Ritmo Circadiano 012

NE35CH21-Takahashi ARI 14 May 2012 14:57
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1
Department of Neuroscience, 2 Howard Hughes Medical Institute, University of Texas
Southwestern Medical Center, Dallas, Texas 75390-9111;
email: Jennifer.Mohawk@UTSouthwestern.edu, Carla.Green@UTSouthwestern.edu,
Joseph.Takahashi@UTSouthwestern.edu
Annu. Rev. Neurosci. 2012. 35:445–62 Keywords

First published online as a Review in Advance on clock genes, suprachiasmatic nucleus, oscillator coupling, metabolism,
April 5, 2012
temperature
The Annual Review of Neuroscience is online at
neuro.annualreviews.org Abstract
This article’s doi:
The circadian system of mammals is composed of a hierarchy of oscilla-
10.1146/annurev-neuro-060909-153128
tors that function at the cellular, tissue, and systems levels. A common
Copyright c 2012 by Annual Reviews.
molecular mechanism underlies the cell-autonomous circadian oscilla-
All rights reserved
tor throughout the body, yet this clock system is adapted to different
0147-006X/12/0721-0445$20.00
functional contexts. In the central suprachiasmatic nucleus (SCN) of
the hypothalamus, a coupled population of neuronal circadian oscilla-
tors acts as a master pacemaker for the organism to drive rhythms in
activity and rest, feeding, body temperature, and hormones. Coupling
within the SCN network confers robustness to the SCN pacemaker,
which in turn provides stability to the overall temporal architecture of
the organism. Throughout the majority of the cells in the body, cell-
autonomous circadian clocks are intimately enmeshed within metabolic
pathways. Thus, an emerging view for the adaptive significance of cir-
cadian clocks is their fundamental role in orchestrating metabolism.
445
a transcriptional autoregulatory feedback loop.

Contents In mammals, these include Clock, Bmal1, Per1,
Per2, Cry1, and Cry2. Researchers have iden-
INTRODUCTION . . . . . . . . . . . . . . . . . . 446
tified another dozen candidate genes that play
MOLECULAR MECHANISM
additional roles in the circadian gene network
OF THE CIRCADIAN CLOCK
such as the feedback loop involving Rev-erbα.
IN MAMMALS . . . . . . . . . . . . . . . . . . . 447
Early work on mammalian rhythms used
CENTRAL CIRCADIAN
rhythmic behavior as a readout of the clock,
OSCILLATORS . . . . . . . . . . . . . . . . . . 448
and the hypothalamic suprachiasmatic nucleus
Suprachiasmatic Nucleus . . . . . . . . . . . 448
(SCN) was identified as the dominant circadian
PERIPHERAL CLOCKS . . . . . . . . . . . . . 451
pacemaker driving behavioral rhythms (Welsh
ORGANIZATION OF THE
et al. 2010). However, the discovery of “clock
CIRCADIAN SYSTEM . . . . . . . . . . . 451
genes” led to the realization that the capac-

Neural Control of Peripheral
ity for circadian gene expression is widespread

Oscillators: The Autonomic
throughout the body (Dibner et al. 2010). Us-
Nervous System . . . . . . . . . . . . . . . . 452
ing circadian gene reporter methods, one can
Hormonal Control
demonstrate that most peripheral organs and
of Peripheral Oscillators . . . . . . . . . 453
tissues can express circadian oscillations in iso-
Temperature . . . . . . . . . . . . . . . . . . . . . . 453
lation yet still receive, and may require, input
Behavioral and Homeostatic
from the SCN in vivo. The cell-autonomous
Regulation: Local Cues Feed
clock is ubiquitous, and almost every cell in
Back into the Clock . . . . . . . . . . . . . 454
the body contains a circadian clock (Balsalobre
OTHER OSCILLATORS:
et al. 1998, Nagoshi et al. 2004, Welsh et al.
FOOD AND DRUGS . . . . . . . . . . . . . 455
2004, Yoo et al. 2004). It is now evident that
The Food-Entrainable Oscillator . . . 455
the circadian oscillators within individual cells
The Methamphetamine-Sensitive
respond differently to entraining signals, con-
Circadian Oscillator . . . . . . . . . . . . . 456
trol different physiological outputs, and interact
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . 457
with each other and with the system as a whole.
These discoveries have raised a number of ques-
tions concerning the synchronization and co-
herence of rhythms at the cellular level as well
INTRODUCTION as the architecture of circadian clocks at the sys-
Circadian rhythm: Living systems possess an exquisitely accurate tems level (Hogenesch & Ueda 2011). Here we
an endogenously internal biological clock that times daily events discuss recent work that addresses these organi-
generated oscillation ranging from sleep and wakefulness in humans zational issues and examines a number of levels
with a period of ∼24 h;
to photosynthesis in plants (Takahashi et al. of complexity within the circadian system. We
can entrain to external
cues and is 2008). These circadian rhythms represent an review mechanisms by which circadian clocks
temperature evolutionarily conserved adaptation to the en- govern biological processes as well as mecha-
compensated vironment that can be traced back to the earli- nisms by which these processes feed back into
Suprachiasmatic est life forms. In animals, circadian behavior can the circadian system. Perhaps the most impor-
nucleus (SCN): be analyzed as an integrated system—beginning tant example of this is the intimate and recip-
the site of the master with genes and leading ultimately to behavioral rocal interaction between the circadian clock
circadian pacemaker in
outputs. In the past 15 years, the molecular system and fundamental metabolic pathways
mammals, comprising
∼20,000 individual mechanism of circadian clocks has been uncov- (Bass & Takahashi 2010, Green et al. 2008,
neurons that couple to ered by the use of phenotype-driven (forward) Rutter et al. 2002). In addition, there exist ad-
form a robust genetic analysis in a number of model systems ditional oscillatory processes in the circadian
oscillatory network (Lowrey & Takahashi 2011). Circadian oscilla- time domain that are observable in the pres-
tions are generated by a set of genes forming ence of scheduled meals or methamphetamine
446 Mohawk · Green · Takahashi

