, 2006). SCN lesions eliminate circadian locomotor rhythms, but not odor-induced c-Fos rhythms in the olfactory bulb or piriform cortex. Olfactory bulb oscillators drive rhythms in spontaneous and odor-evoked activity within the bulb and also in its primary synaptic targets in the piriform cortex. In the sense that olfactory bulb oscillators express circadian rhythms

in the absence of the SCN, persist in constant darkness and are required for rhythms in the piriform cortex, Vorinostat concentration these oscillators can be considered master circadian pacemakers in the olfactory system. That said, in the intact animal, under unperturbed conditions, the SCN sets the phase of the olfactory bulb and other independent oscillators. The SCN modulates temporal activity in these cellular oscillators, such that each bears regulated phase relationships to SCN pacemakers and hence to each other. Such findings

led to the interpretation that the circadian clock mechanism modulates find more the activity of genes in a tissue-specific manner (Akhtar et al., 2002; Duffield et al., 2002; Miller et al., 2007; Silver & Lesauter, 2008; Hughes et al., 2009). This process can be accomplished either directly by CLOCK:BMAL1 activation through an E-box domain on their gene promoters (i.e. clock-controlled genes) or indirectly via downstream actions of clock-controlled gene products to optimize system-wide functioning on a daily schedule (Fig. 2). For example, the thrombomodulin, a cofactor for thrombin that is expressed on the surface of endothelial cells to reduce blood coagulation, gene contains an E-box domain in its promoter and is directly regulated by the CLOCK:BMAL1 complex (Takeda et al., 2007). The resulting rhythm in thrombomodulin probably contributes to daily changes in the likelihood of cardiovascular events. Generally, the risk of cardiovascular events peaks in

the morning and evening; the morning time point is associated with a daily peak in rhythmic cortisol and epinephrine, whereas the night-time peak is associated with peak blood pressure and a trough in cardiac vagal modulation (Scheer et al., 2010). These broad implications expanded the audience of investigators and disciplines attending to the workings of the circadian timing system. Ceramide glucosyltransferase Not only were the salient phenomena, such as sleep–wake cycles, of immediate interest, but also the invisible circadian oscillations such as seen in the workings of the heart, or in the timing of cell division. Finally, the occurrence of sex differences in circadian rhythms (Bailey & Silver, 2013) and the demonstration of diseases associated with altered clock gene function rendered it necessary to consider the circadian timing system in a broad array of apparently unrelated disciplines, both applied and basic. The finding of extra-SCN oscillators begged the question of the relationship of the brain master clock to these other clocks.