Review TRENDS in Neurosciences Vol.28 No.

3 March 2005

Orchestrating time: arrangements of

the brain circadian clock
Michael C. Antle1 and Rae Silver2,3,4
1
Department of Psychology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
2
Department of Psychology, Barnard College, Barnard College, 3009 Broadway, New York, NY 10027, USA
3
Department of Psychology, Columbia University, 1190 Amsterdam Avenue, New York, NY 10027, USA
4
Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University,
630 West 168th Street, P&S 12-513, New York, NY 10032, USA

Daily oscillations in physiology and behavior are regu- circadian pacemaker located in the SCN. This conclusion
lated by a brain clock located in the suprachiasmatic rests on decades of research from numerous laboratories [2].
nucleus (SCN). Individual cells within this nucleus Circadian rhythmicity is abolished by SCN lesions [3,4]
contain an autonomous molecular clock. Recent dis- and restored by SCN transplants [5]. The restored
coveries that make use of new molecular and genetic behavioral rhythm expresses properties of the donor, not
data and tools highlight the conclusion that the SCN is a the host [6,7]. These studies led to a dispute reminiscent of
heterogeneous network of functionally and phenotypi- the classic aggregate-field versus localization-of-function
cally differentiated cells. Neurons within SCN sub- debate because the lesion results suggest that, as long as
regions serve distinctly separate functions in 15–25% of the SCN remains intact, rhythmicity persists
regulating the overall activity of the circadian clock: [8–11]. When the lesion data were integrated with the
some cells within the SCN rhythmically express ‘clock’ observation that individual neurons within the SCN are
genes, whereas others exhibit induced expression of rhythmic and exhibit a range of circadian periods [12–17],
these genes after the organism has been exposed to a it appeared that an organism needed only a small number
light pulse. The coordinated interaction of these func- of clock cells to exhibit overt rhythmicity. In determining
tionally distinct cells is integral to the coherent function- whether a lesion would eliminate rhythmicity, location of
ing of the brain clock. the lesion and identity of the cells spared or destroyed
appeared to be less important than the amount of tissue
Introduction removed. This led to the question of how a single unified
One of the earliest controversies in neuroscience con-
output emerged from this assembly of independent
cerned localization of function in the brain. Pierre
oscillators. In one model, individual cells within the SCN
Flourens and Karl Lashley, advocates of the aggregate
are weakly coupled such that the oscillators become
field theory that all brain regions participate in all mental
synchronized and oscillate with the mean period of the
functions, tested localization of function by making lesions
population [13].
throughout the brains of rats in an attempt to eliminate
The past decade has witnessed rapid breakthroughs in
specific behaviors. These crude experiments led to the
our understanding of how the circadian clock functions at
conclusion that observed deficits were a consequence of
the cellular and molecular levels (Figure 1). Individual
the size, rather than the location, of the lesion. Modern
neuroscience now rejects the aggregate field theory, based SCN neurons express self-sustained circadian oscillations
on convincing evidence for localization of function. [12] driven by autoregulatory transcription–translation
However, although the suprachiasmatic nucleus (SCN) is feedback loops [1,18]. The discovery of core molecular
possibly one of the best examples of localized neural components of the cellular circadian clock enables exam-
function, the argument of localized versus distributed ination of SCN function at high spatial and temporal
function has been recapitulated as our understanding of resolution, revolutionizing our understanding of how the
brain clock assembly has evolved. different cell populations within the SCN are arranged to
form separate functional units. These studies challenge in
two ways the view that the SCN is functionally homo-
Keeping time: how to synchronize 20 000 clocks geneous. First, some SCN cells are not endogenously
Biological processes exhibit daily rhythms that enable rhythmic with respect to clock gene expression; only some
organisms to exploit temporal niches in their environment cells receive direct retinal input and immediately express
and coordinate physiological processes to optimize meta- clock genes following photic stimulation. Second, indi-
bolic efficiency. In mammals, these rhythms exhibit vidual clock cells within the SCN exhibit various phases
periods of about a day and are endogenously generated and free-running periods [15,17,19]. These phenomena
by the 20 000 neurons [1] that constitute the master are difficult to explain by coupling alone. An alternative
Corresponding author: Antle, M.C. ([email protected]). ‘network’ model suggests that it is precisely this hetero-
Available online 21 January 2005 geneity of the SCN that is integral to keeping the
www.sciencedirect.com 0166-2236/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2005.01.003
146 Review TRENDS in Neurosciences Vol.28 No.3 March 2005