CYTOPLASM
RORs REV-ERBs
RORs
RRE Bmal1 REV-ERBs
BMAL1 CLOCK
β-TrCP
E-box Rorα SCF
CK1
+Ub 26S
Repression E-box Rev-erbα
PERs Proteosome
E-box Per1/Per2
AMPK
CRYs +Ub 26S

E-box Cry1/Cry2 FBXL3
SCF
PER
CRY Nuclear PER
CK1ε/δ translocation CRY
CK1ε/δ
BMAL1 CLOCK
Clock outputs/
E-box Ccg
rhythmic biological processes
NUCLEUS
Figure 1
The molecular mechanism of the circadian clock in mammals. Constituting the core circadian clock is an autoregulatory transcriptional
feedback loop involving the activators CLOCK and BMAL1 and their target genes Per1, Per2, Cry1, and Cry2, whose gene products
form a negative-feedback repressor complex. In addition to this core transcriptional feedback loop, other feedback loops are also driven
by CLOCK:BMAL1. One feedback loop involving Rev-erbα and Rorα that represses Bmal1 transcription leads to an antiphase
oscillation in Bmal1 gene expression. CLOCK:BMAL1 also regulates many downstream target genes known as clock-controlled genes
(Ccg). At a post-transcriptional level, the stability of the PER and CRY proteins is regulated by SCF (Skp1-Cullin-F-box protein) E3
ubiquitin ligase complexes involving β-TrCP and FBXL3, respectively. The kinases, casein kinase 1ε/δ (CK1ε/δ) and AMP kinase
(AMPK), phosphorylate the PER and CRY proteins, respectively, to promote polyubiquitination by their respective E3 ubiquitin ligase
complexes, which in turn tag the PER and CRY proteins for degradation by the 26S proteasome complex.
treatment. These oscillators can generate be- of this clock network are the transcriptional ac-
havioral rhythms in vivo in the absence of the tivators, CLOCK (and its paralog, NPAS2) and
SCN (Honma & Honma 2009). BMAL1, which positively regulate the expres-
sion of the Period (Per1, Per2) and Cryptochrome
(Cry1, Cry2) genes at the beginning of the
MOLECULAR MECHANISM cycle. Per and Cry gene products accumulate,
OF THE CIRCADIAN CLOCK dimerize, and form a complex that translocates
IN MAMMALS into the nucleus to interact with CLOCK
In mammals, the mechanism of the circadian and BMAL1, repressing their own transcrip-
clock is cell autonomous and arises from an tion. This feedback cycle takes ∼24 h, and the
autoregulatory negative-feedback transcrip- turnover of the PER and CRY proteins is tightly
tional network (Lowrey & Takahashi 2004, regulated by E3 ubiquitin ligase complexes.
Takahashi et al. 2008) (Figure 1). At the core There are additional feedback loops interlocked
www.annualreviews.org • Circadian Clocks In Mammals 447

with the core CLOCK-BMAL1/PER-CRY insensitive to transient light signals that are
loop. Prominent among these is a loop in- not associated with the solar light cycle. Al-
volving Rev-erbα (Nr1d1) and Rora, which are though ipRGCs appear to be optimal circadian
also direct targets of CLOCK-BMAL1. The photoreceptors, they do not act alone; rod and
feedback effects of this loop impinge on the cone photoreceptors also have photic inputs to
transcription of Bmal1 (and to a lesser extent the SCN. Interestingly, these nonvisual inputs
on Clock) to cause an antiphase oscillation of from rods and cones to the SCN are mediated
BMAL1. Other feedback loops involve the by the ipRGCs (Chen et al. 2011, Guler et al.
PAR-bZip family members, DBP, HLF, and 2008). An emerging theme is that melanopsin-
TEF; the bZip protein, E4BP4 (Nfil3); and the positive ipRGCs are involved in a surprisingly
bHLH proteins, DEC1 and DEC2 (Bhlhb2, broad array of nonvisual photic responses in
Bhlhb3), all of which are transcriptional targets mammals. The complexity of the ipRGCs and
of CLOCK-BMAL1 (Gachon 2007, Lowrey their contribution to circadian rhythms and

& Takahashi 2004, Takahashi et al. 2008). other behaviors are beyond the scope of this
The discovery of a ubiquitous, cell- discussion, but recent reviews have covered this
autonomous clock in mammals has led to a re- topic in depth (Do & Yau 2010, Schmidt et al.
evaluation of central and peripheral oscillators: 2011).
Are they fundamentally similar in mechanism,
how do they function in different cellular con-
texts, and what role does coupling in the central Suprachiasmatic Nucleus
SCN clock play in its functional properties? The SCN is composed of ∼20,000 neurons,
each of which is thought to contain a cell-
autonomous circadian oscillator. The SCN
CENTRAL CIRCADIAN functions as a network in which the population
OSCILLATORS of SCN cells are coupled together and oscillate
The hypothalamic SCN acts as a master pace- in a coherent manner (Herzog 2007). The
maker for the generation of circadian behav- dynamics of the spatial and temporal coordina-
ioral rhythms in mammals (for a review, see tion of rhythms in the SCN have been studied
Welsh et al. 2010). Classic work not reviewed recently, enabled by the advent of single-cell
here has shown that the SCN is both neces- circadian reporter technology, which has re-
sary and sufficient for the generation of circa- vealed unexpected complexity in the temporal
dian activity rhythms in rodents. The SCN re- architecture of the nucleus (Evans et al. 2011,
ceives direct photic input from the retina from Foley et al. 2011, Yamaguchi et al. 2003). At the
a recently discovered photoreceptor cell type single-cell level, SCN neurons exhibit a wide
termed the intrinsically photoreceptive retinal range in cell-autonomous circadian periods
ganglion cell (ipRGC) (reviewed in Do & Yau that vary from 22 h to 30 h (Ko et al. 2010, Liu
2010). These ipRGCs express a novel photopig- et al. 1997, Welsh et al. 1995). Intercellular
ment, melanopsin, that renders them intrinsi- coupling among SCN neurons acts to mutually
cally photosensitive to short-wavelength irradi- couple the entire population to a much nar-
ation. Interestingly, ipRGCs are depolarizing rower range that corresponds to the circadian
photoreceptors that employ a phototransduc- period of the locomotor activity rhythm, which
tion mechanism that is analogous to that seen is extremely precise (a standard deviation
in invertebrate photoreceptors. The photore- in period that is ∼0.2 h or 12 min in mice)
sponse in ipRGCs has slow kinetics and a rel- (Herzog et al. 2004). The heterogeneity in
atively high threshold to light, making them intrinsic period of the SCN cells confers at least
ideally suited to function as circadian photore- two important functions: phase lability and
ceptors, which must integrate light informa- phase plasticity. The phases of the rhythms of
tion over relatively long durations and must be individual SCN neurons are highly stereotyped

