WWW.JNEUROSCI.ORG
-
The Journal of Neuroscience
QUICK SEARCH:   [advanced]


     
-


HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an eLetter
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (99)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Horikawa, K.
Right arrow Articles by Shibata, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Horikawa, K.
Right arrow Articles by Shibata, S.

 Previous Article  |  Next Article 

The Journal of Neuroscience, August 1, 2000, 20(15):5867-5873

Nonphotic Entrainment by 5-HT1A/7 Receptor Agonists Accompanied by Reduced Per1 and Per2 mRNA Levels in the Suprachiasmatic Nuclei

Kazumasa Horikawa1, Shin-ichi Yokota1, Kazuyuki Fuji1, Masashi Akiyama1, Takahiro Moriya2, Hitoshi Okamura3, and Shigenobu Shibata1, 2

1 Department of Pharmacology and Brain Science and 2 Advanced Research Center for Human Sciences, School of Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan, and 3 Department of Anatomy and Brain Science, Kobe University School of Medicine, Chuo-ku, Kobe 650-0017, Japan


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In mammals, the environmental light/dark cycle strongly synchronizes the circadian clock within the suprachiasmatic nuclei (SCN) to 24 hr. It is well known that not only photic but also nonphotic stimuli can entrain the SCN clock. Actually, many studies have shown that a daytime injection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT), a serotonin 1A/7 receptor agonist, as a nonphotic stimulus induces phase advances in hamster behavioral circadian rhythms in vivo, as well as the neuron activity rhythm of the SCN in vitro. Recent reports suggest that mammalian homologs of the Drosophila clock gene, Period (Per), are involved in photic entrainment. Therefore, we examined whether phase advances elicited by 8-OH DPAT were associated with a change of Period mRNA levels in the SCN. In this experiment, we cloned partial cDNAs encoding hamster Per1, Per2, and Per3 and observed both circadian oscillation and the light responsiveness of Period. Furthermore, we found that the inhibitory effect of 8-OH DPAT on hamster Per1 and Per2 mRNA levels in the SCN occurred only during the hamster's mid-subjective day, but not during the early subjective day or subjective night. The present findings demonstrate that the acute and circadian time-dependent reduction of Per1 and/or Per2 mRNA in the hamster SCN by 8-OH DPAT is strongly correlated with the phase resetting in response to 8-OH DPAT.

Key words: suprachiasmatic nucleus; 8-OH DPAT; Per mRNA; 5-HT1A/7 receptor; hamster; circadian rhythm; NIH Image


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus has been shown to be a primary circadian pacemaker of locomotor activity and various physiological phenomena (Hastings, 1997). Recent studies on the molecular aspects of clock genes have produced a functional model of circadian rhythms (for review, see Dunlap, 1999).

mPer1, mPer2, and mPer3, cloned as mouse homologs of the Drosophila clock gene, Period (Per), exhibit circadian rhythmic expressions in the SCN (Albrecht et al., 1997; Shearman et al., 1997; Sun et al., 1997; Tei et al., 1997; Takumi et al., 1998a,b; Zylka et al., 1998). Brief exposure to light during subjective night results in a large and rapid induction of mPer1 expression (Albrecht et al., 1997; Shigeyoshi et al., 1997). mPer2 mRNA expression in the SCN is also induced in response to light stimuli (Shearman et al., 1997; Takumi et al., 1998a). On the other hand, mPer3 mRNA levels do not respond to light during either the subjective night or subjective day (Takumi et al., 1998b; Zylka et al., 1998). Recently, we demonstrated that light-induced phase delays in locomotor activity at CT16 were significantly inhibited when mice were pretreated with mPer1 antisense phosphorothioate oligodeoxynucleotide (ODN) (Akiyama et al., 1999). Therefore, we suggest that the gated expression of mPer1 may be an important step in causing photic entrainment.