SCN core neuron SCN shell neuron

P Cytoplasm
Nucleus GRP Cytoplasm
IPGC

CREB
P VIP Nucleus

CREB
RHT
Per1
CRE CB Per1,2,3
Glutamate Ca2+ E box
SP MAPK P GABA P Cr

CREB
CB Cry1,2
PACAP cAMP Per2 SP E box
CRE ?
CB Rev-Erbα
E box
Rev-Erbα
RORa BMAL1
ROR

VIP
VP
GRP Diffusible
GABA
GABA signal
Targets
TRENDS in Neurosciences

Figure 1. Molecular regulation of the intracellular circadian clock. Light is transduced into a neural signal by intrinsically photoreceptive ganglion cells (IPGCs) in the retina and
conveyed to the SCN core along the retinohypothalamic tract (RHT), resulting in the release of the neurotransmitter glutamate and the neuromodulators substance P (SP) and
pituitary adenylyl cyclase activating peptide (PACAP) onto retino-recipient cells in the SCN core. Glutamate activates NMDA receptors, causing an influx of Ca2C, which activates
kinases such as mitogen-activated protein kinase (MAPK), resulting in phosphorylation of cAMP-response-element-binding protein (CREB). Activated CREB binds to the
Ca2C/cAMP response element (CRE) in the promoter region of both Per1 and Per2, activating their transcription. Neurons in the SCN core communicate with the rhythmic SCN shell
and SCN targets using a variety of neurotransmitters, including vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP) and SP. Additionally, almost all SCN cells
are GABAergic [24]. Cells in the rhythmic SCN shell contain molecular clocks driven by an autoregulatory transcription–translation loop [1,69]. CLOCK (C) and BMAL (B) dimerize
and bind to E-boxes in the promoter region of Period (Per) genes, Cryptochrome (Cry) genes and Rev-Erba, activating their transcription. As PER (P) and CRY (Cr) proteins
accumulate in the cytoplasm, they dimerize and translocate to the nucleus where they inhibit the activity of CLOCK–BMAL, thus inhibiting their own transcription. At the same time,
transcription of BMAL is regulated by an RAR-related orphan receptor (ROR) element that is activated by RORa and inhibited by Rev-Erba [70]. SCN shell neurons communicate with
SCN targets using VP and GABA as neurotransmitters. Additionally, the SCN communicates with some target sites using a diffusible signal [68].

population of oscillators ticking in a coherent fashion [20]. driven by the retina [27]. These cells are called ‘cap’
This model hypothesizes that the phases of individual cells owing to their appearance, in hamsters, of sitting
oscillators are synchronized by a daily signal from a subset above CalB-containing cells [28]. Gastrin-releasing
of SCN cells. By pulling the phases closer together, the peptide (GRP)-containing cells overlap with cap cells
overall output of the system remains rhythmic. Central to (Han S. Lee, PhD thesis, University of Cincinnati, 2003)
this model are recent discoveries demonstrating that the and CalB-containing cells in hamsters [29], and with
morphological and peptidergic heterogeneity of the SCN VIP-containing cells in rats [30,31]. The spatial relation-
reflects its functional heterogeneity. ship of these phenotypically distinct regions is presented
schematically in Figure 2, and Figure 3 highlights the
Working in concert: every cell has a role phenotypic heterogeneity.
Classically, the SCN has been subdivided into a dorso-
medial shell and a ventrolateral core, based initially on The rhythm section of the orchestra: the vasopressin
retinal innervation patterns and later on the observation region
that these regions are defined by phenotypically distinct Some cells within the SCN exhibit self-sustained rhyth-
cell types [21] (Figure 2). This general arrangement has micity [12] driven by the autoregulatory transcription–
been noted in hamsters, mice, rats and humans [22–25]. translation feedback loop that regulates expression of the
Although the hamster SCN will form the framework for Period (Per) and Cryptochrome genes [1]. Rather than
the following discussion, some important species-specific being uniformly distributed in the SCN, these intrinsi-
differences are noted. Phenotypically, the SCN shell is cally rhythmic cells are largely confined to the SCN shell,
delineated by vasopressin (VP)-containing cells [22–25], occupying roughly the same area as VP-containing cells
whereas the SCN core contains a variety of cell pheno- (Figure 2) [32–34]. This region of the SCN receives little
types. The most ventral populations is a group of vaso- retinal innervation [21,24] and displays delayed clock gene
active intestinal polypeptide (VIP)-containing neurons expression following phase-shifting light exposure [32].
[23–25]. In hamsters, the caudal, ventrolateral SCN
contains a cluster of calbindin (CalB)-expressing cells Conducting the show: a role for the SCN core
[26]. Dorsal to the CalB-containing cells is a group of Cells in the SCN core receive direct retinal innervation
neurons in which the rhythm of phosphorylation of the [35,36] and express c-fos, Per1 and Per2 in response to
extracellular signal-regulated kinase 1/2 (p-ERK) is phase-shifting light pulses [26,32,33,37–39]. Among the
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 Review TRENDS in Neurosciences Vol.28 No.3 March 2005 147

