The rat circadian clockwork and its photoperiodic entrainment during development.

The mammalian circadian pacemaker is located in the suprachiasmatic nucleus (SCN), which is composed of dorsomedial (dm) and ventrolateral (vl) regions. The molecular clockwork responsible for the SCN rhythmicity consists of clock genes and their transcriptional-translational feedback loops. The rat SCN rhythmicity and clockwork are affected by the photoperiod. The aim of this study was to elucidate development of the rat SCN rhythmicity, namely of the rhythmicity of the dm- and vl-SCN and of expression of clock genes and to ascertain when the photoperiod starts to affect the SCN rhythmicity. Rhythmicity of the dm-SCN, measured as the rhythm in spontaneous c-FOS production, developed earlier than that of the vl-SCN, which was measured as the rhythm in c-FOS photoinduction. However, photoperiodic affection of the rhythmicity occurred earlier in the vl-SCN than in the dm-SCN. From the 4 clock genes (Per1, Per2, Cry1 and Bmal1) studied, the expression of Bmal1 and Per1 was rhythmic already in 1-day-old rats; at this age, the Per2 mRNA rhythm just started to form and no rhythm in Cry1 expression was detected. After the second postnatal day, all 4 genes were expressed in a rhythmic manner. Thereafter, the rhythms matured gradually via increasing amplitude. Per1 and Per2 mRNA rhythms started to be affected by the photoperiod at the 10th postnatal day. The data suggest that the rhythms in clock genes expression in the rat SCN develop mostly postnatally. The molecular clockwork may start to be photoperiod-dependent around the 10th postnatal day.

Setting the biological time in central and peripheral clocks during ontogenesis.

In mammals, the principal circadian clock within the suprachiasmatic nucleus (SCN) entrains the phase of clocks in numerous peripheral tissues and controls the rhythmicity in various body functions. During ontogenesis, the molecular mechanism responsible for generating circadian rhythmicity develops gradually from the prenatal to the postnatal period. In the beginning, the maternal signals set the phase of the newly developing fetal and early postnatal clocks, whereas the external light-dark cycle starts to entrain the clocks only later. This minireview discusses the complexity of signaling pathways from mothers and the outside world to the fetal and newborn animals' circadian clocks.

[Development of the mammalian circadian system]. / Ontogenetický vývoj cirkadiánního systému savcu.

Many behavioral, physiological and molecular processes exhibit diurnal rhythms. Endogenous rhythms with period close to 24 hours are called circadian rhythms. Light entrains circadian rhythms to a 24 period of solar day. Circadian system consists of pacemaker, which is in mammals located in the suprachiasmatic nuclei of hypothalamus (SCN), its input and output pathways and peripheral clocks in numerous tissues. The generation of circadian rhytmicity is based on interactive transcription-translational feedback loops in SCN. These feedback loops consist of so called clock genes and their protein products which positively or negatively regulate their own transcription. Studies in rodent embros and neonates demonstrate that individual components of circadian system matures gradually during prenatal and postnatal period Mechanism of light entrainment of the circadian system develops postnatally. During early postnatal period, the developing circadian system is synchronized mainly by maternal cues.

Insight into molecular core clock mechanism of embryonic and early postnatal rat suprachiasmatic nucleus.

Rhythmicity of the rat suprachiasmatic nucleus (SCN), a site of the circadian clock, develops prenatally. A molecular clockwork responsible for the rhythmicity consists of clock genes and their negative and positive transcriptional-translational feedback loops. The aim of the present study was to discover the development of the clockwork during ontogenesis. Daily profiles of Per1, Per2, Cry1, Bmal1, and Clock mRNA in the SCN of fetuses at the embryonic day (E)19 and of newborn rats at the postnatal day (P)3 and P10 were assessed by the in situ hybridization method. In addition, daily profiles of PER1, PER2, and CRY1 proteins at E19 were assessed by immunohistochemistry. As early as at E19, all the studied clock genes were already expressed in the SCN. However, no SCN rhythm in their expression was detected; Per1, Cry1, and Clock mRNA levels were low, whereas Bmal1 mRNA levels were high and Per2 mRNA levels were medium. Moreover, no rhythms of PER1, PER2, and CRY1 were detectable, as no immunoreactive cells were present at E19. At P3, rhythms in Per1, Per2, Cry1, and Bmal1, but not in Clock mRNA, were expressed in the SCN. The rhythm matured gradually; at P10, the amplitude of Per1, Per2, and Bmal1 mRNA rhythms was more pronounced than at P3. Altogether, the data show a gradual development of both the positive and negative elements of the molecular clockwork, from no detectable rhythmicity at E19 to highly developed rhythms at P10.