On the other hand, nonphotic manipulation such as novel wheel-running (Reebs and Mrosovsky, 1989), social interaction (Mrosovsky, 1988), and saline injection and/or handling (Mead et al., 1992) reportedly causes big phase advances in the hamster circadian clock when performed during subjective day. Additionally, many studies have shown that a daytime injection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT), a serotonin 1A/7 receptor agonist, induces a phase advance in hamster behavioral circadian rhythms in vivo (Tominaga et al., 1992; Edgar et al., 1993; Cutrera et al., 1996; Mintz et al., 1997), as well as the neuron activity rhythm of the SCN in vitro (Shibata et al., 1992; Prosser et al., 1993). Thus, serotonin (5-HT) has been implicated in phase shifts of the circadian system during subjective day in response to nonphotic stimuli. Because light exposure induces mPer1 and mPer2 expression during subjective night, we questioned whether injection of 8-OH DPAT modifies the Per mRNA levels during subjective day. Almost all behavioral experiments investigating nonphotic-induced phase advances were performed using hamsters, so we attempted to clone partial cDNAs encoding the golden hamster Per1, Per2, and Per3. Therefore, we first established that oscillations and light responses of hamster Per gene mRNA were similar to what has previously been published in the mouse. Second, we found that injection of 8-OH DPAT at CT6, but not at CT1 or CT20, reduced the amount of Per1 and Per2, but not Per3 mRNA in the hamster SCN. Third, we demonstrated that nonphotic phase shifting with 8-OH DPAT is strongly correlated with an 8-OH DPAT-dependent, transient decrease in Per1 and Per2 mRNA levels.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Cloning of partial cDNAs encoding hamster Per genes. For analysis of Per gene expression by in situ hybridization, we attempted to clone partial cDNAs encoding the golden hamster Per genes. Total RNA was extracted from the golden hamster brain using Trizol (BRL, Bethesda, MD) and was reverse-transcribed using the Superscript one-step RT-PCR system (BRL). RT-PCR was performed using a DNA Thermal Cycler 9600 (Perkin-Elmer, Norwalk, CT) with specific primers derived from mouse and human sequences of Per genes. The sequences of the primers were as follows: Per2 (nucleotide position 822-1601 of mPer2; GenBank accession number AF035830): 5'-ACACCACCCCTTACAAGCTTCC-3', 5'-CGCTGGATGATGTCTGGCTC-3'; Per3 (nucleotide position 1956-2754 of mPer3; GenBank accession number AF050182): 5'-GAACTGTATCGACAGTGTCATC-3', 5'-GGCCATATCTTGGAGGGGAAA-3'. The PCR protocol was executed under the following conditions: cDNA synthesis and predenaturation at 50°C for 30 min followed by 94°C for 2 min, PCR amplification for 35 cycles with denaturation at 94°C for 15 sec, annealing at 55°C for 30 sec, extension at 72°C for 1 min, and final extension at 72°C for 5 min. These PCR products were subcloned into the pGEM-T Easy Vector (Promega, Madison, WI) and were sequenced using ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin-Elmer). A partial cDNA encoding hamster Per1 corresponding to the nucleotide position 726-1367 of mPer1 (GenBank accession number AB002108) was also cloned (S. Yamamoto and H. Okamura, data not shown).

Animals. Male golden hamsters (Mesocricetus auratus, Tokyo Laboratory Animals Science Co. Ltd., Tokyo, Japan) purchased 6 weeks postpartum were maintained on a 12 hr light/dark cycle with lights on at 8:30 A.M. (room temperature at 23 ± 2°C). Animals were given food and water ad libitum. For assessment of wheel-running activity, hamsters were housed individually in transparent plastic cages (36 × 20 × 20 cm) equipped with a running wheel (13 cm in diameter) that closed a microswitch with each revolution. The number of wheel rotations was measured, and data were stored on a personal computer.

Behavioral experiment. Because 8-OH DPAT has an asymmetrical carbon, this compound has two optical isomers: R(+) and S(-) 8-OH DPAT. A few studies have investigated the relationship between binding affinity of 5-HT1A and 5-HT7 receptors and the effect of each optical isomer on circadian rhythms (Lovenberg et al., 1993; Eriksson and Evrin, 1996; Miller et al., 1996; Ying and Rusak, 1997). After free-running for 14-20 d in constant darkness, hamsters were randomly assigned to an intraperitoneal injection of 8-OH DPAT (1.0 or 5.0 mg/kg; Research Biochemicals, Natick, MA), (+) 8-OH DPAT (2.5 mg/kg, Research Biochemicals), triazolam (20 mg/kg, Upjohn), or vehicle [sterilized saline for both 8-OH DPAT and (+) 8-OH DPAT or dimethyl sulfoxide (Wako) for triazolam]. Injection was performed at circadian time (CT; CT12: onset time of wheel-running activity) 1, CT6, CT8, CT14, or CT20. Animals were then returned to their individual cages. The phase of the rhythm was assessed visually by applying a straight edge to the onset of activity on successive days before and after drug injection and determining the difference in phases on the day of drug injection (Daan and Pittendrigh, 1976).