function as gates that relay photic signals when open, and

Phenotype Gene expression that block these signals when closed.
Despite a lack of intrinsic rhythmicity in clock gene
3V expression, the CalB-expressing subregion is essential for
SCN function as the master circadian pacemaker. Animals
lose all locomotor, hormonal and physiological rhythms
following partial SCN ablations that spare up to 50% of
cells in the rhythmic SCN shell but eliminate the CalB
region [45,46]. Larger lesions that spare the CalB region
do not result in loss of rhythmicity. A recent model
suggests that this region provides a daily signal that
maintains synchronization among the clock cells in the
SCN shell [20]. It is predicted that without this signal,
oscillators become desynchronized, yielding an arrhyth-
mic system. This phenomenon has recently been demon-
strated in vitro using coronal brain slices from transgenic
animals in which luciferase reports Per1 expression [17].
Although expression in each individual cell peaks at a
OX
particular time of the day that is stable for that cell over
several cycles, peak expression for the population as a
VP VIP Rhythmic
CalB GRP
whole occurs during the middle of the day. When the
Light induced
‘Cap’ Rhythmic antiphase dorsal third of the nucleus is surgically separated from the
GRP-induced ventral portion that contains the core, coordinated
TRENDS in Neurosciences rhythmic output persists in only the ventral portion [17].
Individual cells in the dorsal portion remain rhythmic but
Figure 2. Spatial organization of the different cell populations in hamster SCN at the
mid-caudal level. The left SCN depicts the different phenotypic subregions. The
coherent phase relationships among cells are lost, result-
SCN shell is delineated by vasopressin (VP)-expressing cells (pink). The SCN core is ing in a tissue without net rhythmic output.
composed of four cell groups: gastrin-releasing peptide (GRP)-expressing cells
(dark blue), calbindin (CalB)-expressing cells (red), vasoactive intestinal polypep-
tide (VIP)-expressing cells (light blue), and ‘cap’ cells (green). VIP-containing cells
The gene expression duet: signal spreading from core
are located along the ventral margin of the SCN; CalB-containing cells lie just dorsal to shell
to VIP. The phenotype of the cap cells, so called as they resemble a cap sitting For the circadian clock to be phase-shifted or entrained by
just dorsal to the CalB subregion, has not yet been identified. The cap cells are
GRP-responsive and contain phosphorylated extracellular signal-regulated kinase light, photic information must be relayed from the light-
1/2 (p-ERK) during the night. In hamsters, GRP-containing cells overlap with both induced cells to the rhythmic cells, which must respond
the CalB-positive and the cap cell populations. In rats, GRP-expressing cells overlap appropriately to the resetting signal (with delays and
with those expressing VIP. The right SCN depicts the different regions as defined by
Period gene expression. Cells that rhythmically express Period genes are located in advances to early-night and late-night light exposure,
the pale orange region; the gray region within the SCN represents cells that show respectively). Detailed examination of the temporal and
light-induced Period gene expression, and cells in the green region express the
spatial patterns of gene expression reveal that Per1 and
Period genes following GRP administration. In mice and rats, a small group of cells
(blue) expresses Period genes rhythmically in antiphase to the expression pattern Per2 are regulated separately in a phase-specific and
observed in the SCN shell. Abbreviations: 3V, third ventricle; OX, optic chiasm. region-specific manner [38,47]. Following phase-shifting
light pulses, Per expression is first induced in the SCN
core [30,32–34,39]. In the mouse, early-night delaying
different cell populations in the core, CalB-expressing cells light pulses induce mPer1 and mPer2 expression initially
lack both rhythmic electrical activity [40] and rhythmic in the SCN core, followed later by mPer2 expression in the
expression of clock genes [32,34]. Although mice do not SCN shell. Late-night advancing light pulses induce
have a cluster of CalB-expressing cells in their SCN expression of mPer1 but not mPer2. This mPer1
core, they nevertheless have SCN cells with the same expression occurs first in the core and later in the shell.
features as those of the CalB region of hamsters. In mice, Mid-night light pulses that do not alter circadian phase
GRP-expressing cells in the SCN core are light-inducible induce mPer1 expression only in the SCN core. Based on
[41]. It has been observed that cells in the core of the these findings, it appears that the spread of mPer2
mouse SCN either lack rhythmic expression of Per1 and expression to the shell underlies phase delays, whereas
Per2 [41] or express these genes in antiphase to the a similar spread of mPer1 underlies phase advances
expression in the SCN shell [42]. Cells in the core oscillate [38,47]. Phase delays to light are impaired in mPer2
in their responsiveness to photic input: although light mutant mice [48,49] and following Per2 antisense treat-
exposure always increases firing rates in SCN neurons [43], ment [50]. The role of mPer1 in light-induced phase shifts
light induces clock gene expression in the SCN only during is less clear [48,49,51], although Per1 antisense treatment
the night [1,44]. This gene expression pattern is mirrored by also attenuates phase delays [50].
changes in the subcellular localization of CalB, with the
cellular nucleus devoid of CalB during the night [44]. The soloists: neurotransmitters underlying intra-SCN
Decreasing CalB levels using antisense oligonucleotides communication
eliminates behavioral and molecular responses to nocturnal Given that various SCN regions communicate in a
light pulses [44]. This suggests that CalB-expressing cells temporally ordered fashion, it becomes important to
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148 Review TRENDS in Neurosciences Vol.28 No.3 March 2005

