Review
Circadian clocks: genes, sleep, and
cognition
Charalambos P. Kyriacou1 and Michael H. Hastings2
1
Department of Genetics, University of Leicester, Leicester LE1 7RH, UK
2
MRC Laboratory of Molecular Biology, Division of Neurobiology, Cambridge CB2 0QH, UK
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 eukar-
yotes has revealed a conserved intracellular mechanism
that, if disrupted by mutation, can have significant
implications for mental and physical health. These mol-
ecular clocks tick away in different brain areas, and their
circadian phases and anatomical relationships to the
central brain pacemakers indicate new ways for under-
standing the mechanisms of interaction between circa-
dian clocks, sleep and cognition.
Clocks and human health
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), the circadian
rhythms driven by the pacemaker continue relentlessly,
but can be resynchronised (entrained) by lighting sche-
dules, by feeding-related or social cues. Under normal
circumstances, these periodic signals ensure that the cir-
cadian system and the rhythms that it drives are synchro-
nised with the outside world, anticipating and preparing
for the challenges and opportunities that day and night
present. Disruptions to the circadian clock or its entrain-
ment, for example during shift work or jet lag, disturb sleep
and lead to physiological and cognitive malaise. The con-
sequences of this desynchronisation are evident in the
workplace, leading to serious, sometimes fatal, accidents
due to compromised alertness or problem solving [1,2].
More widely, several neurological, neurodegenerative
and psychiatric conditions are characterised by perturbed
sleep, and systemic illnesses such as cardiovascular dis-
ease and metabolic syndrome can also carry a circadian
component [3–5].
In this review, we shall describe briefly the underlying
molecular-genetic basis of the circadian oscillator, and
Corresponding author: Kyriacou, C.P. (cpk@leicester.ac.uk).
1364-6613/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tics.2010.03.007 Trends in Cognitive Sciences 14 (2010) 259–267
show how induced and natural genetic variants can disrupt
not only circadian behaviour and sleep, but also learning
and memory, mood and metabolism. We shall focus our
discussion predominantly on the mammal, drawing
occasionally on the fly because it has played the major role
in the identification of clock genes. Our principal focus,
however, will be on the recently discovered local circadian
clocks across the brain and peripheral organs and their
relationship to the hypothalamic master-oscillator, the
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 sleep on non-
24-h schedules so that their internal  24-h clock systematically drifts in and
out of phase with sleep time.
Free-running: Under constant conditions such as darkness, the circadian clock
‘free-runs’ with its own endogenous period. A free-running period is thus free
from its usual entrainment stimuli (light and temperature cycles).
Hypertension: Elevation of blood pressure.
Internal synchronisation: Clocks in different tissues are often set in different
phases, reflecting the cyclical functions of each organ. This synchrony needs to
be maintained for optimal performance and health.
Kinase: The enzyme that phosphorylates a protein.
Negative feedback: A product, usually a protein, negatively regulates its own
gene transcription.
Orthologue: A gene in species 1 is said to be orthologous to a gene in species 2
if it was derived from a common ancestral sequence.
Paralogue: A gene within a species is paralogous to another one in the same
species if they were derived by duplication of a common ancestral sequence.
Period ( per): The first clock gene identified in higher organisms, originally in
the fly, but later in mammals (see Box 1).
Phosphatase: An enzyme that dephosphorylates a protein.
Phosphorylation: The addition of phosphate groups to a protein.
Pleiotropy: A gene mutation can have many effects on apparently unrelated
phenotypes.
Polymorphism: In genetics this refers to DNA variation in a gene sequence.
Every human gene is polymorphic, meaning that somewhere, somebody will
carry a different sequence for gene X.
Post-translational: After a protein is translated, it is often modified, for
example by phosphorylation.
Procedural memory: Long-term memory of procedures or skills.
Proteome: The entire set of proteins expressed by a genome within a tissue of
interest.
REM: Rapid eye movement phase of sleep lasting between 90 and 120 minutes.
NREM: Non rapid eye movement. The three phases of sleep in which there is
no REM, and which is electroencephalographically (EEG) distinct from REM.