In situ hybridization using digoxigenin. In situ hybridization using digoxigenin (DIG) was applied to determine the semiquantity or histochemical distribution of Per mRNA levels in coronal sections of the hypothalamus. Hamsters were entrained to the light/dark cycle for at least 14 d and then kept in constant dark conditions. On the third day of constant darkness at CT6 or CT20, hamsters were intraperitoneally injected with each drug and then deeply anesthetized with ether 1, 2, or 4 hr after injection and intracardially perfused with 0.1 M phosphate buffer (PB) containing 4% paraformaldehyde (PFA). In some cases, hamster brains were obtained for observation of circadian changes in Per gene expression in the SCN. To make this observation, light (60 lux, 15 min) was applied at CT14 or CT20, and hamsters were killed 1 or 2 hr after the initiation of light exposure. Brains were removed, post-fixed in 0.1 M PB containing 4% PFA for 24 hr at 4°C, and transferred into 20% sucrose in PBS for 24 hr at 4°C. Frontal sections (40 µm thick) were collected and placed in PBS for 30 min, followed by treatment with 6 × SSC for 30 min. Sections were incubated in hybridization buffer [50% formamide, 6 × SSC, 0.1 mg/ml denatured salmon sperm DNA, 1 × Denhardt's solution (0.02% Ficoll, 0.02% polyvinyl pyrolidone, 0.02% bovine serum albumin), and 10% dextran sulfate] containing labeled cRNA probes overnight at 60°C. DIG-UTP (Roche Molecular Biochemicals, Indianapolis, IN)-labeled antisense cRNA was made using a standard protocol for cRNA synthesis. After hybridization, these sections were rinsed in 2 × SSC/50% formamide for 45 min followed by 15 min at 60°C and treated with RNase A for 30 min at 37°C, 2 × SSC/50% formamide for 2 × 15 min at 60°C, and 0.4 × SSC for 30 min at 60°C. Sections were processed for immunocytochemistry by following the DIG nucleic acid detection kit (Roche Molecular Biochemicals) protocol. Photomicrographs were taken with a Fujix digital camera (HC-300, Fujifilm, Tokyo Japan) and captured with photograb-300 (Fujifilm). The density of Per gene expression was semiquantified on a Macintosh computer using the public domain NIH Image program (written by Wayne Rasband, National Institutes of Health).

In situ hybridization using radioisotope. In situ hybridization using radioisotope (RI)-labeled probes was applied to determine the quantity of Per1, Per2, and Per3 mRNA levels in coronal sections of the hypothalamus. Hamsters were entrained to the light/dark cycle for at least 14 d and then kept in constant dark conditions. On the third day of constant darkness at CT1, CT6, or CT20, hamsters were intraperitoneally injected with each drug and then deeply anesthetized for 2 hr after injection and intracardially perfused with 0.1 M PB containing 4% PFA. Brains were removed, post-fixed in 0.1 M PB containing 4% PFA for 24 hr at 4°C, and transferred into 20% sucrose in PBS for 24 hr at 4°C. Frontal sections (30 µm thick) were collected and placed in 2 × SSC and then treated with proteinase K (1.0 µg/ml, 10 mM Tris buffer, pH 7.5, 10 mM EDTA) for 10 min at 37°C, 4% PFA in 0.1 M PB for 5 min, and 2 × SSC for 5 min followed by 0.25% acetic anhydride in 0.1 M triethanolamine for 10 min and 2 × SSC for 2 × 5 min. RI [alpha [33P]UTP (New England Nuclear)]-labeled antisense cRNA was made using a standard protocol for cRNA synthesis. Hybridization and posthybridization washing steps were the same as the protocol for DIG in situ hybridization. RI in situ hybridization images were visualized by autoradiogram and BioMax film (Kodak) and analyzed using an image analyzing system (MCID, Imaging Research Inc.) after conversion into optical density by 14C-autoradiographic microscales (Amersham, Arlington Heights, IL). The values were expressed as means ± SEM. For statistical analysis, one-way ANOVA followed by the Student's t test was applied.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Oscillation and light response of SCN Per mRNA expression

