Neuroscience Research 54 (2006) 295 301
www.elsevier.com/locate/neures
Peripheral clock gene expression in CS mice with
bimodal locomotor rhythms
Tsuyoshi Watanabe, Mayumi Kojima, Shigeru Tomida, Takahiro J. Nakamura,
Takashi Yamamura, Nobuhiro Nakao, Shinobu Yasuo,
*
Takashi Yoshimura, Shizufumi Ebihara
Division of Biomodeling, Graduate school of Bioagricultural Sciences, Nagoya University, Furo-cho,
Chikusa-ku, Nagoya-shi 464-8601, Japan
Received 8 September 2005; accepted 16 December 2005
Available online 25 January 2006
Abstract
CS mice show unique properties of circadian rhythms: unstable free-running periods and distinct bimodal rhythms (similar to rhythm splitting,
but hereafter referred to as bimodal rhythms) under constant darkness. In the present study, we compared clock-related gene expression (mPer1,
mBmal1 and Dbp) in the SCN and peripheral tissues (liver, adrenal gland and heart) between CS and C57BL/6J mice. In spite of normal robust
oscillation in the SCN of both mice, behavioral rhythms and peripheral rhythms of clock-related genes were significantly different between these
mice. However, when daytime restricted feeding was given, no essential differences between the two strains were observed. These results indicate
that unusual circadian behaviors and peripheral gene expression in CS mice do not depend on the SCN but rather mechanisms outside of the SCN.
# 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Keywords: CS mice; Circadian rhythm; Suprachiasmatic nucleus; Peripheral clocks; Clock genes; Restricted feeding
1. Introduction many of the same clock molecules as the SCN and widespread
peripheral tissues sustain the oscillation in vitro even after
In mammals, behavioral and physiological circadian lesions of the SCN (Yoo et al., 2004). Thus the current notion of
rhythms are driven by the suprachiasmatic nucleus (SCN) in the mammalian circadian hierarchical structure is that the SCN
the hypothalamus, which receives photic input from the retina works to coordinate peripheral circadian rhythms of self-
and conveys the timing information to the peripheral organs by sustained rather than damped oscillators (Yamazaki et al., 2000;
way of a variety of signaling pathways (Panda and Hogenesch, Yoo et al., 2004). Among several time cues to entrain peripheral
2004; Reppert and Weaver, 2001). Although it is relatively well rhythms, feeding has been known as a dominant synchronizer,
understood how the SCN receives the environmental light dark but this does not affect the phase of the SCN (Damiola et al.,
(LD) cycle, the output pathways from the SCN to coordinate 2000; Hara et al., 2001; Stokkan et al., 2001). Because the SCN
temporal physiology and behavior are not well understood controls feeding time, it is likely that the SCN synchronizes
because multiple and complex pathways are involved in this peripheral oscillators via feeding which directly affects the
process. oscillators, although other time cues also seem to be involved in
Recent progress of molecular dissection of the circadian peripheral entrainment (Brown et al., 2002).
clock has revealed that the self-sustained oscillation is CS mice used in the present study are reported to show
generated by feedback loops based on transcription and unique properties of circadian rhythms such as unstable free-
translation of multiple clock genes. The discovery of these running periods (usually longer than 24 h) and distinct bimodal
clock genes led to a new finding that peripheral tissues contain rhythms under constant darkness (DD) (Abe et al., 1999). This
behavioral pattern is similar to rhythm splitting observed in
hamsters, but we will use the term   bimodal rhythms  in CS
mice. In contrast to other reports (de la Iglesia et al., 2000;
* Corresponding author. Tel.: +81 52 789 4066; fax: +81 52 789 4066.