SCN: Suprachiasmatic nuclei, the master clock in mammals situated in the
hypothalamus.
SWS: Slow wave sleep, the last phase of NREM sleep, in which deep sleep
occurs, and characterised by delta waves in the EEG.
Transcriptome: The entire set of RNA molecules that are transcribed from a
tissue of interest.
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suprachiasmatic nuclei (SCN) [6]. For decades it has been
known that the SCN is crucial for rhythmic locomotor beha-
viour and physiology in mammals, and indeed cycling clock
gene expression can be visualised in the neurons of the SCN
using sophisticated gene-reporter systems [6]. However,
what has become clear is that different regions of the brain,
or peripheral organs such as the liver, kidneys and heart,
also have local clocks that utilise the same basic molecular
components as the SCN. The role of the SCN is to keep these
local clocks in synchrony, with each other and with the solar
cycle. We will explore the inter-relations among these local
molecular circadian clocks, the SCN, and the rhythmic
phenotypes of sleep and cognitive performance.
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 intimate and pervasive regulator
of cognition and mood, with roles far beyond the timing of
sleep. Before addressing the relationship between sleep
and cognitive and emotional states, however, let us present
the crucial evidence that the circadian oscillator mediates
cognitive performance directly, as well as indirectly,
through sleep.
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 cogni-
tion has been revealed by clever ‘forced desynchrony pro-
tocols’ 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 the sleep and
wakefulness schedules (e.g. 20 h or 28 h), so it breaks away
and free runs at its intrinsic period of ca 24 h (Figure 1a).
The consequent disengagement between intervals of sleep/
wakefulness and the circadian timer means that over the
course of several experimental weeks, sleep and wakeful-
ness will occur at all phases of the circadian cycle. Cru-
cially, this protocol provides the opportunity to assess
mental function across all circadian phases, independently
of time since awakening [7,8]. In addition, performance can
be assessed simply as a function of time spent awake,
collapsed across all circadian phases. Such studies effec-
tively take sleep out of the equation and provide a rela-
tively uncontaminated measure of sleep-independent

Figure 1. Forced desynchrony protocols reveal circadian clock control over cognition and vigilance that is independent of time spent awake. (a) Schematic representation of
forced desynchrony protocols in which subjects are forced to sleep on a 28- or a 20-h cycle. Consequently times of sleep (coloured bars) and wakefulness scan across all
phases of the circadian cycle, as monitored by peak of melatonin secretion and nadir of core body temperature which free run at their intrinsic period of ca 24 h. (b) Double
plots of experimental data for cognitive throughput (addition/subtraction test ADD) and psychomotor vigilance task (PVT) plotted (left) relative to circadian phase and
independent of wake time, and (right) wake time independent of circadian phase. Plotted points show deviation from mean values so the lower the point the greater the
impairment. Lower graph shows median reaction time during a 28 h forced desynchrony schedule in a reaction time task. Dotted lines show performance during the
circadian temperature trough and filled lines during the temperature peak. Note pronounced circadian modulation of performance. Redrawn with permission from Refs
[7,8]. (c) Prolonged loss of synchrony between circadian phase and sleep cycle compromises cognitive performance. Redrawn with permission from Ref [9].

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effects of the clock upon cognitive and emotional state. The
important finding and one that runs counter to the ‘clocks
only work through sleep’ hypothesis, is that cognitive
competence varies systematically across circadian time
even when time spent awake has been controlled. Con-
versely, these studies also show that, as expected, once
circadian time has been controlled, our mental abilities
and emotional state are sensitive to time spent awake,
declining with prolonged wakefulness. In addition to the
independent effects of circadian time and duration of
wakefulness, better cognitive performance is associated
with higher core body temperature, that is itself a reflec-
tion of optimal metabolic function [9]. Finally, when sleep
does occur at inappropriate stages of the circadian cycle,
learning over the course of several weeks is impaired [9].