Figure 3. The SCN is heterogeneous in structure and function. (a) Calbindin (CalB) expression in the hamster SCN from rostral (left) to caudal (right). (b) Heterogeneity of the
SCN at the mid-caudal level, as depicted by (i) peptidergic phenotype [expression of CalB, vasopressin (AVP) and gastrin-releasing peptide (GRP)], (ii) functional response
(light-pulse-induced c-fos expression, with CalB and AVP as anatomical markers) and (iii) clock-controlled gene expression (AVP mRNA). Abbreviations: 3V, third ventricle;
OX, optic chiasm. Panels (a) and (b,iii) are reprinted, with permission, from Ref. [34] q Blackwell Publishing; panels (b,i) and (b,ii) are from unpublished work of M.C. Antle and
R. Silver. Scale bar, 100 mm.

understand intercellular communication signals. A phase- SCN [28,58]. Attenuated responses to GRP administration
resetting signal would be expected to adjust the phase of are observed in GRP-receptor-deficient mice and in
the circadian clock and to synchronize the activity of clock hamsters in which ERK1/2 phosphorylation has been
cells. Impairment of this signal would be expected to result pharmacologically blocked [28,58]. Although GRP-receptor-
in dampened or arrhythmic output. The neurotrans- deficient mice exhibit attenuated responses to bright light
mitters and neuromodulators implicated in intra-SCN pulses, they have normal responses to dim light pulses
communication of photic signals, including substance P and their locomotor behavior is rhythmic in constant
(SP), GRP and VIP, will now be discussed in turn. conditions [58]. These data suggest that GRP is an output
SP-containing cells are found within the retino-recipi- signal of the SCN core that works in concert with other
ent SCN core. In hamsters, almost all SP-positive cells signaling molecules to modulate responses to different
coexpress CalB [29]. When applied to the rat SCN in vitro, light intensities.
SP phase-shifts the circadian rhythm in electrical firing VIP-containing cells are found within the SCN core
rate, with delays during the early night and advances [21], clustered in the ventral SCN adjacent to the optic
during the late night [52]. SP antagonists attenuate light- chiasm. In hamsters, VIP expression is occasionally
induced c-fos expression in the shell but not in the core colocalized with that of CalB. In rats, VIP-containing
SCN [53]. These findings are consistent with SP being an cells can be divided into a medial GRP-free group and a
output signal of the retino-recipient cells. However, when lateral group that contains GRP [30]. Only the lateral
microinjected into the SCN of hamsters, SP produces group expresses Per1 following a light pulse [30]. Few
small phase delays during only the early night [54]. VIP-containing cells rhythmically express Per1 or Per2
Together these findings suggest that, although SP might [31,59]. When VIP is microinjected into the SCN, alone or
be an intra-nuclear signal from the SCN core, it probably in a peptide cocktail, it produces photic-like phase shifts
works in concert with other transmitters. [55,56]. When applied to the SCN in vitro, VIP produces
GRP-containing cells are found within the SCN photic-like phase shifts [60] and induces Per1 and Per2
core. In rats they are colocalized with a lateral popu- expression [61]. VIP-deficient mice, or knockout mice
lation of VIP-expressing cells [30], whereas in hamsters lacking the VIP receptor VPAC2, have severely disrupted
GRP-containing cells are located more dorsally and activity rhythms in constant conditions [62,63]. Recent
frequently contain CalB [45]. In rats, GRP-containing findings suggest that, although these animals and SCN
VIP-positive cells receive retinal input [36] and express slices prepared from them are frequently arrhythmic,
c-fos following light exposure [37]. Cells in the GRP-positive individual SCN cells might continue to be rhythmic in
electrical activity [64,65]. These data are consistent with
region of the rat and mouse also express Per1 and c-fos
VIP acting as a signal that maintains the phase relation-
following light exposure [30,31,41]. When microinjected to
ship among clock cells.
the SCN, alone or in a peptide cocktail, GRP produces
phase shifts in locomotor activity rhythms that mimic
those produced by light exposure [55,56]. Similarly, when The slow arpeggio of rhythmic expression
applied to the SCN in vitro, GRP produces photic-like Cells in the SCN shell have a specific spatial arrangement.
phase shifts [57]. Microinjections of GRP lead to transient Daily rhythmic expression of Per1, Per2 and VP does not