E-mail address: ebihara@agr.nagoya-u.ac.jp (S. Ebihara). Edelstein et al., 2003; Ohta et al., 2005), circadian rhythms of
0168-0102/$  see front matter # 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
doi:10.1016/j.neures.2005.12.009
296 T. Watanabe et al. / Neuroscience Research 54 (2006) 295 301
First strand cDNA was synthesized using ReverTra Ace (TOYOBO, Japan). To
clock gene expression of the SCN under distinct bimodal
analyze the expression level of each mRNAs in peripheral tissues, real-time PCR
rhythmicity are essentially the same as normal rhythmic mice
was performed using ABI PRISM 7000 detection system (Applied Biosystems,
(Abe et al., 2001; Watanabe et al., 2003), indicating that the
USA). Gene specific primers were designed using Primer Express software
coupling between the SCN and behavioral rhythms is not robust
(Applied Biosystems, USA). Primer sequence were 50-CGACTCCGGCAA-
in CS mice. These data lead to the proposal that in CS mice, the GATCGAA-30, 50-GGTCCCCCAGGCTCTCTACT-30 for mouse cyclophilin
(GenBank accession number, X58990), 50-AGAAGAAAACAGCACCAGCT-
SCN cannot properly coordinate peripheral oscillators. To
30, 50-TCTTGAGTTATAAGAACCCCAACATG-30for mouse Per1 (AF022992),
consider this hypothesis, we examined several behavioral
50-TGGCCGCTGTAGACACTACATT-30, 50-CTCTATCCAGTAAGCTTCA-
rhythms and peripheral rhythms, comparing CS and normal
CAGACTGTAA-30 for mouse Bmal1 (AB014494) and 50-CGCGCAGGCTT-
C57BL/6J mice.
GACATCTA-30, 50-GGATCAGGTTCAAAGGTCATTAGC-30 for mouse Dbp
(AK140243). Real-time PCR amplification was performed after 30 s of denature
at 95 8C, and then run for 45 cycles at 95 8Cfor 5s, 608C for 31 s. We confirmed
2. Materials and methods
that single amplicon was detected in each real-time PCR reaction using the
dissociation curve of SDS 1.0 software (Applied Biosystems, USA). Quantifica-
tion of cDNAs was determined by comparing the threshold cycles for amplifica-
2.1. Animal and housing
tion of the unknowns with those of six concentrations of each standards using SDS
1.0 software (Applied Biosystems, USA). After the calculation of concentration of
Male CS mice (10 15 weeks old) bred in our colony and male C57BL/6J mice
cDNAs, mPer1, mBmal1 and Dbp mRNA levels were normalized using cyclo-
(10 15 weeks old, Clea, Japan) purchased from a breeder were used. CS strain was
philin mRNA levels. Each relative value was obtained by normalizing using the
established from hybrids between NBC and SII strains in 1956 at the Department
maximum value that was set to 100.
of Animal Genetics, Nagoya University (Festing, 1996). Before the experiment,
mice were maintained under 12 h-light 12 h-dark (LD12:12) cycles at 23 1 8C.
Food and water were available ad libitum. In all of the experiments, animals were 2.6. In situ hybridization
treated in accordance with the guideline of Nagoya University.
To analyze mPer1 and mBmal1 mRNA levels in the SCN of CS and C57BL/
6J mice, in situ hybridization was carried according to a previous report
2.2. Measurement of behavioral rhythms
(Yoshimura et al., 2000). Antisense 45 mer oligonucleotide probes (50-
GTCCCTGGTGCTTTACCAGATGCACATCCTTACAGATCTGCTGGA-30
Mice were housed individually in cages equipped with running wheels.
for mPer1, GenBank accession number, AF022992; 50-GCCATTGCTGCCT-
Activity rhythms were measured by a computer system (The Chronobiology
CATCGTTACTGGGACTACTTGATCCTTGGTCG-30for Bmal1, AB014494)
Kit, Standord Software System, CA). The activity time (a) was measured by an
were labeled with [33P]dATP (NEM Life Science Products, Boston, MA).
eye-fitted method connecting the activity onsets and offsets. The light intensity
Coronal 20 mm sections of the SCN were prepared using a cryostat. Hybridiza-
was 300 500 and 0 lx in L and D phase of LD cycles, respectively. Water and
tion was carried out overnight at 42 8C. After glass slides were washed, they
food intake rhythms were also measured with the Chronobiology Kit.
