Review
Circadian clocks: genes, sleep, and cognition

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The endogenous circadian clock modulates cognitive performance over the daily 24-h cycle. Environmental disturbance of the clock, such as shift work or jet lag schedules, compromises sleep, alertness and problem solving. What is not generally appreciated, however, is that the circadian clock also modulates cognitive activity independently of time spent awake. The molecular identification of circadian clock genes in higher eukaryotes has revealed a conserved intracellular mechanism that, if disrupted by mutation, can have significant implications for mental and physical health. These molecular clocks tick away in different brain areas, and their circadian phases and anatomical relationships to the central brain pacemakers indicate new ways for understanding the mechanisms of interaction between circadian clocks, sleep and cognition.

Section snippets

Clocks and humanhealth

It is common experience that our cognitive performance and mood vary predictably over the daily, 24-h cycle. These rhythms are intimately linked with our cycle of sleep and wakefulness and are driven by our internal circadian clock, a biological pacemaker with a period of approximately (circa) one day (dian). The intrinsic properties of this pacemaker are best revealed by holding experimental subjects (human and animal) in temporal isolation. Under such ‘free-running’ conditions (see Glossary),

Cognition and clocks: is it all about sleep?

Although it is well established that cognitive abilities of humans and experimental animals vary as a function of time of day (reviewed in [1]), there is still a widespread view that the clock has a singular role in cognition: that of controlling the timing of sleep. Once it has established an appropriate sleeping pattern, the clock falls out of the equation and all that matters for cognitive maintenance is the quality and duration of sleep. By contrast, our thesis is that the clock is a more

Circadian control of cognition beyond sleep timing

By controlling sleep, the clock will inevitably influence cognition, and decrements in cognitive performance during periods of circadian instability would presumably be due to the associated sleep deprivation. However, the more direct and fundamental influence of the circadian clock on cognition has been revealed by clever ‘forced desynchrony protocols’ in which subjects sleep on non-24-h schedules 7, 8. The human circadian clock cannot run at these rather extreme experimental cycles adopted by

Sleep and memory consolidation

In general, restorative sleep tunes up cognitive function during the subsequent waking phase, and the following consolidation of memory is sleep-dependent, both for procedural and declarative memory 10, 11. In both animal and human studies, declarative memory is sensitive to loss of slow wave sleep (SWS), otherwise termed ‘non rapid eye movement’ (NREM) sleep whereas REM might contribute more to procedural memory. A crucial observation is the sleep-dependent reactivation of cortical and

The intracellular clock

What is the intracellular clock and what are its molecular components? What do we know of it and how might it fit into the general scheme? The basic features of the higher eukaryotic molecular clock have been endlessly reviewed 3, 5, 21, 22, and are described briefly in Box 1, from which it is clear that the intracellular molecular mechanisms are largely conserved, with evolution tweaking or swapping the roles of some of these clock components among taxa. The basic oscillatory mechanism

Mutations in clock genes: sleep and other disorders

The rhythm of sleep is driven by an interaction between the circadian clock and the homeostatic drive (‘need’) for sleep [25]: Box 2 shows several sleep relevant pathways and their relationship to the SCN. Under normal circumstances, appropriate circadian control of neural activity across these sites ensures a smooth daily progression of the cycle. With the identification of clock genes in flies and mammals, natural genetic variants in humans were subsequently discovered and studied for their

Local brain clocks: are they the orchestrators of sleep- and wake-dependent cognition?

As noted above, optimal cognitive performance depends on temporal alignment between sleep and clock-driven mechanisms, but the sophistication and complexity of this relationship is underlined further by the recent discovery that the SCN is not the only brain pacemaker. Molecular and real-time bioluminescent imaging approaches have shown that most major organs contain the same (or roughly the same) molecular-feedback pacemaker as that within the SCN. Moreover, local semi-autonomous clocks are

The clock, cAMP, memory and sleep

Our thesis, therefore, is that optimal mental function requires the temporal alignment between local clock control over neuronal functions appropriate for the ongoing states of sleep and wakefulness. To achieve this coincidence, the SCN plays a central role: it determines the timings of sleep and wakefulness and simultaneously synchronises the multitude of local brain clocks to a complementary circadian programme. Is it possible, therefore, to take one candidate cellular pathway to explore this

Future prospects

As noted by Eckel-Mahan and Storm [66], how the SCN matches the synchronisation of local brain clocks to the daily programme of behaviour and sleep, and how local clocks contribute to temporal regulation of synaptic plasticity, are major unanswered questions. Is it the case that tight circadian synchronisation of neural programmes across brain areas is required to enhance the cortico-hippocampal circuit-based, redistributive processes that are thought to underlie sleep- and

Acknowledgements

CPK and MHH thank the BBSRC, MRC and EUCLOCK (EU FP6 project 018741) for grant support.

Glossary

cAMP signalling
Second messenger synthesised from ATP by adenylyl cyclase, which activates PKA (protein kinase A) allowing it to phosphorylate its targets.
Declarative memory
Memory of facts that have been stored and can be discussed (declared), for instance textbook memory.
EEG
Electroencephalogram.
Entrainment
A free-running clock, once placed under an environmental cycle, for example LD (light dark) 12:12, will entrain to this 24-h rhythm.
Forced desynchrony
A situation in which subjects are made to

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