phosphorylation of ERK1/2 and induce expression of c-fos, occur in all cells simultaneously, but rather spreads and
Per1 and Per2 in the cap cells above the CalB cluster in the recedes through the SCN similar to water over a tidal
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 Review TRENDS in Neurosciences Vol.28 No.3 March 2005 149

basin [34]. In hamsters this is detected in the rostral components and their connections. An analogous conun-
half of the SCN, where the shell occupies a much larger drum occurs in trying to understand functions of cortical
area of the coronal SCN than it does at the level of the interneurons. When classified according to spontaneous
CalB-expressing subregion. Rhythmic expression of Per1, electrical activity and morphology, 14 types of cortical
Per2 and VP starts in a small group of cells located interneurons can be identified. However, when the
adjacent to the third ventricle in the extreme dorsomedial functions of these interneurons are examined, these 14
SCN and spreads ventrolaterally over 4–8 h. It then types collapse into three functional classes [66]. Similarly,
recedes until expression is again limited to the dorso- although cells within the SCN can be described according
medial region [34]. The same pattern of expression has to their morphology, peptidergic phenotype, pattern of
been observed in vitro using transgenic mice in which gene expression, and spontaneous and induced electrical
luciferase reports Per1 expression [17]. The circadian activity, understanding their function will expand our
phase of individual cells can be tracked over multiple understanding of their role in the circadian network.
circadian cycles using this preparation. Expression Several distinct functions can be assigned to cells in the
initially occurs in the dorsomedial periventricular SCN SCN network, including input cells that gate photic
and spreads slowly to the ventral SCN over several hours. information and rhythmic cells that are endogenous
Blocking protein synthesis or electrical activity reveals oscillators. A recently identified population of light-
functional aspects of SCN organization. Because the inducible cap cells that expresses a circadian rhythm
intracellular clock is driven by an autoregulatory tran- driven by the retina forms a third compartment that is
scription–translation feedback loop, individual clocks can liable to have a novel function. It is likely that other
all be reset to a common phase by a protein synthesis aspects of the network remain to be identified.
inhibitor. When the inhibitor is removed, cells begin to
oscillate in phase with one another, but re-establish
their original phase relationships after several cycles The next concerto: questions for the future
(Figure 4). Furthermore, maintaining this phase relation- The SCN is not simply a collection of 20 000 clock cells;
ship requires electrical signaling, either between indi- rather, it is a heterogeneous structure composed of
vidual cells or between the core and the shell. When action multiple functional compartments. A new era of work
potentials are blocked with tetrodotoxin, circadian pat- examining gene expression patterns has highlighted the
terns of luminescence in individual cells persist but the spatial heterogeneity that reflects underlying functional
system as a whole becomes desynchronized [17]. These heterogeneity. As each of these separate cell types is
data reveal that, although individual cells within the SCN investigated further, a picture of how they work together
can sustain oscillations, the specific phases of such to produce a unified output will emerge. Key to under-
oscillations are regulated by the network properties of standing the arrangements of the SCN will be determin-
the SCN. ing the nature of communication among its neurons.
Given the spatial pattern of rhythmic expression observed
in the SCN shell [17,34], it will be important to determine
Assembling a symphony from its movements: whether all oscillator cells are equivalent, or whether
conclusions and integrations signals from distinct input regions of the SCN reach only a
The circadian system has become a model for under- subset of the oscillator cells. Beyond understanding how
standing neural regulation of complex behaviors. The the individual components of the SCN are arranged to pro-
SCN epitomizes localization of function, but understand- duce a coherent daily output, it will be essential to under-
ing how it functions requires understanding of its different stand how this information is communicated to peripheral