were air-dried and appose to Biomax-MR film (Kodak, Rochester, NY) for 2
14
weeks with C-labeled standards (America Radiolabeled Chemicals). The
2.3. Genes expression in LD and DD condition
relative optical density was measured by using a computed image-analyzing
system (MCID Imaging Research) and converted into the radioactive value
After entrainment to LD condition or keeping under constant darkness (DD)
14
(nCi) using the C-labeled standard measurement. Subtracting background
condition for 2 weeks, mice were humanely decapitated after cervical transloca-
values obtained from the corpus callosum normalized the data.
tion according to the law (no. 105) and notification (no. 6) of the Japanese
Government and the tissues (SCN, liver, adrenal gland and heart) were collected at
2.7. Statistics
either zeitgeber time (ZT) or circadian time (CT) 0, 3, 6, 9, 12, 15, 18, 21. We
selected these tissues, because (1) the tissues show robust oscillation of clock gene
Results were expressed as mean S.E.M. Two-way ANOVA and un-paired
expression that is necessary to compare the pattern between CS mice and C57BL/
Student s t-test were used for comparison among multiple groups and between
6J mice and (2) clock gene expression in these tissues is affected by a change of
two groups, respectively.
environmental cues including feeding and photoperiod (Carr et al., 2003; Stokkan
et al., 2001). In addition, we selected the adrenal gland, a pituitary-dependent
endocrine organ, which secretes glucocorticoids affecting the mouse peripheral
3. Results
clock (Balsalobre et al., 2000). In the experiment under DD condition, because not
all CS mice showed clear bimodality, we selected only distinctive ones for the
3.1. Behavioral rhythms
experiment. Activity onsets of evening components were defined as CT12 in the
bimodal mice (Abe et al., 2001; Watanabe et al., 2003).
Activity profile analysis revealed that a is longer in CS than
2.4. Restricted feeding schedule C57BL/6J mice under LD condition (Fig. 1A). Mean value of a
was 16.08 0.17 h for CS (n = 28) and 12.47 0.11 h for
To examine the effects of restricted feeding (RF) on peripheral clock (liver),
C57BL/6J (n = 25) mice (Student s t-test, P<0.0001). The
mice were given a RF schedule for 6 days. During the RF schedule, mice were
level of an evening peak was clearly lower in CS mice than that
allowed to access food for 4 h starting at ZT5. On seventh day, mice for RF
C57BL/6J. In addition, total counts of wheel running per day
group were given no food. Free feeding (FF) group were allowed to feed
were significantly lower in CS than C57BL/6J (P<0.001). In
throughout the experiment. This RF schedule has been proved to be effective for
phase-shifting circadian rhythms of mPer1, mPer2 and Dbp expression in the
CS mice, a morning component remarkably increased and its
liver (Hara et al., 2001). Liver tissues were collected at ZT0, ZT3, ZT6 and ZT9
duration extended to the middle of daytime. Typical bimodal
in both RF and FF group on seventh day.
rhythms in CS mice, thus, are in the state that two components
with the same amplitude diverge with a long interval. This
2.5. Real-time quantitative PCR
typical rhythm was more frequently observed under DD
condition than LD condition, although some mice showed the
Total RNA in peripheral tissues (liver, adrenal gland and heart) of the mice
was isolated using Trizol Regent. Genomic DNA was degraded using DNaseI. typical bimodal pattern in LD condition as DD condition
T. Watanabe et al. / Neuroscience Research 54 (2006) 295 301 297
Fig. 1. Behavioral rhythms of CS mice and C57BL/6J mice under LD condition. (A) Locomotor activity rhythms of CS mice and C57BL/6J mice. Representative
locomotor activity rhythms are shown in an upper column. Wheel running counts per 20 min were represented as mean S.E.M. for 10 days (n = 28 for CS mice,
n = 25 for C57BL/6J mice) in a lower column. Water intake rhythms (B) and food intake rhythms (C) are shown. Representative water and food intake rhythms of CS
(left) and C57BL/6J (center) mice are shown. Number of access to water or food was represented every 20 min as mean counts for 6 days. The ratio of access during
*
the dark (ZT12-0) to a whole day is compared between CS and C57BL/6J mice (right). P<0.01, un-paired Student s t-test. In all experiments, the animals were kept
in LD 12:12 shown as the bar above each column.
