Proceedings of The Physiological Society

Sleep Sleep and Circadian Rhythms (London, UK) (2018) Proc Physiol Soc 42, SA15

Research Symposium

Cellular and molecular basis to circadian rhythms in mammals and its relevance to metabolic and neurological disease

M. Hastings1

1. Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.

Circadian rhythms are cycles of metabolism, physiology or behaviour that persist with a period of approximately one day (hence circa- -dian) when organisms are held in temporal isolation. Their persistence is evidence of an internal timing mechanism, a circadian clock. The award of the 2017 Nobel Prize in Physiology or Medicine to Hall, Rosbash and Young provided the climax to a decades-long pursuit to identify the molecular-genetic basis of such clocks, in their case that of the fruit-fly Drosophila. In mammals, as in flies, the circadian mechanism is a transcriptional/ translational negative feedback loop (TTFL). The positive regulators CLOCK and BMAL1 drive expression of Period and Cryptochrome genes, the protein products of which, PER and CRY, subsequently inhibit CLOCK/BMAL1-dependent transcription. Progressive degradation of PER and CRY then releases the negative regulation and a new cycle is initiated approximately 24 h after the previous one. Remarkably, the self-sustaining TTFL mechanism is present in just about every cell-type and major organ system. These local TTFLs drive cell-type-specific circadian programmes of gene expression that are the determinants of the circadian cycles of metabolism, physiology or behaviour that anticipate, and thereby adapt organisms to, the solar cycle of light and darkness. Circadian regulation of cellular functions is therefore pervasive, and ab initio, critical to health. It is regulated in a hierarchical manner, with the principal circadian clock of mammals being the suprachiasmatic nucleus (SCN) of the hypothalamus. The 10,000 or so neurons and astrocytes of the SCN are capable of maintaining circadian cycles of TTFL function and electrical activity indefinitely when isolated in culture. It is a powerful circadian timing circuit that in vivo is entrained to solar time by direct innervation from retinal ganglion cells. In turn, via its innervation of the hypothalamus and brain stem, the SCN directs a complex series of endocrine, autonomic and behavioural cues that synchronise the innumerable local TTFLs across the body, forging them into a single adaptive temporal programme. This presentation will review recent developments in understanding the cellular and network-level properties of SCN time-keeping, and highlight how the new understanding of the TTFL and the hierarchical organisation of the mammalian circadian timing system will provide a platform for the next challenge to circadian biologists: how to apply circadian knowledge to understand and treat metabolic and neurological disease.

Where applicable, experiments conform with Society ethical requirements