Trends in Cognitive Sciences
ReviewCircadian clocks: genes, 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
References (88)
The meter of metabolism
Cell
(2008)- et al.
The contribution of sleep to hippocampus-dependent memory consolidation
Trends Cogn. Sci.
(2007) Are spatial memories strengthened in the human hippocampus during slow wave sleep?
Neuron
(2004)Mechanisms of sleep-dependent consolidation of cortical plasticity
Neuron
(2009)- et al.
Sleep function and synaptic homeostasis
Sleep Med. Rev.
(2006) - et al.
Cellular oscillators: rhythmic gene expression and metabolism
Curr. Opin. Cell Biol.
(2005) Cellular circadian pacemaking and the role of cytosolic rhythms
Curr. Biol.
(2008)Large ventral lateral neurons modulate arousal and sleep in Drosophila
Curr. Biol.
(2008)Modeling of a human circadian mutation yields insights into clock regulation by PER2
Cell
(2007)PER3 polymorphism predicts sleep structure and waking performance
Curr. Biol.
(2007)