Circuit development in the master clock network of mammals

Abstract

Daily rhythms are generated by the circadian timekeeping system, which is orchestrated by the master circadian clock in the suprachiasmatic nucleus (SCN) of mammals. Circadian timekeeping is endogenous and does not require exposure to external cues during development. Nevertheless, the circadian system is not fully formed at birth in many mammalian species and it is important to understand how SCN development can affect the function of the circadian system in adulthood. The purpose of the current review is to discuss the ontogeny of cellular and circuit function in the SCN, with a focus on work performed in model rodent species (i.e., mouse, rat, and hamster). Particular emphasis is placed on the spatial and temporal patterns of SCN development that may contribute to the function of the master clock during adulthood. Additional work aimed at decoding the mechanisms that guide circadian development is expected to provide a solid foundation upon which to better understand the sources and factors contributing to aberrant maturation of clock function.

Keywords: circadian clock; clock genes; postnatal development; suprachiasmatic nucleus.

Figure1.

Development of the circadian timekeeping system. A. In adulthood, the suprachiasmatic nucleus (SCN) receives light input via the retinohypothalamic tract and provides daily outputs signals to downstream tissues to coordinate the timing of overt rhythms. B. Simplified model of the circadian molecular clock in mammals, which is composed of self-sustained transcriptional-translational feedback loops that regulate daily expression of clock genes and their protein products. In SCN neurons, the transcription factors CLOCK and BMAL1 dimerize and activate Period (Per) and Cryptochrome (Cry) expression during the day. After translation, PER and CRY dimers repress their own transcription at night. This core feedback loop is interlocked with other transcriptional loops that stabilize and augment circadian function. For example, REV-ERB and ROR regulate the daily expression of Bmal1. C. The shell-core model of the adult SCN network illustrating the spatial location of five neuronal subclasses in mice. AVP: Arginine Vasopressin, VIP: Vasoactive Intestinal Polypeptide, GRP: Gastrin-Releasing Peptide, CB: Calbindin; CR: Calretinin. Note: all five peptides are also expressed in rats and hamsters although the expression of CB and CR differs among rodent species. D. Timeline of SCN development. Important milestones are illustrated for SCN development in rodents. Most information illustrated on the timeline derives from studies using mice, but detailed information on the timing of fetal metabolic/electrical rhythms, Rev-erb rhythms, synaptogenesis, and glial maturation are only available for rats. Early genetic markers of SCN differentiation are labeled purple to represent those for which effects on SCN development have been reported. Color version of this figure can be viewed online.