Temporal Precision in the Mammalian Circadian System: A Reliable Clock from Less Reliable Neurons

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Abstract
The mammalian SCN contains a biological clock that drives remarkably precise circadian rhythms in vivo and in vitro. This study asks whether the cycle-to-cycle variability of behavioral rhythms in mice can be attributed to precision of individual circadian pacemakers within the SCN or their interactions. The authors measured the standard deviation of the cycle-to-cycle period from 7-day recordings of running wheel activity, Period1 gene expression in cultured SCN explants, and firing rate patterns of dispersed SCN neurons. Period variability of the intact tissue and animal was lower than single neurons. The median variability of running wheel and Period1 rhythms was less than 40 min per cycle compared to 2.1 h in firing rate rhythms of dispersed SCN neurons. The most precise SCN neuron, with a period deviation of 1.1 h, was 10 times noisier than the most accurate SCN explant (0.1 h) or mouse (0.1 h) but comparable to the least stable explant (2.1 h) and mouse (1.1 h). This variability correlated with intrinsic period in mice and SCN explants but not with single cells. Precision was unrelated to the amplitude of rhythms and did not change significantly with age up to 1 year after birth. Analysis of the serial correlation of cycle-to-cycle period revealed that approximately half of this variability is attributable to noise outside the pacemaker. These results indicate that cell-cell interactions within the SCN reduce pacemaker noise to determine the precision of circadian rhythms in the tissue and in behavior.