The interplay between the independent effects of the clock
and wakefulness therefore operates both acutely, over the
course of hours, and also chronically, affecting performance
over many days. The following sections will therefore focus
on a series of points. First, what is the relationship of sleep
to memory formation, without considering the clock other
than as a timer of sleep? Second, what is the genetic nature
of the clock and what are the consequences of clock gene
mutations on sleep and other functions? Third, we shall
then consider the role of local clocks throughout the brain
as the mediators of the combined effects of sleep and
circadian phase on cognition, closing with an exploration
Box 1. Simplified generic higher eukaryotic intracellular transcription/translational oscillator model
The generic higher eukaryotic model in a generic clock cell has two
negative regulators (N1 and N2) and two positive regulators (Clock (C)
and BMAL1 (B, also known as CYCLE in the fly)) that bind the
promoters of the negative regulators. The N regulators are tran-
scribed during the day (ZT1-12, Zeitgeber time ZT 12, is dusk and
ZT24/0 is dawn on a 12:12 light–dark cycle). The mRNAs are
transported to the cytoplasm and translated into their respective N1
and N2 proteins early at night (ZT14). However a series of kinase
modulators, M, phosphorylate the N proteins and alter their
stabilities, leading to, in the case of N1, degradation via ubiquitination
and the proteosome (dustbin). As the night proceeds, the N1 and N2
proteins stabilise each other by dimerising (ZT18). The N1, N2 and M
components translocate back to the nucleus, and sequester C and B,
thereby repressing their own N1 and N2 genes (ZT22). At dawn
(ZT24+), a photoreceptor, P, is activated, and this will enhance the
destabilisation by a modulator, M, of the N regulators (at least in the
fly). A different set of Ms will also destabilise N1 and N2 at subjective
dawn even under constant darkness (DD). In the absence of stable N1
and N2, C and B can bind the N1 and N2 promoters and begin the next
circadian cycle of transcription/translation. The M-mediated delay
between N mRNA and protein peaks is necessary otherwise the
negative regulators would feed back within a few hours (not 24) to
shut down their own transcription Figure I.
In flies, per and tim are the N1 and N2 molecules respectively,
whereas in mammals there are three transcribed mPer (mPer1–3, N1),
and two Cryptochrome genes (mCry1–2, N2). In both organisms, a
crucial modulator M is CK1 that tags N molecules for degradation. This
key event provides a necessary delay into the feedback loop. Other
kinases and phosphatases are also involved in modulating N stability,
as are ubiquitin ligases. The net result of all these post-translational
modifications to N proteins is that as they are generated in the early
night they are eliminated, and this puts the molecular feedback loop on
‘hold’ for a few hours. If we take the fly as the best understood example,
after a few hours of PER being phosphorylated by CK1e and then
degraded during the early to middle of the night phase, levels of TIM
(N2) rise before PER, and these TIM molecules start to dimerize with the
Trends in Cognitive Sciences Vol.14 No.6
of current views on cAMP signalling as a biochemical
substrate for this phenomenon.
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 pro-
cedural 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 hippocampal
circuits that occurs in association with consolidation of
memory, in both human and animal studies. For example,
the characteristic neural activation observed when spatial
navigation tasks are learned during the waking phase is
‘re-played’ during SWS and the intensity of this replay is
correlated with the degree of memory consolidation [12].
Boosting slow oscillations by trans-cranial stimulation
during sleep can even improve the consolidation of declara-
tive memory [13]. Moreover, by using olfactory cues to
provide a context association during the learning of a
declarative task, the degree of consolidation can be
enhanced by presentation of the odour during SWS [14].
It is probable that the mechanisms underlying
sleep-dependent consolidation of memory share common
available PER molecules. This effectively protects PER molecules from
further phosphorylation and degradation, and so PER levels build up by
continuing to dimerise with TIM. Eventually, late at night, the PER-TIM
dimer moves into the nucleus and represses the transcription of its own
genes, per and tim, by interfering with the actions of the positive
factors, CLOCK (C) and CYCLE (B).
