Challenging the omnipotence of the suprachiasmatic timekeeper: are circadian oscillators present throughout the mammalian brain?

Abstract

The suprachiasmatic nucleus of the hypothalamus (SCN) is the master circadian pacemaker or clock in the mammalian brain. Canonical theory holds that the output from this single, dominant clock is responsible for driving most daily rhythms in physiology and behaviour. However, important recent findings challenge this uniclock model and reveal clock-like activities in many neural and non-neural tissues. Thus, in addition to the SCN, a number of areas of the mammalian brain including the olfactory bulb, amygdala, lateral habenula and a variety of nuclei in the hypothalamus, express circadian rhythms in core clock gene expression, hormone output and electrical activity. This review examines the evidence for extra-SCN circadian oscillators in the mammalian brain and highlights some of the essential properties and key differences between brain oscillators. The demonstration of neural pacemakers outside the SCN has wide-ranging implications for models of the circadian system at a whole-organism level.

Forebrain oscillators ticking with different clock hands

“…Differences of expression may originate in a differential role for both proteins as respective mutants show altered patterns of Cry1 expression in ad libitum and HF conditions. It reinforces the growing hypothesis that there is not one single clock, but a system of multiple brain oscillators (Roenneberg and Merrow, 2003;Guilding and Piggins, 2007) ticking with different clock hands and differentially sensitive to nutritional cues. It would be interesting to distinguish between motivational and metabolic responses to hypocaloric feeding and their interpretation in each forebrain region.…”

“…A number of extra-SCN oscillators have been identified in the mammalian forebrain (reviewed in Guilding and Piggins, 2007). Here we found that PER1 immunoreactivity (IR) is observed alone in the DMH, aPirC and dST and concomitant with PER2 in the PVT, CA1, DG, CEA and Arc.…”

“…A number of extra-SCN oscillators have been identified in the mammalian brain (reviewed in Guilding and Piggins, 2007). For instance, rhythmic expression of Per1 and Per2 mRNA is observed in forebrain structures such as olfactory bulbs, piriform and cerebral cortices, hippocampus, paraventricular and arcuate hypothalamic nuclei (Asai et al, 2001;Wakamatsu et al, 2001;Abe et al, 2002;Granados-Fuentes et al, 2004).…”

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

“…Abnormal rhythms of melatonin secretion has been associated with childhood and adult ADHD. 9,10 Cortisol circadian profiles have been reported to be either unaltered in ADHD 12 or altered in association primarily with the hyperactive subtype of ADHD. 13,14 The molecular basis of such circadian rhythm generation consists of positive and negative transcriptional/translational feedback loops of 'clock' genes and their protein products, and single-nucleotide polymorphism in clock genes have been associated with ADHD.…”

“…11 The master clock is in the suprachiasmatic nuclei (SCN) of the hypothalamus and it is entrained to the 24 h day via retinal photic input with further semiautonomous oscillators present throughout the brain and periphery. 12 SCN output is responsible for driving circadian rhythms in a number of hormones, including melatonin and cortisol. Abnormal rhythms of melatonin secretion has been associated with childhood and adult ADHD.…”