anatomically and appear as a wave that spreads these mutations are non-cell autonomous. This
across the nucleus over time (Evans et al. 2011, occurs as a consequence of the intercellular cou-
Foley et al. 2011, Yamaguchi et al. 2003). pling in the SCN network, which is capable of
Intrinsically shorter-period cells have earlier rescuing a cell-autonomous defect in the indi-
phases and intrinsically longer-period cells vidual cells (Figure 2). This transformation of
have later phases within the SCN, reflecting the oscillatory capability of SCN neurons from
phase lability (Yamaguchi et al. 2003). Under damped to self-sustained is an important illus-
different photoperiods (e.g., long- versus short- tration of the robustness of the SCN network.
photoperiod light cycles), the waveform of the Indeed, Ko et al. (2010) have found that the
SCN population rhythm is modulated such SCN network is capable of generating oscilla-
that in short photoperiods the SCN waveform tions in the circadian domain in the complete
is narrow and has a high amplitude, whereas absence of cell-autonomous oscillatory poten-
in long photoperiods the SCN waveform is tial. In Bmal1-knockout mice, which are ar-
broad and has a low amplitude, reflecting phase rhythmic at the behavioral level, SCN explants
plasticity (Inagaki et al. 2007, VanderLeest unexpectedly express stochastic oscillations in
et al. 2007). In addition to the heterogeneity of the circadian range that are highly variable.
SCN oscillator period and phase, it has been When the individual cells are no longer rhyth-
proposed that the cell-autonomous SCN os- mic, the coupling pathways within the SCN
cillators are not intrinsically uniformly robust network can propagate stochastic rhythms that
(Webb et al. 2009). Rather, the intercellular are a reflection of both feed-forward coupling
coupling of SCN neurons appears critical to mechanisms and intracellular noise. Thus, in
the robustness of the SCN network oscillatory a manner analogous to central pattern genera-
system. tors in neural circuits, rhythmicity can arise as
With the discovery of peripheral oscilla- an emergent property of the network in the ab-
tors (Balsalobre et al. 1998, Yamazaki et al. sence of the component pacemaker or oscillator
2000, Yoo et al. 2004) and the apparent ubiq- cells.
uity of clock mechanisms (Yagita et al. 2001), In addition to the generation of sustained os-
a critical question arises concerning the simi- cillations by the SCN network, the SCN is also
larity and differences in the SCN pacemaker as robust to perturbations from environmental
compared with peripheral oscillators. To ad- inputs. In wild-type mice, the phase-resetting
dress this question, Liu et al. (2007a) exam- curve to light pulses is characteristic of Type
ined whether canonical clock mutations pre- 1 or weak resetting (low amplitude) (Vitaterna
viously assessed in vivo affected the SCN and et al. 2006). This is a reflection of the robust-
peripheral oscillators in a similar manner. Us- ness of the SCN pacemaker because inputs
ing Per2::luciferase reporter mice, they found such as light can perturb the phase of the
that the effects of the Period and Cryptochrome oscillation only to a limited extent. In contrast,
loss-of-function mutations were the same in genetic mutations that lower the amplitude
SCN explants as those seen previously at the of the molecular oscillation in the SCN lead
behavioral level. By contrast, in peripheral tis- to increases in the sensitivity to light-induced
sues, single loss-of-function mutations that are phase shifts (Type 0 resetting) without chang-
subtle at the behavioral level, such as Per1 or ing the strength of the light signals impinging
Cry1 knockouts, produced very strong loss-of- on the SCN (Vitaterna et al. 2006). Similar
rhythm phenotypes. Interestingly, the effects of effects are seen with temperature cycles.
these mutations are cell autonomous in both Peripheral oscillators are exquisitely sensitive
fibroblasts and in isolated SCN neurons, sup- to the phase-shifting effects of temperature and
porting the idea that the cell-autonomous clock can be entrained strongly by low-amplitude
is similar in these two cell types. However, when temperature cycles that are equivalent to the
the SCN population is coupled, the effects of circadian fluctuation in core body temperature

SCN slice Dispersed neurons
a 13
3V
24.5 b 2 14
36 47.5 25 37
c d
13 36 59 82 105 2 25 48 71 94
Time (h) Time (h)
e Wild-type individual neurons

20 60 20
50
50
15 15 15 40
40
10 10 30 10 30
Photons per min
20 20
5 5 5
10 10
0 0 0 0
25 80 40 40
20
60 30 30
15
40 20 20
10
5 20 10 10
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
Time (days)
f Cry1 –/– individual neurons
40 130 90 60
50
30
Photons per min
100 70 40
20
30
10 70 50 20
100 170 100

60 40
140 30
60 60 40
110 20
80 20 10
20 20
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
Time (days)

