Circadian system from conception till adulthood

Abstract

In mammals, the circadian system is composed of the central clock in the hypothalamic suprachiasmatic nuclei and of peripheral clocks that are located in other neural structures and in cells of the peripheral tissues and organs. In adults, the system is hierarchically organized so that the central clock provides the other clocks in the body with information about the time of day. This information is needed for the adaptation of their functions to cyclically changing external conditions. During ontogenesis, the system undergoes substantial development and its sensitivity to external signals changes. Perinatally, maternal cues are responsible for setting the phase of the developing clock, while later postnatally, the LD cycle is dominant. The central clock attains its functional properties during a gradual and programmed process. Peripheral clocks begin to exhibit rhythmicity independent of each other at various developmental stages. During the early developmental stages, the peripheral clocks are set or driven by maternal feeding, but later the central clock becomes fully functional and begins to entrain the periphery. During the perinatal period, the central and peripheral clocks seem to be vulnerable to disturbances in external conditions. Further studies are needed to understand the processes of how the circadian system develops and what degree of plasticity and resilience it possesses during ontogenesis. These data may lead to an assessment of the contribution of disturbances of the circadian system during early ontogenesis to the occurrence of circadian diseases in adulthood.

Introduction

The mammalian internal timekeeping system, which temporally controls many processes in our body, undergoes developmental changes as an organism grows and matures. Increasing awareness of the mechanisms of how the system operates at molecular level facilitates studies of the development of the system from its very early stages, that is, far before the overt rhythms driven by the system can be used as a marker of its functional stage. These studies may uncover the mystery of when the circadian clock begins to tick independent of the maternal environment. It is possible that the circadian clock is functional early prenatally when it resides in the maternal body and the mother's role is just to adjust its phase according to the external light/dark (LD) cycle to ensure that her offspring are born with fully entrained clocks. Alternatively, it is also possible that the developing circadian clock is first directly driven by maternal signals as a slave oscillator in utero and develops into a self-sustained clock that is sensitive to the external LD cycle only gradually after birth. Both possibilities would ensure that the newborn leaves the maternal body with its clock properly entrained with the external environment, but it remains unclear which of these possibilities would be evolutionally more advantageous. It is also possible that different species utilize various scenarios of the development. This issue is important for understanding the significance of mother-to-fetus and mother-to-neonate communication for proper development of the circadian system. Enormous amounts of data have been accumulated to demonstrate that a malfunction of the circadian system leads to the distortion of temporal control of physiology and results in the development of serious diseases. Studies on the ontogenesis of the circadian system may reveal whether its malfunction in adulthood may result from an insult during early developmental stages, which might arise from the disruption of the endogenous timekeeping system during pregnancy.

The circadian system is composed of hierarchically organized circadian clocks forming an integral regulatory system that gives the organism the daily temporal program and helps it adapt to the external environment. Circadian clocks reside in nearly every, if not all, mammalian cells (for a review, see Schibler et al., 2003). These clock cells are equipped with a set of so-called clock genes, which are genes that are indispensable for circadian function. In mammals, Per1, Per2, Cry1, Cry2, Bmal1, Clock, Rev-erbα, and Rora have been recognized as clock genes (for a review, see Takahashi et al., 2008). Cellular clocks are regularly entrained by the master pacemaker located in the suprachiasmatic nuclei (SCN) of the ventral hypothalamus just above the optic chiasm (Klein et al., 1991). The SCN is a complex structure, which is composed of a cluster of independent cellular oscillators (Welsh et al., 1995) that are mutually coupled by a web of synapses. This intercellular communication is responsible for synchrony among the cells (Liu et al., 2007). Moreover, the SCN cells are organized into morphologically and functionally distinct subpopulations (Klein et al., 1991) which also communicate among each other. The most prominent subpopulations are located in the ventrolateral (core) and dorsomedial (shell) regions of the SCN (for a review, see Welsh et al., 2010), but there are also other subdivisions, including a functional specialization in populations of cells in the rostro-caudal dimension of the SCN (Brown and Piggins, 2009, Morin, 2007, Sosniyenko et al., 2009). As a result of this intercellular communication, the SCN generates a synchronized output signal to the rest of the body that entrains the peripheral clocks with the external LD cycles.

This chapter provides a summary of our latest knowledge and offers some hypotheses on the processes by which the circadian system develops in mammals from its origin through weaning and adulthood. The summary includes mostly data from rodent models. For a more extensive overview of the subject, the readers are encouraged to refer to previous reviews (e.g., Weinert, 2005, Sumova et al., 2006a, Sumova et al., 2006b, Sumova et al., 2008, Seron-Ferre et al., 2007).