2000
CHX 36 h

1500
Luminescence
(counts h–1)

1000

500

0
02 44 87 29 6 120 144 168 192 216
Time (h)

Figure 4. Resetting and reorganizing the synchrony of cell rhythm using cycloheximide (CHX). Recording of bioluminescence of representative individual cells (inset; scale
bar, 100 mm). Each cell has a characteristic bioluminescence signal with a specific phase relationship with respect to the other cells. Bioluminescence and circadian
rhythmicity is lost during application of CHX. Following removal of CHX, bioluminescence rhythms reappear. The peaks are initially in phase but gradually resume their pre-
treatment phase relationships. Modified, with permission, from Ref. [17] q (2003) AAAS (http://www.sciencemag.org).

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150 Review TRENDS in Neurosciences Vol.28 No.3 March 2005

oscillators and other targets in the body. SCN efferents 22 Mai, J.K. et al. (1991) Evidence for subdivisions in the human
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23 Card, J.P. and Moore, R.Y. (1984) The suprachiasmatic nucleus of the
monosynaptic SCN target site [67], and a diffusible signal golden hamster: immunohistochemical analysis of cell and fiber
from the SCN is sufficient to maintain locomotor rhythms distribution. Neuroscience 13, 415–431
but not endocrine rhythms [68]. Understanding the roles 24 Moore, R.Y. et al. (2002) Suprachiasmatic nucleus organization. Cell
of these distinct signals will be fundamental to under- Tissue Res. 309, 89–98
standing how endogenous signals from the SCN are 25 Abrahamson, E.E. and Moore, R.Y. (2001) Suprachiasmatic nucleus in
the mouse: retinal innervation, intrinsic organization and efferent
integrated with exogenous environmental cues to projections. Brain Res. 916, 172–191
produce coherent daily oscillations in functioning of the 26 Silver, R. et al. (1996) Calbindin-D28K cells in the hamster SCN
brain and body. express light-induced Fos. NeuroReport 7, 1224–1228
27 Lee, H.S. et al. (2003) The eye is necessary for a circadian rhythm in
the suprachiasmatic nucleus. Nat. Neurosci. 6, 111–112
Acknowledgements 28 Antle, M.C. et al., (in press) Signaling within the brain’s master
This work was supported by NIH grant NS37919 (R.S.) and by a clock: localized activation of MAP kinase by gastrin-releasing peptide.
fellowship from the Canadian Institutes of Health Research (M.C.A.). J. Neurosci.
29 LeSauter, J. et al. (2002) Calbindin-D(28K) cells selectively contact
intra-SCN neurons. Neuroscience 111, 575–585
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