(∼2.5◦ C oscillation in mice) (Brown et al. in the manner in which these peripheral clocks
2002, Buhr et al. 2010). Interestingly, the SCN are reset and in the output pathways that are
is resistant to entrainment by low-amplitude under their control. These endogenous cellu-
Entrainment:
temperature cycles, and this resistance depends lar clocks drive extensive rhythms of gene tran- synchronization and
on the intercellular coupling of SCN neurons scription, with 3–10% of all mRNAs in a given phase control of a
(Abraham et al. 2010, Buhr et al. 2010). As was tissue showing circadian rhythms in steady- rhythm to a regularly
the case for genetic mutations on the generation state levels (Akhtar et al. 2002, Duffield et al. occurring
environmental cycle
of rhythms, the effects of temperature pertur- 2002, Hughes et al. 2009, Miller et al. 2007,
(usually ∼24 h)
bations on the SCN are cell autonomous when Panda et al. 2002, Storch et al. 2002). However,
intercellular coupling is eliminated. Thus, both the genes that are under circadian control are
SCN and peripheral oscillators are sensitive largely nonoverlapping in each tissue, reflect-
to temperature cycles at the cell-autonomous ing the need for temporal control of the cellu-
level; however, coupling within the SCN lar physiology relevant to each unique cell type.
network confers robustness and makes the As a result, the circadian clock exerts broad-
SCN network resistant to temperature pertur- ranging control over many biological pro-
bations. As discussed below, the temperature cesses, including many aspects of metabolism
resistance of the SCN makes functional sense such as xenobiotic detoxification (Gachon et al.
because the SCN drives the body-temperature 2006), glucose homeostasis (Lamia et al. 2008,
rhythm, and this temperature signal, which Marcheva et al. 2010, So et al. 2009, Turek et al.
can serve as an entraining signal for peripheral 2005), and lipogenesis (Gachon et al. 2011, Le
clocks, may otherwise feed back and interfere Martelot et al. 2009).
with the SCN (Buhr et al. 2010).
ORGANIZATION OF THE
PERIPHERAL CLOCKS CIRCADIAN SYSTEM
Rhythms of clock gene and/or protein ex- For biological clocks to be effective, they must
pression have been observed in cells and tis- accurately keep time and adjust to environ-
sues throughout the body in mammals, and mental signals. In an organized circadian sys-
these rhythms persist in culture, demonstrating tem, this requires SCN control of peripheral
that non-SCN cells also contain endogenous oscillators, and loss of the SCN results in pe-
circadian oscillators (Balsalobre et al. 1998, ripheral circadian clocks that become desyn-
Yamazaki et al. 2000, Yoo et al. 2004). Al- chronized (Yoo et al. 2004). However, tissue-
though the core clock machinery is conserved specific gene expression patterns are likely to
in these different cellular clocks, there are sig- be regulated by both “local” as well as cen-
nificant differences in the relative contributions tral mechanisms. This concept was elegantly
of the individual clock components, as well as demonstrated through genetic disruption of the
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 2
Network and autonomous properties of suprachiasmatic nucleus (SCN) neurons. Network properties of the SCN can compensate for
genetic defects affecting rhythmicity at the cell-autonomous level. (a) Bioluminescence images of a Cry1−/− SCN in organotypic slice
culture. Note the stable, synchronized oscillations. Numbers indicate hours after start of imaging; 3V indicates the third ventricle.
(b) Bioluminescence images of dissociated individual Cry1−/− SCN neurons showing cell-autonomous, largely arrhythmic patterns of
high bioluminescence intensity. (c,d ) Heat-map representations of bioluminescence intensity of individual Cry1−/− neurons in an (a)
SCN slice and (b) dispersed culture. Values above and below the mean are shown in red and green, respectively, for 40 SCN neurons in
each condition. (e,f ) Ten single SCN neuron rhythms from (e) wild-type and ( f ) Cry1−/− mice. Imaging began immediately following a
media change at day 0. Dissociated Cry1−/− SCN neurons are largely arrhythmic, whereas dissociated wild-type cells are rhythmic. By
contrast, in organotypic slice cultures, both wild-type and Cry1−/− SCN cells are robustly rhythmic and tightly synchronized. Figure
and legend adapted and reprinted from Liu et al. (2007a), with permission from Elsevier.

SCN synchronize these systems, and SCN transplant

studies (Ralph et al. 1990, Silver et al. 1996) and
parabiosis experiments in mice (Guo et al. 2005)
have demonstrated that both humoral and non-
humoral pathways are important for SCN coor-
dination of circadian output rhythms. In addi-
Feeding tion, complex feedback loops link the circadian
clock with rhythmic metabolic networks, in-
Autonomic Body
Glucocorticoids tegrating these systems in a light-independent
innervation temperature
(HSF1) Homeostatic manner. Circadian control of metabolism oc-
regulation curs at the central (SCN) as well as local levels
(metabolites, nuclear receptors)
and involves clocks within a number of periph-
eral tissues including the liver, pancreas, skele-

tal muscle, intestine, and adipose tissue (for

a review, see Bass & Takahashi 2010, Green
et al. 2008). This intimate relationship between
clocks and metabolism is an example of how the
circadian “system” is integrated with, and influ-
Figure 3 enced by, the physiology that is under its con-
Pathways of peripheral clock entrainment. The master circadian pacemaker trol. Therefore, organization of the circadian
within the suprachiasmatic nucleus (SCN) relays temporal information to system requires a combination of (a) autonomic
peripheral oscillators through autonomic innervation, body temperature, innervation of peripheral tissues, (b) endocrine
humoral signals (such as glucocorticoids), and feeding-related cues. signaling, (c) temperature, and (d ) local signals
Independent of the SCN, local signaling pathways can also affect peripheral
oscillators.
(Figure 3).
circadian clock mechanism specifically in the

Neural Control of Peripheral
hepatocytes of mice, while leaving the circa-
Oscillators: The Autonomic
dian clock intact in the SCN and other cell
Nervous System
types throughout the body (Kornmann et al.
2007). Microarray analysis of mRNAs in the The SCN controls peripheral oscillators
livers from these mice demonstrated that the through both sympathetic and parasympathetic
disruption of the circadian molecular feedback pathways (Kalsbeek et al. 2010, Ueyama et al.
loop specifically within the liver results in ar- 1999). SCN projections through the para-
rhythmicity of most hepatic transcripts. Thus, ventricular nucleus–superior cervical ganglia
most circadian oscillations of hepatic function (PVN-SCG) pathway provide the dominant
rely on an intact liver clock. However, a subset entraining signal for the submandibular salivary
of transcripts, including the core clock compo- glands (Ueyama et al. 1999, Vujovic et al. 2008).
nent Per2, continued to cycle robustly even in Sympathetic innervation from the SCN to the
the absence of a functional liver clock. In livers PVN to the liver results in daily rhythms of
maintained in explant culture, rhythms in Per2 plasma glucose, presumably by directly influ-
transcription were observed in livers with intact encing the rhythm of hepatic gluconeogenesis
clocks but were absent in livers with inactivated (Cailotto et al. 2005, Kalsbeek et al. 2004).
clocks. Thus, rhythmic gene expression can be Autonomic pathways from the SCN relay
driven by both local intracellular clocks and by photic information to oscillators in the adrenal
extracellular systemic cues. gland and liver (Buijs et al. 1999, Cailotto et al.
What are these systemic cues? The photi- 2009, Ishida et al. 2005). Sympathetic innerva-
cally entrained SCN is thought to convey sig- tion also modulates the sensitivity of the adrenal
nals to light-insensitive peripheral clocks to to adrenocorticotropic hormone (ACTH) and

