The authors sought to understand how the SCN communicates with clocks in peripheral organs. They knew that the SCN uses daily light–dark signals from the eyes to control the circadian rhythm of body temperature and therefore asked whether internal temperature might itself act as the entraining signal — as occurs in bacteria, plants and lower vertebrates. To answer this question, the authors studied lung, pituitary, liver, kidney and olfactory bulb tissue from mice in which Per2, a crucial clock gene, was fused to luciferase (Per2–luc). By maintaining the tissues at a range of physiologically relevant temperatures and monitoring bioluminescence, they found that even minor fluctuations in temperature resulted in phase shifts in Per2–luc expression. By contrast, expression in SCN-derived tissue remained stubbornly impervious to temperature change. Far from being an anomalous result, this finding provided crucial proof of principle: if temperature were indeed the entraining cue, the master clock would have to be resistant to temperature changes to avoid undesirable feedback mechanisms.
The authors delved deeper into this unique property of the SCN and showed that inhibition of voltage-gated sodium channels or L-type calcium channels (by treatment with tetrodotoxin or nimodipine, respectively) could sensitize the SCN to temperature-induced phase shifts. Moreover, the SCN's thermoresistance was independent of GABA (γ-aminobutyric acid) signalling and required both the dorsal and ventral regions of the nucleus. This indicates that individual cell-autonomous clocks within the SCN are responsive to temperature change, but that its collective resistance must reflect a higher-order network property that is dependent upon cell–cell communication.
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