J. D., Grossman, G. H., Farnbauch L. 8r DiNardo, L. (2003). Midbrain raphe modulation of nonphotic circadian clock resetting and 5-HT release in the mammalian suprachiasmatic nucleus. J. Neurosci. 23, 7451-60. 

Hunt, A. E., A1 Ghoul, W. M., Gillette, M. U. Dubocovich, M. L. (2001). Activation of MT2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am. J. Physiol. Cell. Physiol. 280, 010-18. 

A role for the 5-HT7 receptor in the regulation of circadian rhythms has been implicated. As discussed above, 5-HT has been known for some time to induce phase shifts in behavioral circadian rhythms and modulate neuronal activity in the suprachiasmatic nucleus, the likely site of the mammalian circadian clock. The pharmacological characteristics of the effect of 5-HT on circadian rhythms are consistent with 5-HT7 receptor. Moreover, mRNA for the 5-HT7 receptor is found in the suprachiasmatic nucleus. There is also increasing evidence that the 5-HT7 receptor may play a role in psychiatric disorders. The regional distribution of 5-HT7 receptors in brain includes limbic areas and cortex. Atypical antipsychotics, such as clozapine and risperidone, and some antidepressants display high affinity for this receptor. In the periphery, 5-HT7 receptors havebeenshown to mediate relaxation of vascular smooth muscle. 

Ramelteon (Rozerem). Recently approved by the FDA for treatment of insomnia in the US, ramelteon acts via a completely novel mechanism of action, that is, stimulating so-called melatonin Ti and T2 receptors in the brain s suprachiasmatic nucleus (SCN). The SCN is regarded as the body s master clock that regulates the sleep-wake cycle and other circadian rhythms. The effects of ramelteon in some respects mimic those of melatonin. Ramelteon, in clinical trials, administered at bedtime doses of 8 mg, outperformed placebo with respect to several indices of sleep disturbance (see Table 9.4). 

Circadian clock-controlled rhythms provide most organisms with an orchestrated temporal programme that allows for appropriate timing of physiology (i.e. blood pressure, hormonal levels) and behaviour (i.e. alertness, sleep-wake cycle). The mammalian central circadian pacemaker resides in the suprachiasmatic nucleus (SCN) of the brain (Weaver 1998). At the molecular level, the core oscillator driving the mammahan clock consists of interconnected autoregulatory... 

Herzog ED, Takahashi JS, Block GD 1998 Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat Neurosci 1 708—71 KobayashiK, Kanno S, Smit B, van der Horst GTJ, Takao M, Yasui A 1998 Characterization of photolyase/blue-hght receptor homologs in mouse and human cells. Nucleic Acids Res 26 5086-5092... 

Kara R, Wan K, Wakamatsu H et al 2001 Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus. Genes Cells 6 269—278 Selby CP, Thompson C, Schmitz TM, Van Gelder RN, Sancar A 2000 Functional redundancy of cryptochromes and classical photoreceptors for nonvisual ocular photoreception in mice. Proc Natl Acad Sci USA 97 14697-14702... 

Davidson AJ, Stephan FK 1999 Feeding-entrained circadian rhythms in hypophysectomized rats with suprachiasmatic nucleus lesions. Am J Physiol 46 R1376-R1384 Filipski E, King M, Li X et al 2002 Host circadian clock as a control point in tumor progression. J Natl Cancer Inst 94 690-697... 

Stephan FK 2002 The other circadian system. Food as a Zeitgeber. J Biol Rhythms 17 284-292 Stephan FK, Swann JM, Sisk CL 1979 Anticipation of 24-hr feeding schedules in rats with lesions of the suprachiasmatic nucleus. Behav Neural Biol 25 346—363 Stephan FK, Zucker I 1972 Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA 69 1583-1586 Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M 2001 Entrainment of the circadian clock in the liver by feeding. Science 291 490-493... 

Ueyama T, Krout KE, Nguyen XV et al 1999 Suprachiasmatic nucleus a central autonomic clock. Nat Neurosci 2 1051-1053... 

The relationship between central and peripheral oscillators is different in flies and mammals. In mammals, these oscillators form a hierarchy in which the central oscillator, which resides in the suprachiasmatic nucleus (SCN), functions as a master clock that is entrained by photic signals from the eye, and in turn drives subservient peripheral oscillators via humoral signals (Moore et al 1995, Yamazaki et al 2000, Kramer et al 2001, Cheng et al 2002). In contrast, both central and peripheral oscillators operate autonomously and are directly entrainable by light in Drosophila (Plautz et al 1997), thus obviating the need for a hierarchical system. Our results support the concept of independent oscillators in flies since central (sUN ) oscillators are not necessary for olfaction rhythms and local oscillators in antennae appear to be sufficient. 

Expression of clock gene products in the suprachiasmatic nucleus in relation to circadian behaviour... 

Maywood ES, Okamura H, Hastings MH 2002 Opposing actions of neuropeptide Y and light on the expression of circadian clock genes in the mouse suprachiasmatic nucleus. Eur J Neurosci 15 216-220... 

The circadian clock driving locomotor activity and other circadian behaviours, such as the sleep—wake cycle, is located within the suprachiasmatic nucleus (SCN) of the hypothalamus (Klein et al 1991). 

Klein DC, Moore RY, Reppert SM 1991 Suprachiasmatic nucleus the mind s clock. Oxford University Press, New York... 

Pittendrigh CS, Daan S 1976a A functional analysis of circadian pacemakers in nocturnal rodents. 1. The stability and lability of spontaneous frequency. J Comp Physiol A 106 223-252 Pittendrigh CS, Daan S 1976b A functional analysis of circadian pacemakers in nocturnal rodents. IV. Entrainment pacemaker as clock. J Comp Physiol [A] 106 291—331 Ralph MR, Foster RG, Davis FC, Menaker M 1990 Transplanted suprachiasmatic nucleus determines circadian period. Science 247 975-978 Redlin U, Mrosovsky N 1999 Masking by light in hamsters with SCN lesions. J Comp Physiol [A] 184 439-448... 

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