Cells and Circuits of the Suprachiasmatic Nucleus and the Control of Circadian Behaviour and Sleep

Circadian rhythms set the tempo of our lives and their disruption by ageing and modern lifestyles is associated with a wide range of systemic illness. The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian clock, entrained by direct retinal input to ensure that internal time matches external, solar time. The SCN is a powerful biological timekeeper. In this review, we consider the molecular-genetic and cellular basis of circadian timekeeping in mammals, with a focus on the transcription-translational feedback loop (TTFL). We then discuss the circadian properties of SCN neurons and how the TTFL interacts with electrical activity. This is followed by examination of the circuit architecture of the SCN as a cellular network and the role of paracrine neuropeptidergic signalling in sustaining and synchronising cellular TTFLs. Complementing daytime neural activity, the nocturnal activity of astrocytes further binds the SCN circuit together to create stable and precise daily times that are conveyed by SCN neural outputs to various targets, local to the hypothalamus and also in the brain stem. In this way, they co-ordinate daily cycles of behaviour and physiology. The dominant cycle is that of sleep and wakefulness and we consider how interactions between the SCN and local distributed circadian clocks confer effective sleep and sleep-dependent memory. At all stages of biological organisation: molecular, cellular, neurochemical and behavioural, nested re-entrant feedback loops confer the unique stability and robustness of SCN timekeeping. Finally, we note some potential future directions for research in this field.