Clock-Talk: Interactions between Central and Peripheral Circadian Oscillators in Mammals

In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types. The synchronization signals (Zeitgebers) can be controlled more or less directly by the SCN. In mice and rats, feeding– fasting rhythms, which are driven by the SCN through rest– activity cycles, are the most potentZeitgebers for the circadian oscillators of peripheral organs. Signaling through the glucocorticoid receptor and the serum response factor also participate in the phase entrainment of peripheral clocks, and these two pathways are controlled by the SCN independently of feeding–fasting rhythms. Body temperature rhythms, governed by the SCN directly and indirectly through rest –activity cycles, are perhaps the most surprising cues for peripheral oscillators. Although the molecular makeup of circadian oscillators is nearly identical in all cells, these oscillators are used for different purposes in the SCN and in peripheral organs. The rotation of the Earth around its own axis generates daily light – dark cycles that affect the lifestyle of all photosensitive organisms from cyanobacteria to humans. The phylogenetic adaptation to recurring daily environmental changes resulted in diurnal activity cycles, driven by time periods during which food availability is high, predator abundance low, and temperature, humidity, and/or lighting conditions compatible with an organism’s lifestyle. Anticipating these changes—rather than just reacting to them—is expected to increase the fitness of organisms by optimizing their physiology and behavior with regard to both external factors and internal time-sensitive parameters. Indeed, most photosensitive organisms from photosynthetic bacteria to mammals have evolved internal timing devices, known as circadian clocks, which coordinate behavior and physiology in an anticipatory fashion. For example, plants induce the expression of photosynthetic genes a few hours before sunrise to optimize photosynthesis (Dodd et al. 2005), marine zooplankton species swim toward deeper layers at dawn or during the night before genotoxic ultraviolet light hits them (Gehring and Rosbash 2003; Tosches et al. 2014), and mice up-regulate the expression of hepatic detoxification enzymes before the activity period during which they absorb food and associated toxins (Gachon and Firsov 2011; Zmrzljak and Rozman