directly influences glucocorticoid release (Buijs factor) HNF4α. HNF4α is responsive to

et al. 1999, Kalsbeek et al. 2010, Kaneko et al. glucocorticoids (Reddy et al. 2007), contains
1981). Oscillators in both the adrenal cortex E-boxes, which may allow for transcriptional
PPAR: peroxisome
and medulla respond to neural inputs emanat- control by CLOCK:BMAL1 (Reddy et al. proliferator-activated
ing from the SCN (Buijs et al. 1999, Mahoney 2007), and can interact with PER2 (Schmutz receptor
et al. 2010). The adrenal clock is of particular in- et al. 2010). Other metabolically relevant HSF1: heat shock
terest given the strong case for glucocorticoids nuclear receptors, including peroxisome factor 1
as a humoral entraining signal for peripheral proliferator-activated receptor (PPAR)α, also
clocks. respond to glucocorticoids (Lemberger et al.
1994). Nuclear receptor activation by clock
components and glucocorticoids provides
Hormonal Control another point of circadian input to metabolic
of Peripheral Oscillators
pathways as described below.

Although a number of hormones may have roles

in mammalian circadian organization, gluco- Temperature
corticoids have received the most attention. In most organisms, temperature is a powerful
Rhythmic glucocorticoids result both from the entraining agent for circadian rhythms. How-
sympathetic inputs discussed above and from an ever, in mammals, external temperature cy-
underlying rhythm of corticotropin releasing cles are very weak entraining agents (Refinetti
hormone (CRH) and ACTH function (Kaneko 2010); this has been attributed to the fact that
et al. 1980, Kaneko et al. 1981). The adrenal homeotherms regulate their body temperature
clock also provides temporal control of sensi- and can defend their body temperature against
tivity to ACTH-induced glucocorticoid release environmental fluctuations. It has long been
(Oster et al. 2006). known that body temperature is circadian and
The demonstration that dexamethasone (a the rhythm is driven by the SCN. Peripheral
glucocorticoid analog) could shift the phase oscillators, including fibroblasts, liver, kidney,
of peripheral tissues in vivo (Balsalobre et al. and lung, are exquisitely sensitive to temper-
2000) provided the first definitive evidence that ature changes (Abraham et al. 2010, Brown
glucocorticoids were entraining signals for pe- et al. 2002, Buhr et al. 2010, Kornmann et al.
ripheral oscillators. Dexamethasone was ini- 2007). These oscillators can be strongly reset by
tially shown to shift the phase of clock gene low-amplitude temperature pulses that mimic
expression in the liver, kidney, and heart as the range of circadian variation, and temper-
well as cultured fibroblasts. What provides glu- ature profiles that match circadian body tem-
cocorticoid input into the clock at the local perature rhythms strongly entrain peripheral
level? Glucocorticoid-response elements exist clocks (Brown et al. 2002, Buhr et al. 2010).
in the regulatory regions of the core clock However, as described above, the SCN is re-
genes, Bmal1, Cry1, Per1 (Reddy et al. 2007, sistant to temperature cycles in the circadian
Yamamoto et al. 2005), and Per2 (So et al. 2009). range. Because of this system design, the SCN
These glucocorticoid-response elements may is ideally situated to utilize circadian tempera-
lead to the transcriptional activation of a num- ture cycles as a universal entraining signal for
ber of clock genes and clock-controlled genes peripheral oscillators. The influence of tem-
by glucocorticoids. perature on peripheral oscillators likely occurs
Glucocorticoids can synchronize circa- through the transcription factor heat shock
dian expression of much of the oscillatory factor 1 (HSF1). HSF1 transcriptional activ-
component of the liver transcriptome in ity oscillates with a circadian rhythm in the
SCN-lesioned mice (Reddy et al. 2007). This liver and can be driven by temperature cycles
is accomplished, in part, through activation of (Reinke et al. 2008). HSF1 inhibitors block
the nuclear receptor (and hepatic transcription temperature-induced resetting in extra-SCN