In flies, the photoreceptor P is Cryptochrome (CRY), it is activated
by light and interacts physically with TIM (N2), leading to TIM, and
subsequently PER degradation, as the latter is now exposed to CK1e
phosphorylation. As PER/TIM levels fall during the day, CLOCK and
CYCLE resume their transcription of per and tim, and the transcrip-
tion–translation cycle starts again. In mammals, P is melanopsin, and
signals to the SCN via the retinohypothalamic tract, leading to acute
upregulation of mPer [85]. One of the C and B molecules in each
species is also regulated in a cyclical manner by other activator/
repressors, providing an interconnection of loops that seems to
mutually stabilise and reinforce these molecular cycles (from [4,86]).
Figure I. Simplified generic circadian oscillator in higher eukaryote.
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Review
elements with other examples of sleep-dependent synaptic
plasticity, for example the establishment of ocular dom-
inance in the developing visual cortex [15]. Similarly in
Drosophila, sleep regulation and memory consolidation
share the cAMP pathway as well as the same anatomical
substrate, the mushroom bodies [16]. In mammals, one
proposal is that during SWS the hippocampus and neo-
cortex enter a dialogue that binds together cortical
modules relevant to the memory, and with repetitive
transfers during sleep episodes the centre of gravity of a
memory migrates from hippocampus to cortex [17]. Thus,
the most recent memories are more sensitive to sleep
disturbance. The second model, the synaptic homeostasis
hypothesis, proposes that SWS globally suppresses, rather
than enhances, synaptic connectivity, providing a counter-
weight to the progressive increase in synaptic connectivity/
function inherent to new learning during the waking state
[18]. This would retain strong signal-to-noise ratios in
recently active (i.e. memory-relevant) pathways, even
though absolute synaptic strength might decline, while
Box 2. Distributed local clocks throughout the brain, synchronised by the SCN pacemaker, underpin the interactions between
sleep, circadian timing and cognition
(a) Schematic representation of the network of local circadian clocks
widely distributed across brain centres implicated in sleep and
wakefulness (brain stem, thalamus ventrolateral pre-optic area
(VLPO), and cerebral cortex) and cognition (cerebral cortex, hippo-
campus). Dispersed cell groups in the VLPO, which express the
peptide galanin, are likely to be mediators of the homeostatic drive
(the ‘need’) to sleep. By contrast, the noradrenergic locus coeruleus
(LC), serotonergic raphe nuclei (SRN) in the brain stem and the
histaminergic tubero-mammillary nucleus (TMN) and orexinergic
cells of the hypothalamus, promote wakefulness. These sleep- and
activity-promoting sites interact antagonistically in the manner of a
flip-flop switch, such that activity within the two groups is mutually
exclusive: if one is on, the other is off. The internal structure of sleep,
in particular the switching between REM and nonREM (NREM or
SWS) every 90 minutes, could also involve a flip-flop switch, in this
Figure I. Local clocks in mammalian brain.
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at the same time re-scaling global synaptic potential to
its normal and most effective operating range. Recent work
in Drosophila has revealed that synaptic proteins accumu-
late during the waking state or sleep deprivation, and are
reset with sleep [19], mirroring a similar synaptic turnover
process in cortical and hippocampal regions of the rat brain
[20].
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 consists of a delayed
negative feedback loop, incorporating rhythmic transcrip-
tion, translation and post-translational processes. Cru-
case between mutually inhibitory REM-on and REM-off areas in the
mesopontine tegmentum (reviewed in [87]). The balance between the
competing systems that promote either sleep or wakefulness is
governed by their spontaneous activity, prior wakefulness (‘sleep
debt’) and the demands of the circadian programme. Thus, for the
entire network to operate effectively, sustaining the global states of
sleep and wakefulness, the circadian programmes in all areas have to
be synchronised, one to another, and to external solar time. This is
achieved by coordinating signals that emanate from the ‘master’
pacemaker of the SCN Figure I.
(b) Representative bioluminescence recordings from organotypic
slices in culture confirm the presence of autonomous local clocks in
some relevant brain areas, whereas in other regions their presence is
inferred from the expression of clock genes and proteins.
Figure redrawn from [6,87].
