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 and in 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.
Highlights
Circadian clocks are biological pacemakers that drive daily rhythms in physiology and behaviour, such as sleep, metabolism, core body temperature and hormone secretion (Piggins & Guilding, 2011)
We hypothesised that the suprachiasmatic nuclei (SCN) and pituitary gland (PIT) oscillators are more susceptible to phase-resetting when cultured, a phenomena we have previously demonstrated in lower amplitude circadian oscillators (Guilding et al 2009; Hughes et al 2011)
We provide the first examination of phase-shifting behaviour in these mice and uncover rare Type 0 resetting, which is associated with enhanced phase-resetting of molecular clocks in vitro
Summary
Circadian clocks are biological pacemakers that drive daily rhythms in physiology and behaviour, such as sleep, metabolism, core body temperature and hormone secretion (Piggins & Guilding, 2011). Using brain tissues from PER2 reporter mice (PERIOD2::LUCIFERASE (PER2::LUC); Yoo et al 2004), we have demonstrated that circadian rhythms are detectable in a number of extra-SCN brain sites. These include hypothalamic structures involved in feeding behaviour and metabolic control, such as the dorsomedial hypothalamus (DMH), arcuate nucleus (Arc) and median eminence (ME), as well as the pars tuberalis (PT) of the pituitary gland (PIT) and the habenula (Hb) of the epithalamus (Guilding et al 2009, 2010). It is clear that a network of clocks located across the brain and body orchestrates circadian rhythms in behaviour and physiology
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