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Suppressed cellular oscillations in after-hours mutant mice are associated with enhanced circadian phase-resetting

Lookup NU author(s): Dr Clare Guilding

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Abstract

Key points• The master circadian clock in the brain's suprachiasmatic nuclei provides daily timing cues for other circadian oscillators in the brain and body, and is itself synchronised to the external world through recurring changes in environmental light levels.• Here we show that in addition to lengthening circadian period, the after-hours (Afh) mutation alters daily rhythms in metabolism, and reduces the amplitude of oscillations in circadian timekeepers in the brain and periphery. Such suppression in circadian oscillation could be visualised in single brain cells. Intriguingly, the Afh mutation greatly enhanced resetting of the circadian system to stimuli such as environmental light.• Collectively the results indicate unusual consequences of the Afh mutation, from single cells to whole animal physiology and behaviour.Abstract Within the core molecular clock, protein phosphorylation and degradation play a vital role in determining circadian period. The ‘after-hours’ (Afh) mutation in mouse slows the degradation of the core clock protein Cryptochrome, lengthening the period of the molecular clock in the suprachiasmatic nuclei (SCN) and behavioural wheel-running rhythms. However, we do not yet know how the Afh mutation affects other aspects of physiology or the activity of circadian oscillators in other brain regions. Here we report that daily rhythms of metabolism and ingestive behaviours are altered in these animals, as are PERIOD2::LUCIFERASE (PER2::LUC) rhythms in mediobasal hypothalamic nuclei, which influence these behaviours. Overall there is a trend towards period lengthening and a decrease in amplitude of PER2::LUC rhythms throughout the brain. Imaging of single cells from the arcuate and dorsomedial hypothalamic nuclei revealed this reduction in tissue oscillator amplitude to be due to a decrease in the amplitude, rather than a desynchrony, of single cells. Consistent with existing models of oscillator function, this cellular phenotype was associated with a greater susceptibility to phase-shifting stimuli in vivo andin vitro, with light evoking high-amplitude Type 0 resetting in Afh mutant mice. Together, these findings reveal unexpected consequences of the Afh mutation on the amplitude and synchrony of individual cellular oscillators in the SCN.


Publication metadata

Author(s): Guilding C, Scott FF, Bechtold DA, Brown TM, Wegner S, Piggins HD

Publication type: Article

Publication status: Published

Journal: Journal of Physiology

Year: 2013

Volume: 591

Issue: 4

Pages: 1063-1080

Print publication date: 01/02/2013

Online publication date: 13/02/2013

Acceptance date: 01/12/2012

ISSN (print): 0022-3751

ISSN (electronic): 1469-7793

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1113/jphysiol.2012.242198

DOI: 10.1113/jphysiol.2012.242198


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