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Table 1. Sleep and cognitive phenotypes of clock mutants

Clock gene Organism Cognitive/Sleep phenotype of mutant
period (per) fly LTM in courtship conditioning compromised [53], and circadian rhythm in STM in olfactory conditioning
predictably affected by period ( per) and timeless (tim) mutants [61]. per mutant does not sensitize to
cocaine nor do cycle, Clk or dbt (CK1e) mutants [67].
cycle fly Hypersensitive to lethal effects of sleep deprivation [68].
(BMAL1)
Bmal1 mouse Disrupted sleep and abnormal response to sleep deprivation [69].
Clock mouse Mania and hyperactivity [39]. Defects in sleep homeostasis [70].
Clock human Polymorphism in 30 untranslated region associated with increased ‘eveningness’ in 620 bipolar and major
depressive disorder patients [71].
NPas2 mouse NPas2 is a Clock paralogue and mutations disrupt cued and contextual fear conditioning [72]. Alters
nocturnal sleep pattern [60].
NPas2 human Association with autism in 110 parent–child trios [73].
Period1 mouse Reduced sensitization to cocaine [74]. Defective in hippocampus-dependent long-term spatial learning paradigm.
Period1 human Haplotype associated with autism [73].
Period2 mouse Mutation reduces MAOA levels thereby increasing dopamine levels in mesolimbic system and gives a
‘depression resistant’ phenotype [75]. Also mutant disrupts gutaminergic uptake by astrocytes and leads to
increased alcohol consumption [76]. Increased sensitization to cocaine [74]. Recall of trace but not cued
fear conditioning affected [77].
Period2 human Mutation in CKI binding region (S662G) gives FASPS [27].
Period3 human Repeat polymorphism associated with DSPS [33] and time of onset of bipolar disorder [38].
Cry1-Cry2 mouse Double Cry mutant disrupts time–place learning [78] and sleep homeostasis [79].
CK1d human Threonine to Alanine mutation gives Advanced Sleep Phase Syndrome (ASPS) and shorter rhythm [80].
Opn4 mouse Melanopsin photoreceptor deletion affects photic regulation of sleep [81].
Dbp mouse Clock output gene expressed cyclically in SCN and periphery and modulates circadian output. Mutant affects
sleep homeostasis and consolidation [82].
Pk2 mouse Rhythmic SCN output molecule – mutant shows disruption in REM and NREM sleep and homeostasis [83].
Dec2 human Negative regulator of CLK-BMAL1 in circadian clock. Proline to Arginine mutation (P385R) causes ‘short
sleeping’ phenotype [84].
Dec2 mouse P385R ‘short-sleeping’ mutation shows enhanced wakefulness, disruption of REM/NREM sleep, attenuated
rebound to sleep deprivation and increased vigilance. Driving the mouse Dec2 mutation in fly also gives less
sleep than control [84].

cially, it drives the oscillatory expression of many down-
stream target genes and proteins, and it is these factors
which in turn produce the rhythmic output of the cell, be it
an electrical firing rhythm in a neuron, or a metabolic cycle
in a liver cell. In Drosophila, the small 150 neuronal
networks crucial for rhythmic locomotor behaviour are
understood at genetic and molecular levels and have
recently been interrogated physiologically [23,24]. It pro-
vides a simpler model than its mammalian counterpart,
the SCN which, with its 10000 neurons, is established as
the master oscillator, sustaining and synchronising local
rhythms across central nervous system (CNS) and periph-
eral tissues (Box 2).
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 circum-
stances, 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 sub-
sequently discovered and studied for their circadian and
homeostatic effects on sleep (Table 1). Nevertheless, it has
proved difficult to determine the neural site of action of
these disruptions. Are they effective in the SCN, in local
circuits or in both, and do indirect pleiotropic effects (see
below), rather than the circadian programme, play a sig-
nificant role?