oscillators (Buhr et al. 2010). Because HSF1 is state. These mediators include members of the
influenced by a wide range of signaling path- nuclear receptor family of transcription fac-
ways in the cell (Akerfelt et al. 2010), tempera- tors, many of which exhibit circadian rhythms
NAD: nicotinamide
adenine dinucleotide ture and HSF1 may form a final common path- of transcription within the liver and other
way for the integration of resetting signals in metabolically relevant tissues (Yang et al. 2006).
peripheral clocks. These rhythmic nuclear receptors regulate
transcription of downstream metabolic path-
ways. Among the rhythmic nuclear receptors
Behavioral and Homeostatic are PPARs and members of the REV-ERB and
Regulation: Local Cues Feed ROR families. As described above, RORα and
Back into the Clock REV-ERBα participate directly in the clock
In addition to controlling hormone secretion mechanism by regulating Bmal1 transcription
and body temperature directly, the SCN coor- (Preitner et al. 2002, Sato et al. 2004), but
dinates rhythms in behavioral processes, such as they are also important for many aspects of
locomotor activity and feeding, which can influ- metabolic regulation. Similar to REV-ERBs
ence endocrine function and body temperature. and RORs, many of the other rhythmic nu-
These behaviors, feeding in particular, can reg- clear receptors are regulators of clock func-
ulate peripheral clocks at the local level, mod- tion, providing a mechanism by which signals
ulating local signaling pathways and metabolic of metabolic status can influence rhythmicity.
processes. Homeostatic signaling pathways also Glucocorticoid receptors, as discussed above,
affect peripheral clocks and their function, al- induce transcription of Per and potentially a
lowing for extra SCN control of circadian pro- number of other clock and clock-controlled
cesses. Studies in which mealtime has been ex- genes (Reddy et al. 2007, So et al. 2009, Ya-
perimentally manipulated to occur antiphase to mamoto et al. 2005). PPARα, which responds
the normal SCN-driven feeding rhythm have to lipid status and glucocorticoids, may also reg-
attempted to elucidate local mechanisms for ulate Bmal1 transcription (Canaple et al. 2006).
controlling clocks in peripheral tissues. PPARγ coactivator-1α (PGC-1α, a tran-
The liver clock, unlike the SCN, is partic- scriptional coactivator) provides a link between
ularly sensitive to resetting by feeding. Hep- the clock and changes in metabolic status.
atic rhythms of clock gene and protein ex- PGC-1α is critical for adaptive responses to nu-
pression rapidly shift their phase to follow the tritional and metabolic state, particularly fol-
timing of a scheduled meal (Damiola et al. lowing fasting (reviewed in Lin et al. 2005).
2000, Stokkan et al. 2001). Similarly, livers of PGC-1α is rhythmic and activates expression
Cry1/Cry2-null mice display rhythms in many of Bmal1 and Rev-erbα through coactivation of
transcripts (including a number of transcripts RORs (Liu et al. 2007b). PGC-1α-null mice
involved in metabolic processes) when fed in display disruptions in a number of circadian
regular 24-h intervals (Vollmers et al. 2009). outputs including locomotor activity, oxygen
Feeding appears to result in cues that by- consumption rate, and expression of both clock
pass the core circadian feedback loop to drive and metabolic genes (Liu et al. 2007b). PGC-
these rhythms. These cues may include feeding- 1α also interacts with SIRTUIN 1 (SIRT1),
induced changes in temperature and HSF1 ac- a nicotinamide adenine dinucleotide (NAD)-
tivity (Kornmann et al. 2007) or activation of dependent histone deacetylase (Rodgers et al.
other metabolically sensitive pathways. 2005).
A number of local mediators of both core Another mechanism by which metabolic
clock components and clock-controlled rhyth- signals can feed into the clock is through
mic transcripts have been identified, and can the adenosine monophosphate-activated pro-
respond to SCN-driven inputs as well as lo- tein kinase (AMPK) (Bass & Takahashi 2010).
cal signals related to homeostasis and metabolic This kinase is a central mediator of metabolic

signals. AMPK activity is robustly rhythmic in polyADP-ribosylates CLOCK and appears

mouse liver and is regulated by nutrient status, to temporally regulate the interaction of
as reflected in the ratio of AMP to ATP. Ac- CLOCK:BMAL1 with PER2 and CRYs. The
tive AMPK directly regulates the central clock circadian regulation of PARP-1 by feeding,
mechanism by phosphorylating and destabiliz- and subsequent consequences for the circadian
ing the clock component CRY1 (Lamia et al. clock, are likely not entirely mediated through
2009). NAD+ . Regardless of the mechanism, PARP-1
Cellular redox state can also serve as a mech- provides another way for metabolic signals to
anism by which the metabolic status of the cell influence timekeeping by the core molecular
can impact the circadian system. NAD levels clock.
exhibit circadian oscillations in the liver, likely
owing to transcriptional regulation of nicoti-
OTHER OSCILLATORS:
namide phosphoribosyltransferase (Nampt, en-

FOOD AND DRUGS
coding the rate-limiting enzyme in the

NAD+ salvage pathway) by CLOCK:BMAL1 The circadian system consists of a web of inter-
(Nakahata et al. 2009, Ramsey et al. 2009). connected oscillators and feedback loops. The
NAD levels also vary with cellular redox state core molecular clock within cells keeps time and
as a consequence of metabolic changes, which, responds to cues from the SCN (through neu-
in turn, can directly impact clock function. The ral, hormonal, and activity-driven pathways) as
ratio of NAD+ to NADH influences binding well as signals from the local cellular environ-
of NPAS2:BMAL1 and CLOCK:BMAL1 to ment. These cell- and tissue-level clocks result
DNA in vitro, suggesting one way in which in rhythms of physiologically relevant outputs,
NAD could interact with clock components including glucose production, fat storage, and
(Rutter et al. 2001). hormone production. These outputs, in turn,
NAD+ -dependent SIRT1 also displays become circadian time-keeping cues relayed to
daily oscillations and feeds back onto the other clocks throughout the body, likely ul-
circadian clock. SIRT1 forms a complex with timately feeding back to the central nervous
CLOCK:BMAL1, leading to the deacetylation system and the SCN. Under normal circum-
of PER2 (Asher et al. 2008) and BMAL1 stances, the SCN maintains temporal organi-
(Nakahata et al. 2008). SIRT1 also suppresses zation of body temperature, activity, feeding,
CLOCK:BMAL1-mediated transcription, and neural output rhythms. This keeps local
resulting in decreased expression of Per2 and systemic circadian signals aligned. In the
(Nakahata et al. 2008, Ramsey et al. 2009) and absence of the SCN, however, the system be-
the clock-controlled gene Dbp (Nakahata et al. comes disorganized. Activity is nonrhythmic
2008). and peripheral tissues and cells drift out of phase
Another molecule with NAD+ -sensitive with one another. There are two striking ex-
activity, poly(ADP-ribose) polymerase 1 ceptions to this phenomenon. Scheduled, re-
(PARP-1), was recently shown to interact with stricted feeding and chronic administration of
the circadian clock (Asher et al. 2010). PARP-1 methamphetamine, a psychostimulant drug of
activity is rhythmic in the liver, and this rhythm abuse, are both capable of organizing the circa-
persists even in the absence of a functional dian outputs in the absence of the SCN.
hepatic circadian clock. The rhythm of PARP-
1 activity can be entrained by scheduled meals,
however, suggesting that the circadian activity The Food-Entrainable Oscillator
of PARP-1 is driven by feeding-related cues. It is not surprising that food and food-related
PARP-1 interacts with CLOCK:BMAL1 in a cues are salient for many biological processes,
rhythmic fashion and inhibits DNA binding by including circadian rhythms. The ability of
the CLOCK:BMAL1 complex. PARP-1 also animals to anticipate food availability is well

