Peripheral Circadian Clocks—A Conserved Phenotype?

Abstract

The circadian system of mammals regulates the timing of occurrence of behavioral and physiological events, thereby optimizing adaptation to their surroundings. This system is composed of a single master pacemaker located in the suprachiasmatic nucleus (SCN) and a population of peripheral clocks. The SCN integrates time information from exogenous sources and, in turn, synchronizes the downstream peripheral clocks. It is assumed that under normal conditions, the circadian phenotype of different peripheral clocks would be conserved with respect to its period and robustness. To study this idea, we measured the daily wheel-running activity (WRA; a marker of the SCN output) in 84 male inbred LEW/Crl rats housed under a 12 h:12 h light-dark cycle. In addition, we assessed the mRNA expression of two clock genes, rPer2 and rBmal1, and one clock-controlled gene, rDbp, in four tissues that have the access to time cues other than those emanating from the SCN: olfactory bulbs (OBs), liver, tail skin, and white blood cells (WBCs). In contrast with the assumption stated above, we found that circadian clocks in peripheral tissues differ in the temporal pattern of the expression of circadian clock genes, in the robustness of the rhythms, and possibly in the number of functional ~24-h-clock cells. Based on the tissue diversity in the robustness of the clock output, the hepatic clock is likely to house the highest number of functional ~24-h-clock cells, and the OBs, the fewest number. Thus, the phenotype of the circadian clock in the periphery is tissue specific and may depend not only on the SCN but also on the sensitivity of the tissue to non-SCN-derived time cues. In the OBs and liver, the circadian clock phenotypes seem to be dominantly shaped by the SCN output. However, in the tail skin and WBC, other time cues participate in the phenotype design. Finally, our study suggests that the basic phenotype of the circadian clock is constructed at the transcript level of the core clock genes. Yet, additional posttranscriptional and translational events can contribute to the robustness and periodicity of the clock output.

Phase Differences in Expression of Circadian Clock Genes in the Central Nucleus of the Amygdala, Dentate Gyrus, and Suprachiasmatic Nucleus in the Rat

“…Interestingly, in a previous study using the same rats, we found that the peak expression of Per2, Bmal1 and Dbp are synchronized across the olfactory bulb, liver and tail skin [8]. Furthermore, the rhythms of expression of each of these genes peaks in close temporal proximity with the rhythm in the DG (Fig.…”

“…Data for olfactory bulb, liver and skin are based on previously published results [8] using the same rats used in the present study for comparison.…”

“…The current analysis was carried out on brain sections from 74 male Lewis (LEW/Crl) rats used in our previous study of PER2 rhythms in the forebrain [3] and in a study of the rhythms of expression of Per2, Bmal1 and Dbp in the olfactory bulb and in the periphery [8]. As previously described, the rats were individually housed and entrained to a 12 h∶12 h LD cycle, and had free access to food and water.…”

Analysis of genetic association and epistasis interactions between circadian clock genes and symptom dimensions of bipolar affective disorder

“…Abnormalities have been observed both during episodes of illness and remission (Etain et al, 2011). There were even suggestions to use peripheral circadian clock as conserved phenotype for genetic analyses (Weigl et al, 2013). PER3 gene is known for its associations with sleep patterns.…”

“…Daily cycle is observed in hormone production, cell regeneration or brain waves activity (Schibler et al, 2003). Organism adapt to its surroundings when circadian clock works appropriate (Ramanathan et al, 2012;Weigl et al, 2013).…”