Familial Advanced Sleep Phase Syndrome (FASPS) is
an excellent example of a principally circadian influence on
sleep. It is an autosomal dominant condition which
advances the habitual sleep phase by several hours under
normal living conditions and shortens the endogenous
cycle by 2 h [26]. Remarkably, the mutation maps to
the human period2 (hPer2) gene, which encodes one of
the three mammalian PER proteins, which act as regula-
tors of the clock mechanism (see Box 1 and Table 1). The
relevant mutation involves a Serine to Glycine missense
mutation in a casein kinase 1 (CK1) binding region [27].
This is reminiscent of the original 19 h pers mutation in the
fly, in which a Serine is mutated to an Asparagine in the
corresponding Doubletime (DBT, also known as CK1e)
binding region, accelerating the clock and, in a 24-h world,
causing a phase advance in the behavioural rhythm
[28,29]. In FASPS, there is decreased phosphorylation of
hPER2 with implications for increased hPer2 transcrip-
tion, hPER2 turnover and reduced nuclear retention that
speed up the clock [27,30]. Conversely, FASPS can also be
caused by mutation in the kinase, CK1d, that phosphor-
ylates hPER2 [31].
A second disorder, Delayed Sleep Phase Syndrome
(DSPS), which has the opposite phenotype to FASPS,
has been associated with several polymorphisms in the
major clock genes (Table 1). Encoded within human
period3 (hPer3), a tandem 18 residue motif containing a
putative CK1 site, is found in 4 or 5 copies. In Japanese and
English subjects, DSPS is associated with the shorter 4-
copy variant [32,33], whereas in Brazil, it is the opposite,
leading to speculation as to whether latitude could be
relevant via a photoperiodically-related environmental
factor [34]. In Europeans, homozygous hPer35/5 repeat
carriers show changes in sleep structure and poorer

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Figure 2. Schematic model for temporally convergent circadian and sleep-dependent regulation of cognitive function. The encoding of information during the waking
phase and the subsequent consolidation of relevant information during sleep are dependent upon contrasting capacities for molecular and electrical signalling. Efficient
alternation between these processes is mediated by circadian coordination. First, the SCN pacemaker entrained to solar time synchronises subordinate local clocks across
the forebrain, which in turn govern local, tissue-specific circadian transcriptomes that determine local capacities for molecular and electrical signalling. Second, the SCN
also modulates the flip-flop switches governing sleep/wakefulness and consequently these alternating brain states are timed to occur coincidently with the expression of
molecular and electrical signalling pathways that best serve their respective neural demands. Misalignment of sleep/wakefulness with circadian phase or genetic
perturbation of the clock mechanism in the SCN and/or locally, will compromise efficient acquisition and encoding of information, and/or consolidation of memory.

performance in cognitive function after sleep loss [35,36].
Tantalisingly, structurally similar amino acid repeats
occur in the per gene of Drosophila species, and these seem
to play a role in accommodating the fly clock to tempera-
ture variation at different latitudes [37]. Mood disorders
have also been cautiously linked to the hPer3 repeat poly-
morphism (e.g. Table 1 [38]), although most of these types
of studies have been small scale and often contradictory
[3,4]. However, the Clk mutant mouse shows behavioural
symptoms of mania, probably mediated by dopaminergic
hyperactivity in the ventral tegmental area [39]. Much of
the stimulus for this psychiatric approach to the clock
comes from observations that circadian rhythms in sleep
onset and temperature rhythms are often disrupted in
mental illness and neurodegeneration, and that sleep
interventions and light therapy in patients or rodent
models can have acute beneficial effects [40,41].
Surveys of the mammalian circadian transcriptome and
proteome reveal that many metabolic enzymes are circa-
dian-regulated and so the effects of clock mutations might
be expected to be more widespread than simply disrupting
sleep phenotypes [42–46]. For example, the normal rhythm
of food intake in Clk mutant mice is disturbed, leading to
obesity and metabolic syndrome [47]. Connections of the
SCN to the appetite centres in the mediobasal hypothala-
mus are implicated, where mRNA levels of appetite-
related neuropeptides are also reduced significantly in
Clk mutants [47]. The important link between cell metab-
olism and the clock is further evidenced by disturbed
glucose metabolism in Clk or Bmal1 mutants [48] and in
human studies implicating polymorphisms in hClk in
metabolic syndrome and obesity [49], and hBmal1 in hy-
pertension and type-2 diabetes [50].
