Lecturer: Michael Hastings, MRC Laboratory of
Molecular Biology, Cambridge, United Kingdom.
Circadian (approximately one day) rhythms dominate our lives, most obviously via the sleep/wake cycle. Driven by internal clocks, they adapt us to the world by preparing tissues to perform appropriate, but very different, functions in anticipated day and anticipated night. The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian clock of the mammalian brain. It is entrained to solar time by direct retinal innervation, and in turn, it co-ordinates innumerable cellular clocks distributed in all major organs across the body. At a cellular level, circadian timekeeping in SCN and other cells pivots around self-sustaining transcriptional/translational feedback loops (TTFLs) in which the positive regulators CLOCK and BMAL1 drive expression of the negative regulators PERIOD (PER) and CRYPTOCHROME (CRY) via E-box
DNA regulatory sequences. Delayed negative feedback by PER and CRY at E-boxes, followed by degradation of PER and CRY, establishes a
spontaneous oscillation with a period of approximately 24 hours. This mechanism orchestrates local cell type-specific circadian transcriptomes, synchronized by SCN-dependent behavioral, neuroendocrine, and autonomic cues. These programs in turn sustain the coherent 24-hour cycles of local gene expression that underpin circadian behavior, metabolism, and physiology. This presentation will review recent advances in understanding of the molecular genetic basis of the cell-autonomous clock mechanism of the SCN. It will then consider how circuit-level cellular interactions establish the SCN as a powerful self-sustained clock. Finally, it will consider how the SCN directs circadian behavior and physiology. Where
appropriate, it will illustrate how developments in real-time imaging of neuronal function and genetic code expansion have been useful in elucidating the clock’s inner mechanism. The overarching message from the circadian neurobiology field is that our bodies are extremely sophisticated 24-hour machines, an observation with significant implications for health and disease.