(Fig. 5). To see other behavioral rhythms in CS mice, water and 3.3. Gene expression rhythms in peripheral tissues
food intake rhythms were measured in LD condition. As shown
in Fig. 1B and C, both water and food intake exhibited evening In the liver, there were significant differences in the pattern
and morning peaks, which corresponded to those observed in of mPer1 and mBmal1 expression between CS and C57BL/6J
wheel running activity. The ratio of night-time access to water mice (two-way ANOVA, F(1, 36) = 21.30, P<0.0001 for
and food was 53.8 2.2% (Student s t-test, P<0.01, n =5) mPer1 and F(1, 36) = 16.18, P<0.001 for mBmal1) (Fig. 3).
and 67.3 2.5% (P<0.01, n = 7), respectively in CS mice, In CS mice, mBmal1 expression exhibited two peaks and the
and 74.2 2.5% (P<0.01, n = 6) and 78.9 1.8% (P<0.01, amplitude of mPer1 rhythms was significantly reduced. In the
n = 7) in C57BL/6J mice. adrenal gland, mPer1 and Dbp expression patterns differed
significantly between the two strains (F(1, 36) = 7.71, P<0.01
3.2. Gene expression rhythms in the SCN for mPer1, F(1, 36) = 18.89, P<0.0001 for Dbp) and the
amplitude of these genes decreased in CS mice. In the heart,
mPer1 and mBmal1 expression rhythms in the SCN showed expression patterns of all genes examined were different
the peak at ZT6 and ZT15, respectively in both CS and C57BL/ between the two strains (F(1, 36) = 23.20, P<0.0001 for
6J mice and the patterns were essentially similar with no mPer1, F(1, 36) = 5.09, P<0.05 for mBmal1 and F(1,
significant differences between the two strains (Fig. 2). 36) = 18.13, P = 0.0001 for Dbp). Under DD condition, the
298 T. Watanabe et al. / Neuroscience Research 54 (2006) 295 301
Fig. 2. Expression profiles of clock genes in the SCN of CS and C57BL/6J mice under LD condition. (A) Representative autoradiographs of mPer1 and mBmal1 are
shown for CS and C57BL/6J mice. (B) Temporal changes of mPer1 and mBmal1 values are indicated in CS (open circle) and C57BL/6J mice (closed circle). The bar
above each graph means LD condition. Each value is the mean S.E.M. (n = 3 4).
Fig. 3. Expression profiles of clock genes in peripheral tissues of CS and C57BL/6J mice under LD condition. Bars above each graph are LD condition. Large
asterisks show significant differences between CS (open circle) and C57BL/6J (closed circle) mice analyzed by two-way ANOVA (P<0.05). Small asterisks
represent significant differences at each time point between two strains by un-paired Student s t-test (P<0.05). Each value is indicated as mean S.E.M. (n = 3 4).
T. Watanabe et al. / Neuroscience Research 54 (2006) 295 301 299
Fig. 4. Locomotor activity rhythms and expression profiles of clock genes in peripheral tissues of CS and C57BL/6 mice under DD condition. (A) Representative
actograms of CS (left) and C57BL/6J (center) mice in DD condition. E and M means evening component and morning component, respectively. Right column
indicates a of CS and C57BL/6J mice with shaded and white bars representing mean activity time and rest time S.E.M. (n = 35 for CS mice; n = 25 for C57BL/6J
mice), respectively. The bar at the above of each graph means light dark condition. (B) Expression profiles of mPer1 (left), mBmal1 (center) and Dbp (right) in the
liver of CS (open circle) and C57BL/6 (closed circle) mice under DD condition. The black bar at the above of each graph means constant dark condition. A large
asterisk represents significant differences between two strains by two-way ANOVA (P<0.05). Small asterisks represent differences at each time point between two
strains by un-paired Student s t-test (P<0.05). Each value is indicated as mean S.E.M. (n = 3 5).