Thus clock mutations can have serious repercussions,
not simply limited to sleep problems. Most of these dis-
orders are probably due to clock defects, but the possibility
remains that some phenotypes could be truly pleiotropic
and independent of the clock per se. For example, in clock
mutant Drosophila, not only do the 150 cycling target
genes in the head cease their mRNA rhythms, but several
hundred non-cycling transcripts also alter their expression
levels, and some of these genes, we imagine, might not be
associated with circadian phenotypes [51,52]. Thus there is
plenty of scope for clock gene pleiotropy, as observed with
arrhythmic per mutants in Drosophila which show poor
performance in a conditioning paradigm that measures
long-term memory (LTM), whereas other arrhythmic clock
mutants: tim, Clk and cyc (the fly’s BMAL1 orthologue; Box
1, Table 1) are normal [53]. Consequently the effect of per
on this type of memory consolidation would seem to be
clock-independent.
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 mech-
anisms, 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

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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 distributed across the brain, including cerebral cortex,
hippocampus and cerebellum [6]. Hence, the circadian
contribution to cognition probably arises not from ‘the’
clock, but from many clocks. Cognitive performance would
then be dependent on their synchronised activities and,
ordinarily, this internal synchronisation will be imposed
by the SCN pacemaker (Figure 2). Mutations in canonical
clock genes might disrupt the intrinsic functions of local
clocks and/or the SCN pacemaker, or compromise their
behaviour as an integrated network, as in Vpac2 receptor
mutants [54]. Additionally, mutations might conceivably
impair cognition by altering the phase relationship of the
clocks to the cycle of sleep and wakefulness. Finally, by
analogy with studies of the clocks in peripheral organs,
environmental influences such as jet lag and rotational
shift work will lead to a transient loss of phase coherence
both among individual brain clocks, and between the clocks
and sleep episodes, thereby compromising temporal order
and leading to suboptimal cognitive performance and
encoding of information [11,55].
What, therefore, might be the role of the subsidiary clocks
in the cortex, hippocampus and elsewhere? An analogy
exists with the peripheral clock in the liver, which is syn-
chronised to the SCN and drives daily cycles of hepatic gene
and protein expression [42,45,56,57]. Local enzymatic
activity is thus phase-locked to, and hence able to anticipate,
the alternating and conflicting energetic demands of wake-
fulness and sleep, feeding and fast. These abilities to anticip-
ate and to separate competing metabolic demands in time
are key adaptive properties of local clocks. In mice, in which
the liver clockwork is genetically compromised, glucose
homeostasis is temporally disrupted and the waking phase
is characterised by hypoglycaemia, because the ‘clockless’
liver is unable to up-regulate glucose mobilisation in anticip-
ation of SCN-driven physical activity [58].
The same model of temporal partitioning of cellular
functions can be applied to the brain. During daily wakeful-
ness, the predominant brain activity is the real-time acqui-
sition, processing and response to stimuli. These activities
will be supported by a specific profile of gene and protein
expression, with a focus on rapid synaptic signalling, and
short-term cognitive processes typically dependent on post-
translational modifications (e.g. phosphorylation [20]). Con-
versely, during sleep, external stimuli become less relevant
and both global and local neural firing patterns change
dramatically. Short–term memories are consolidated into
more permanent patterns and this is typically dependent
upon de novo gene and protein expression and accompany-
ing synaptic rewiring [59]. Hence, the ‘omic’ profiles
required to sustain the activities of the waking brain are
very different from those associated with, and necessary for,
sleep and its associated consolidation of memory. The adap-
tive value of the local clocks is that they are able to orches-
trate these changes in tissue-specific ways, anticipating and
preparing for the circadian transitions between sleep and
wakefulness. Because the phases of these distributed brain
clocks are set by the central pacemaker of the SCN, daily
cycles of local gene expression are synchronised and orche-
Trends in Cognitive Sciences Vol.14 No.6
strated across the entire neuraxis, thereby sustaining the
global transitions in brain function that underpin sleep and
wakefulness, and cognition. In this regard, clocks can be
viewed as transcriptomic nodes: the central SCN pacemaker
does not need to encode all of the information required to up-
and down-regulate gene expression across the brain because
it delegates that role to the local clockworks which rely on
the SCN solely for their appropriate time cues.
