Circadian Pacemaking in Cells and Circuits of the Suprachiasmatic Nucleus

Abstract

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker of the brain. It co-ordinates the daily rhythms of sleep and wakefulness, as well as physiology and behaviour, that set the tempo to our lives. Disturbance of this daily pattern, most acutely with jet-lag but more insidiously with rotational shift-work, can have severely deleterious effects for mental function and long-term health. The present review considers recent developments in our understanding of the properties of the SCN that make it a robust circadian time-keeper. It first focuses on the intracellular transcriptional/ translational feedback loops (TTFL) that constitute the cellular clockwork of the SCN neurone. Daily timing by these loops pivots around the negative regulation of the Period (Per) and Cryptochrome (Cry) genes by their protein products. The period of the circadian cycle is set by the relative stability of Per and Cry proteins, and this can be controlled by both genetic and pharmacological interventions. It then considers the function of these feedback loops in the context of cytosolic signalling by cAMP and intracellular calcium ([Ca2+]i), which are both outputs from, and inputs to, the TTFL, as well as the critical role of vasoactive intestinal peptide (VIP) signalling in synchronising cellular clocks across the SCN. Synchronisation by VIP in the SCN is paracrine, operating over an unconventionally long time frame (i.e. 24 h) and wide spatial domain, mediated via the cytosolic pathways upstream of the TTFL. Finally, we show how intersectional pharmacogenetics can be used to control G-protein-coupled signalling in individual SCN neurones, and how manipulation of Gq/[Ca2+]i-signalling in VIP neurones can re-programme the circuit-level encoding of circadian time. Circadian pacemaking in the SCN therefore provides an unrivalled context in which to understand how a complex, adaptive behaviour can be organised by the dynamic activity of a relatively few gene products, operating in a clearly defined neuronal circuit, with both cell-autonomous and emergent, circuit-level properties.

Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus

“…Almost all of the cells in the body also have this TTFL, but in the absence of SCN input, the amplitude and synchrony of peripheral circadian oscillations are lost. A defining feature of the SCN, therefore, is its intrinsic ability to sustain stable, high-amplitude circadian rhythms (6). Importantly, this is dependent on neuropeptide-mediated interneuronal communication (7)(8)(9).…”

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

“…Interestingly, RORα is a positive regulator of Bmal1 expression (Sato et al, 2004), Bmal1 is an essential transcription factor in circadian rhythmogenesis and activator of Per gene expression (Hastings et al, 2014;Takahashi, 2016). In adults, RORα knockouts showed slight behavioral abnormalities in circadian rhythms.…”

“…In mammals, the hypothalamic suprachiasmatic nucleus (SCN) is a master circadian pacemaker consisting of approximately 20,000 neurons. Individual cells can generate circadian rhythms via a negative feedback loop involving core clock genes including Per2 (Hastings et al, 2014;Takahashi, 2016). How and when these rhythms arise during development is not known.…”

“Seasonal changes in the neuroendocrine system”: Some reflections

“…This general issue, of course, dominates much of current research on the daily (circadian) rhythms where a "single clock" can time events to occur at different times of the day (Hastings et al, 2014;Xi & Chen, 2014).…”