established and persists even when food is peripheral tissues. The locus (or loci) of the
provided at a time that is out of phase with the FEO is also unknown. A number of struc-
animal’s normal feeding time (Richter 1922, tures, including the olfactory bulbs (Davidson
FEO: food-
entrainable oscillator Stephan et al. 1979). When food is temporally et al. 2001), the ventromedial hypothalamus
restricted to the daytime (the normal rest (Mistlberger & Rechtschaffen 1984), the
DMH: dorsomedial
hypothalamus period), nocturnal rodents will anticipate the paraventricular thalamic nucleus (Landry et al.
arrival of the meal with an increase in activity; 2007), and a large portion of the digestive sys-
Free-running period:
the period of an if the timing of that meal is shifted, rats will tem (Davidson et al. 2003), have been ruled out.
oscillation in the display transients, gradually shifting their The dorsomedial hypothalamus (DMH) has
absence of entraining food-anticipatory activity bout each day until received considerable attention for its role
signals; reflects the it again precedes the start of food availability. in food entrainment. Data supporting a role
intrinsic period of the
In animals with lesions of the SCN, tem- for the DMH in the generation of food-
oscillator uninfluenced
by environmental poral food restriction will induce circadian anticipatory circadian activity are controversial
timing cues rhythmicity of locomotor behavior (Stephan (Gooley et al. 2006, Landry et al. 2006, Moriya
MASCO: et al. 1979) and an accompanying temperature et al. 2009), and the DMH may not be essential
methamphetamine- rhythm (Krieger et al. 1977). Food-anticipatory for the expression of the FEO (Landry et al.
sensitive circadian activity persists on days of total food depri- 2006, Moriya et al. 2009). The DMH does,
oscillator vation, demonstrating that these cycles are however, interact with the SCN under con-
not merely an hourglass phenomenon but are ditions of food restriction and may influence
driven by an underlying oscillator (Stephan the strength of the FEO output, particularly
2002). This food-entrainable oscillator (FEO) in SCN-intact animals (Acosta-Galvan et al.
can take on pacemaking functions—organizing 2011).
rhythms of activity, body temperature, and
peripheral tissues in SCN-lesioned animals.
Peripheral tissues from both SCN-intact and The Methamphetamine-Sensitive
SCN-ablated mice are sensitive to tempo- Circadian Oscillator
rally restricted feeding. In SCN-intact animals, Chronic or scheduled methamphetamine
phase desynchrony among peripheral oscilla- treatment affects circadian outputs in a manner
tors can occur: Some tissues remain in phase similar to food restriction (Honma & Honma
with the (food-unaffected) SCN, and some fol- 2009). Methamphetamine, provided in the
low the phase of food availability (Damiola drinking water of rats and mice, is capable of
et al. 2000, Pezuk et al. 2010). Cues related driving circadian rhythms of locomotor behav-
to the meal must be the dominant entrain- ior in the absence of the SCN (Honma et al.
ing signals in this latter group of tissues. In 1987, Tataroglu et al. 2006). In SCN-intact
SCN-lesioned mice, food entrainment orga- animals, this appears as a lengthening of the
nizes rhythms throughout the periphery, and free-running period of locomotor activity,
stable phase relationships are observed among and in some cases, two activity components
tissues (Hara et al. 2001, Pezuk et al. 2010). (relatively coordinated with each other) are
Interestingly, the FEO does not appear observed. Much like the FEO, these rhythms
to require a functional molecular clock, as persist when the stimulus (in this case, metham-
Bmal1−/− and Per1/Per2−/− mice can entrain phetamine) is withdrawn (Tataroglu et al. 2006)
to restricted feeding (Pendergast et al. 2009, as well as in the absence of a functional molec-
Storch & Weitz 2009). The mechanism ular clock (Honma et al. 2008, Mohawk et al.
by which food drives oscillatory behavior 2009). The methamphetamine-sensitive circa-
throughout the organism is unknown. It is pos- dian oscillator (MASCO) is capable of func-
sible that the FEO exploits some of the same tioning as a pacemaker driving rhythms in lo-
pathways used by the SCN, such as hormone- comotor activity, body temperature, endocrine
and temperature-dependent cues, to organize function, and the oscillators of peripheral

tissues (Honma et al. 1988, Pezuk et al. 2010). idea is supported both genetically—circadian
In the presence of the SCN, methamphetamine mutants have metabolic phenotypes—and
results in desynchrony among internal os- environmentally—nutrient intake can mod-
cillators, as some follow the SCN and some ulate circadian rhythms (Bass & Takahashi
follow the presumed phase of the MASCO 2010). In recent years, considerable progress
(Pezuk et al. 2010). When the SCN is ablated, has been made in unraveling the connections
however, the MASCO organizes oscillators in between the circadian clock and metabolism.
tissues throughout the organism, resulting in a The role of circadian clocks in governing many
coordinated system (Pezuk et al. 2010). other physiological systems has been estab-
The site of the MASCO is also unknown. It lished, but is far less well characterized.
is possible that the FEO and MASCO share an We still know very little about how oscil-
anatomical and mechanistic basis, or, indeed, lators and timing cues are integrated at the
that they represent a single oscillator. Research local and organismal levels to coordinate the
focused on understanding how the MASCO circadian architecture of the animal. Periph-
and FEO relay circadian information to pe- eral clocks must balance (sometimes conflict-
ripheral tissues will likely uncover novel (or un- ing) inputs arising from the SCN with those
derappreciated) mechanisms that control circa- signaling local cellular and metabolic state.
dian rhythms. The role of these oscillators in Moreover, recent work has revealed that the
the absence of food restriction and metham- cell-autonomous oscillator, which normally lies
phetamine must also be determined. It is un- at the foundation of the circadian clockwork,
likely that these oscillators are dormant under is not absolutely crucial for the expression
normal conditions; instead, the FEO, MASCO, of rhythms by other components of the sys-
and SCN probably cooperate in a hierarchically tem. Within the SCN, coupling among indi-
organized, perhaps necessarily redundant, tim- vidual neurons gives rise to a heterogeneous,
ing network. yet elegantly organized, robust oscillatory net-
work, which can overcome impaired rhythmic-
ity at the cellular level (Ko et al. 2010, Liu
SUMMARY et al. 2007a). Food- and drug-sensitive oscil-
It is now clear that there is feedback at nearly lators (FEO, MASCO) can influence circadian
every level of the circadian system. “Outputs” rhythms and drive rhythmic outputs in the ab-
such as body temperature and feeding become sence of the core molecular clock mechanism
inputs to other oscillators and are capable of (Honma et al. 2008, Mohawk et al. 2009, Pen-
influencing the core molecular clockwork, gen- dergast et al. 2009, Storch & Weitz 2009). The
erating complex interconnectivity between the ability of rhythmic circadian outputs to per-
circadian system and the biological outputs it sist in the absence of the SCN necessitates that
controls. Reciprocity between the circadian and any model of the circadian network include al-
metabolic systems makes it likely that pertur- ternative mechanisms for controlling circadian
bations in one system affect the other. This rhythms at the cell, tissue, and organism levels.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holding that
might be perceived as affecting the objectivity of this review.
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Annual Review of
Contents Neuroscience
Volume 35, 2012
The Neural Basis of Empathy