There are several strong predictions arising from this
model. First, compromise of the local clock machinery by
genetic, pharmacological or other means will reduce the
efficiency of temporal adaptation and impair cognitive
function. A good example here is NPAS-2, a cycling para-
logue of Clock that is expressed at very low levels in the
SCN [88] but at high levels in the forebrain, and which in
NPAS2-deficient mice leads to sleep disturbance and atte-
nuated behavioural adaptability ([60], Table 1). Second,
environmental factors, such as jet lag or shift work sche-
dules that disrupt the normally synchronous waves of gene
expression among areas, will also confound temporal adap-
tation. In both circumstances, mental functions, both cog-
nitive and affective, will be perturbed.
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 view on the inter-relation-
ship between clocks, sleep and cognition? Among the variety
of signal transduction cascades implicated in the formation
of memory and induction of long-term potentiation (LTP),
one particular pathway stands out: that from glutamate
receptor activation, via Ca++ and cAMP, to the control of
MAP kinases (MAPK) and their activation of the transcrip-
tional regulator CREB [61,62] (Figure 3). Deficits at all
points in this process can compromise memory consolidation
and its electrophysiological correlates. It is therefore very
significant that in the mouse hippocampus, the activation of
MAPK, cAMP levels and CREB activation are under circa-
dian regulation, peaking during circadian daytime, coinci-
dent with sleep [63]. This regulation by local clocks
recapitulates the circadian control over these molecular
pathways in the SCN, where Ca++ and cAMP rhythms could
constitute part of the pacemaking mechanism and not
simply one of its outputs [64]. Importantly, consolidation
of hippocampus-dependent learning is least effective when
this cascade in the hippocampus is at its circadian trough,
and local interference with the circadian oscillation within
the cAMP/MAPK/CREB pathway can impair the persist-
ence of hippocampus-dependent memory [63]. Thus, circa-
dian reactivation of this signalling pathway, coincident with
sleep, might be important for the persistence of contextual
memory and consolidation. Furthermore, mice deprived of
sleep exhibit a selective impairment of cAMP-dependent
LTP, and this correlates with reduced levels of cAMP and
increased activity of phosphodiesterase 4 (PDE4) [65]. Inhi-
265
 Review
Figure 3. Schematic model for the central role of cAMP-dependent signalling as a
convergent point for the interplay between the circadian clock and sleep in
regulating cognition. Glutamatergic signalling within the hippocampus regulates
long-term potentiation, in part via a cAMP-dependent signalling cascade. The
expression of crucial components of the cascade, including MAPK and CREB are
under circadian regulation that will sustain circadian changes in the strength of
LTP induction (as reported for example in [3]). In parallel to the circadian cycle of
cAMP signalling, hippocampus-dependent memory formation is also circadian in
its effectiveness. Suppression of circadian cAMP signalling compromises memory
formation, whereas sleep deprivation, an established disruptor of memory
formation, in parallel, interferes with cAMP-dependent LTP.
bition of PDE can rescue both LTP and hippocampal-de-
pendent memory in sleep-deprived animals. These recent
findings indicate novel ways to understand the interlinked
roles of clocks, signalling and neural circuits in cognition.
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 hippocampal-dependent
memory? After all, if the cortex were set to ‘day mode’ and
the hippocampus to ‘night mode’, how would they ever link
up and function as a unit? We suspect that in the next few
years we will see these relationships clarified in mouse
models, with some significant contributions also coming
from studies of the fly. We hope that it will be soon be
possible to describe the cognitive and affective con-
sequences of temporal desynchronisation in terms more
explicit than just ‘feeling bad’.
Acknowledgements
CPK and MHH thank the BBSRC, MRC and EUCLOCK (EU FP6 project
018741) for grant support.
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