amplitude of mPer1 rhythms in the liver was significantly situation of typical bimodal rhythms, circadian profiles of clock
reduced in CS mice (F(1, 50) = 20.81, P<0.0001) and this genes in the SCN were essentially similar to those in C57BL/6J
tendency was also observed in Dbp (Fig. 4). A bimodal pattern mice and no asymmetric clock gene expression between the left
of mBmal1 expression in CS mice was similar to that observed and right SCN occurred (Abe et al., 2001; Watanabe et al.,
in LD condition. 2003). In addition, we preliminarily observed that mPer1
promotor activity showed unimodal oscillation in the coronal
3.4. Effects of RF on gene expression rhythms in the liver and horizontal SCN slices in mPer1exhibiting bimodal rhythms which were produced by mating
In C57BL/6J mice, RF schedule shifted the peak time of with CS mice (unpublished observation). Although more
mPer1 and Dbp from ZT9 to ZT3 in the liver (Figs. 3 and 5). precise cellular and regional examination within the SCN might
This schedule also shifted the peak from ZT15 to ZT6 for be required, the results so far suggest that circadian oscillation
mPer1 and from ZT9 to ZT3 for Dbp in CS mice. In addition, in the SCN is not properly reflected in behavior rhythms in CS
RF significantly increased expression levels of both genes mice. Thus CS mice seem to be a unique model to study the
during the period of observation (ZT0-9) in CS mice and as a mechanism of the output pathway from the SCN controlling
result, no essential differences in RF-induced gene expression behavioral rhythms.
between two strains could be observed. Although the amplitude of mPer1 and Dbp rhythm was
significantly decreased in the tissues of CS mice, mBmal1 rhythm
4. Discussion was not clearly attenuated. Instead, mBmal1 particularly in the
liver showed bimodal pattern without attenuation. It is
In the present study, we demonstrated that CS mice exhibit noteworthy that CS mice exhibited different expression pattern
unusual circadian rhythms of behaviors and gene expression in of clock genes in peripheral tissues when compared with other
the peripheral tissues in spite of normal robust oscillation in the mouse strains (Damiola et al., 2000; Hara et al., 2001). Because
SCN. behavioral changes are reported to affect peripheral oscillation
It has been reported that the anti-phase oscillation of clock (Damiola et al., 2000; Stokkan et al., 2001), it is possible that
genes in the left and right SCN is reflected in behavioral rhythm unusual peripheral oscillation of CS mice is due to altered
splitting in hamster and mice exposed to LL condition (de la behavioral rhythms. To test this possibility, we examine the effect
Iglesia et al., 2000; Ohta et al., 2005). In addition, hamsters of RF on peripheral gene expression in CS mice. As a result,
showing rhythm splitting induced by introducing daily novel mPer1 and Dbp expression in the liver of CS mice normally
running wheel exhibited the bimodal expression of mPer1 and responded to RF and showed the similar expression pattern to that
mPer2 in the SCN (Gorman and Lee, 2001; Edelstein et al., of C57BL/6J mice. These results indicate that the peripheral
2003). In these cases, behavioral circadian rhythms clearly clock of CS mice has indistinguishable properties from that of
correlated with oscillatory pattern of clock genes in the SCN. C57BL/6J, which suggests that unusual behavioral rhythms lead
However, this is not the case of CS mice, in which even in the to unusual peripheral gene expression in CS mice, although other
300 T. Watanabe et al. / Neuroscience Research 54 (2006) 295 301
Fig. 5. Effect of daytime restricted feeding (RF) schedule on mPer1 and Dbp expression in the liver of CS and C57BL/6J mice. Expression patterns were compared
between groups of free feeding (FF) and restricted feeding (RF) during the period from ZT0 to ZT9. Bars above each graph mean LD condition (dark and white bars)
*
and RF period (shade bars). Asterisks represent significant differences between FF group and RF group by un-paired Student s t-test (**P<0.01, P<0.05). Each
value is indicated as mean S.E.M. (n = 3 4).
factors such as body temperature cannot be ruled out (Brown Aid from a Ministry of Education, Science and Culture to
et al., 2002). S.E.
If the above-mentioned hypothesis is correct, fundamental
cause of unusual circadian rhythms in CS mice seems to be References
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