Cell-autonomous and Circuit-level Mechanisms of Circadian Timekeeping in Mammals: Genes, Neurons and Astrocytes

In mammals the cell-autonomous circadian clock pivots around a transcriptional/post-translational feedback loop. However, we remain largely ignorant of the critical molecular, cell biological, and circuit-level processes that determine the precision and robustness of circadian rhythms: what keeps them on track, and what determines their period, which varies by less than 5 minutes over 24 hours? The origin of this precision and robustness is the suprachiasmatic nucleus (SCN) of the basal hypothalamus, the principal circadian pacemaker of the brain. The SCN sits atop a circadian hierarchy that sustains and synchronises the innumerable cell-autonomous clocks of all major organs to solar time (and thereby to each other), by virtue of direct retinal innervation that entrains the transcriptional oscillator of the 20,000 or so component cells of the SCN. I shall describe real-time imaging approaches to monitor circadian cycles of gene expression and cellular function in the SCN, and intersectional genetic and pharmacological explorations of the cell-autonomous and circuit-level mechanisms of circadian timekeeping. A particular focus will be on “translational switching” approaches to controlling clock function and the surprising discovery of a central role for SCN astrocytes in controlling circadian behaviour.