Boris C. Bernhardt and Tania Singer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Cellular Pathways of Hereditary Spastic Paraplegia
Craig Blackstone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
Functional Consequences of Mutations in Postsynaptic Scaffolding

Proteins and Relevance to Psychiatric Disorders
Jonathan T. Ting, João Peça, and Guoping Feng p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
The Attention System of the Human Brain: 20 Years After
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Primary Visual Cortex: Awareness and Blindsight
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Evolution of Synapse Complexity and Diversity
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Social Control of the Brain
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Under Pressure: Cellular and Molecular Responses During Glaucoma,
a Common Neurodegeneration with Axonopathy
Robert W. Nickells, Gareth R. Howell, Ileana Soto, and Simon W.M. John p p p p p p p p p p p 153
Early Events in Axon/Dendrite Polarization
Pei-lin Cheng and Mu-ming Poo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 181
Mechanisms of Gamma Oscillations
György Buzsáki and Xiao-Jing Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 203
The Restless Engram: Consolidations Never End
Yadin Dudai p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227
The Physiology of the Axon Initial Segment
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Attractor Dynamics of Spatially Correlated Neural Activity in the
Limbic System
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Neural Basis of Reinforcement Learning and Decision Making
Daeyeol Lee, Hyojung Seo, and Min Whan Jung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287
vii
NE35-FrontMatter ARI 21 May 2012 11:24
Critical-Period Plasticity in the Visual Cortex

Christiaan N. Levelt and Mark Hübener p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 309
What Is the Brain-Cancer Connection?
Lei Cao and Matthew J. During p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 331
The Role of Organizers in Patterning the Nervous System
Clemens Kiecker and Andrew Lumsden p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 347
The Complement System: An Unexpected Role in Synaptic Pruning
During Development and Disease
Alexander H. Stephan, Ben A. Barres, and Beth Stevens p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Brain Plasticity Through the Life Span: Learning to Learn and Action
Video Games
Daphne Bavelier, C. Shawn Green, Alexandre Pouget, and Paul Schrater p p p p p p p p p p p p p 391
The Pathophysiology of Fragile X (and What It Teaches Us about
Synapses)
Asha L. Bhakar, Gül Dölen, and Mark F. Bear p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417
Central and Peripheral Circadian Clocks in Mammals
Jennifer A. Mohawk, Carla B. Green, and Joseph S. Takahashi p p p p p p p p p p p p p p p p p p p p p p p p 445
Decision-Related Activity in Sensory Neurons: Correlations Among
Neurons and with Behavior
Hendrikje Nienborg, Marlene R. Cohen, and Bruce G. Cumming p p p p p p p p p p p p p p p p p p p p p p 463
Compressed Sensing, Sparsity, and Dimensionality in Neuronal
Information Processing and Data Analysis
Surya Ganguli and Haim Sompolinsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 485
The Auditory Hair Cell Ribbon Synapse: From Assembly to Function
Saaid Safieddine, Aziz El-Amraoui, and Christine Petit p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 509
Multiple Functions of Endocannabinoid Signaling in the Brain
István Katona and Tamás F. Freund p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 529
Circuits for Skilled Reaching and Grasping
Bror Alstermark and Tadashi Isa p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 559
Indexes
Cumulative Index of Contributing Authors, Volumes 26–35 p p p p p p p p p p p p p p p p p p p p p p p p p p p 579
Cumulative Index of Chapter Titles, Volumes 26–35 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 583
Errata
An online log of corrections to Annual Review of Neuroscience articles may be found at
http://neuro.annualreviews.org/
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Annu. Rev. Neurosci. 2012. 35:445–62 Keywords

a transcriptional autoregulatory feedback loop.

genes” led to the realization that the capac-

ity for circadian gene expression is widespread

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CRYs +Ub 26S

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of CLOCK-BMAL1 (Gachon 2007, Lowrey their contribution to circadian rhythms and

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SCN slice Dispersed neurons

e Wild-type individual neurons

f Cry1 –/– individual neurons

100 170 100

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SCN synchronize these systems, and SCN transplant

eral tissues including the liver, pancreas, skele-

tal muscle, intestine, and adipose tissue (for

circadian clock mechanism speciﬁcally in the

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directly inﬂuences glucocorticoid release (Buijs factor) HNF4α. HNF4α is responsive to

pathways as described below.

Although a number of hormones may have roles

www.annualreviews.org • Circadian Clocks In Mammals 453

454 Mohawk · Green · Takahashi

signals. AMPK activity is robustly rhythmic in polyADP-ribosylates CLOCK and appears

namide phosphoribosyltransferase (Nampt, en-

coding the rate-limiting enzyme in the

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tissue culture cells. Cell 93:929–37

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coactivators. Cell Metab. 1:361–70

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Volume 35, 2012

The Neural Basis of Empathy

Functional Consequences of Mutations in Postsynaptic Scaffolding

Critical-Period Plasticity in the Visual Cortex

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