hormone receptors (REV-ERBα and RORα). Negative and positive feedback interactions among these clock genes lead to transcriptional oscillations that retain an approximate 24-h periodicity independent of any external entrainer. In order to stay in harmony with environmental changes, clock gene oscillations must be corrected on a daily basis by entraining signals. As such, SCN neurons after receiving the environmental input from light/dark cycles, deliver photic information to the periphery of the body via direct routes such as the circadian secretion of hormones and the neuronal activity of the autonomic nervous system, and indirect routes such as the daily rest/activity cycles that further control the feeding time. This network of interactions among SCN and peripheral tissues reveals a nested level of biological organization where circadian information is retained in various levels of mammalian physiology from rhythmic patterns of clock gene expression to behavioral rhythms of sleep/wake cycles. Systemic integrity is largely dependent on the coherent function of the sub-systems composing the network. Their circadian rhythmicity is further related to the integrity of humoral and neuronal entraining signals, further underscoring the need of a system-level approach in order understand the underlying properties and design principles.
Quantitative mathematical models have been applied to gain mechanistic insights into clock gene network function [4-9] (Table 1). Among them, Becker-Weinmann et al. using a reduced model to simulate clock genes network, denoted that the negative feedback loop among Per and Cry genes is critically important for the maintenance of clock gene oscillations. They showed that even if the positive feedback loop among Bmal, Ror and Rev-erbα genes is substituted by a constantly expressed activator, oscillations can still occur. These modeling results were supported by the experimental evidence showing that Rev-erbα -/- mutant mice have rhythmic behavior even though their positive feedback mechanism is not functional. More