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)
A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder
Neurosci. Lett.
Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder
Biol. Psychiatry
Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus
Curr. Biol.
Coordinated transcription of key pathways in the mouse by the circadian clock
Cell
Circadian orchestration of the hepatic proteome
Curr. Biol.
Proteomic analysis reveals the role of synaptic vesicle cycling in sustaining the suprachiasmatic circadian clock
Curr. Biol.
Circadian regulation of gene expression systems in the Drosophila head
Neuron
Microarray analysis and organization of circadian gene expression in Drosophila
Cell
The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei
Cell
Extensive and divergent effects of sleep and wakefulness on brain gene expression
Neuron
Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood
Curr. Biol.
Circadian time-place learning in mice depends on Cry genes
Curr. Biol.
The circadian timekeeping system of Drosophila
Curr. Biol.
Sleep and circadian rhythms in humans
Cold Spring Harb. Symp. Quant. Biol.
Medical and genetic differences in the adverse impact of sleep loss on performance: ethical considerations for the medical profession
Trans. Am. Clin. Climatol. Assoc.
The genetics of mammalian circadian order and disorder: implications for physiology and disease
Nat. Rev. Genet.
When clocks go bad: neurobehavioural consequences of disrupted circadian timing
PLoS Genet.
Two decades of circadian time
J. Neuroendocrinol.
Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day
Am. J. Physiol.
Relationship between alertness, performance, and body temperature in humans
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Sleep and wakefulness out of phase with internal biological time impairs learning in humans
J. Cogn. Neurosci.
Sleep, memory, and plasticity
Annu. Rev. Psychol.
Boosting slow oscillations during sleep potentiates memory
Nature
Odor cues during slow-wave sleep prompt declarative memory consolidation
Science
Sleep in Drosophila is regulated by adult mushroom bodies
Nature
The organization of recent and remote memories
Nat. Rev. Neurosci.
Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila
Science
Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep
Nat. Neurosci.
Does the morning and evening oscillator model fit better for flies or mice?
J. Biol. Rhythms
The genetic and molecular regulation of sleep: from fruit flies to humans
Nat. Rev. Neurosci.
Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans
Nat. Med.
An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome
Science
Behavior of period-altered rhythm mutants of Drosophila in light:dark cycles
J. Insect Behav.
Molecular mapping of point mutations in the period gene that stop or speed up biological clocks in Drosophila melanogaster
Proc. Natl. Acad. Sci. U. S. A.
Cited by (134)
An association study of clock genes with major depressive disorder
2023, Journal of Affective DisordersEffects of fluoxetine on fish: What do we know and where should we focus our efforts in the future?
2023, Science of the Total EnvironmentChronobiology of Sleep – Circadian Rhythms, Behavior, and Performance
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionGenetic effects
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionLighting up living spaces to improve mood and cognitive performance in older adults
2022, Journal of Environmental PsychologyCircadian rhythm sleep–wake disturbances and depression in young people: implications for prevention and early intervention
2021, The Lancet PsychiatryCitation Excerpt :Rodent models have shown that lesioning the suprachiasmatic nuclei abolishes circadian control of body temperature and sleep–wake cycles, suggesting the central role of the suprachiasmatic nuclei in the circadian system.22 The suprachiasmatic nuclei receives direct input from intrinsically photosensitive retinal ganglion cells, which relay light information from the eyes to brain circuits that regulate mood and sleep–wake cycles among other functions.7,8,23 These cells have a specific sensitivity to blue light.23