Molecular chronobiology

Abstract

Recent years have seen exciting advances in the understanding of the mechanisms that underlie circadian rhythms in a variety of organisms, including mammals. Several key genes have been identified, whose products can be considered to represent bone fide clock molecules. Furthermore it appears that the same genes are important in generating rhythmic behaviour in both insects and man. There are some differences in the way these genes generate circadian output in the different taxa, but overall, the level of conservation of sequence and function is striking. The basic molecular oscillatory mechanism depends on a transcriptional/ translational negative feedback loop, in which the PERIOD proteins play a cardinal role, together with other molecules, which interact to regulate circadian gene expression. In mammals, the brain oscillator resides in the suprachiasmatic nucleus, and its location in the hypothalamic region may have implications for understanding the rhythmic nature of some headache syndromes.

Chronic reduction in cardiac output induces hypoxic signaling in larval zebrafish even at a time when convective oxygen transport is not required

“…Dec2 represses Clock/Bmal-induced transactivation (22) and subsequently per2 transcription (20), which was actually reduced in bre larvae. As Per2 needs to interact with Timeless (Tim) via a PAS domain to inhibit the transcriptional activity of the Clock/Bmal1 complex (28), per2 provides a connection to the chronically reduced tim expression in bre mutant larvae. Tim is also known to pass on the circadian rhythm to the cell cycle (67), and in human cells a downregulation of tim adversely affected intra-S checkpoints and therefore co-regulated development and growth.…”

The circadian clock in mammals

“…It has been noted previously in these pages that the striking circadian pattern of CH and the hypothalamic activation that accompanies these episodes [30] suggest a rather direct physical relationship between the SCN and pain [31]. We doubt there is a causal relationship between circadian rhythms and CH, as discussed briefly in [31], but this intriguing rhythmic disability provides us with opportunities to study the possible genesis of this apparent neurovascular disorder [30]. A mammalian model of CH would be very useful, and the advent of new molecular technologies such as the gene expression array, could be very useful in examining the transcriptional profile in a limited brain area, during an induced CH attack.…”

“…One of the most dramatic examples of the relationship between pain and rhythms is seen with the cluster headache syndrome (CH). It has been noted previously in these pages that the striking circadian pattern of CH and the hypothalamic activation that accompanies these episodes [30] suggest a rather direct physical relationship between the SCN and pain [31]. We doubt there is a causal relationship between circadian rhythms and CH, as discussed briefly in [31], but this intriguing rhythmic disability provides us with opportunities to study the possible genesis of this apparent neurovascular disorder [30].…”

The genetic regulation of SCN in cluster headache may be affected by Th1/Th2 cytokine derangement

“…Since the regulation of the suprachiasmatic nucleus oscillator is controlled by these cytokines, any modification of TH1 and TH2 subsets could be responsible for suprachiasmatic nucleus desynchronization. This may illuminate our understanding of the basic mechanism of cluster headache attack rhythms [17]. Finally, our data are useful for the introduction of new immunotherapeutic protocols in cluster headache treatment.…”