To evaluate the topographic differences of expression profile in hamster Per genes of the SCN, in situ hybridizations using digoxigenin-labeled probes of hamster Per1, Per2, and Per3 were performed. DIG in situ hybridization showed clear signals with the antisense probes in the hamster SCN (Fig. 1). These antisense probe signals were suppressed by competition experiments using the unlabeled antisense probes. Furthermore, the sense probes demonstrated specificity of the antisense hybridization by exhibiting no signals within the SCN (data not shown). The distribution or expression patterns of hamster Per mRNA inside and outside the SCN were consistent with those of already published findings in the mouse (Albrecht et al., 1997; Shearman et al., 1997; Sun et al., 1997; Tei et al., 1997; Takumi et al., 1998a,b; Zylka et al., 1998). Next, we examined the circadian pattern of Per gene expression in the hamster SCN. There were clear circadian rhythms of Per1, Per2, and Per3 expression in the hamster SCN with a peak at CT4 for Per1 and at CT8 for both Per2 and Per3 (Fig. 1). In nocturnal rodents, it is well established that light pulses administered during the early subjective night cause phase delays of the circadian rhythm, whereas pulses delivered during the latter half of the subjective night cause phase advances. Recent reports indicated that mPer1 and mPer2 expression in the mouse SCN was increased rapidly and transiently after brief light exposure during both early and late subjective night, whereas mPer3 expression was not (Takumi et al., 1998b; Zylka et al., 1998). We also observed that Per1 and Per2 expression in the hamster SCN was induced in response to brief light exposure at CT14 or CT20, and Per3 expression was not affected by light stimulation at CT20 (Fig. 2). In both Per1 and Per2 cases, we found that signal intensities were more likely to be stronger in the ventrolateral part of the SCN than in the dorsomedial part. These results were consistent with previous data found in the mouse.



View larger version (54K):
[in this window]
[in a new window]
  		Figure 1.   Circadian expressions of (A) Per1, (B) Per2, and (C) Per3 in the hamster suprachiasmatic nucleus. mRNA expression was demonstrated by DIG in situ hybridization and semiquantified by a Macintosh computer using the public domain NIH Image program (D). There are clear circadian rhythms of Per1, Per2, and Per3 expression in the hamster SCN with a peak at CT4 for Per1 and at CT8 for both Per2 and Per3.



View larger version (83K):
[in this window]
[in a new window]
  		Figure 2.   Effect of light exposure on the expression of (A) Per1, (B) Per2, and (C) Per3 in the hamster suprachiasmatic nucleus. mRNA expression was demonstrated by DIG in situ hybridization, and a more magnified picture is shown. Per mRNA expression was semiquantified by a Macintosh computer using the public domain NIH Image program (D). Hamster was exposed to light (60 lux, 15 min) at CT14 or CT20 and then killed 60 or 120 min after light pulse. Light at CT14 or CT20 induced Per1 and Per2 expression in the SCN; however, Per3 expression was not affected by light exposure at CT20. oc, Optic chiasma; v, third ventricle; (+), light pulses were applied; (-), light pulses were not applied.

Wheel-running activity in response to 8-OH DPAT

Vehicle administration at CT6 did not show any change in phase (Fig. 3A); however, 8-OH DPAT (5.0 mg/kg) administration at CT6 produced a clear phase advance (Fig. 3B). Administration of this compound at CT20 did not affect the wheel-running rhythm (Fig. 3C). Administration of 8-OH DPAT (5.0 mg/kg) at various CTs (CT1, CT6, CT8, CT14, CT20) was compared with vehicle administration (Fig. 3D). Significant phase advances were observed when this compound was administered at CT6 or CT8. There were no significant differences at other CTs. Administration of triazolam (20 mg/kg) at CT6 also caused a phase advance in hamster wheel-running rhythm (data not shown).



View larger version (38K):
[in this window]
[in a new window]
  		Figure 3.   Effects of 8-OH DPAT administration on the hamster circadian wheel-running rhythm. Double-plotted actogram shows wheel-running activity records of (A) vehicle and (B) 8-OH DPAT (5.0 mg/kg, i.p.)-injected hamster at CT6, and (C) 8-OH DPAT (5.0 mg/kg, i.p.) injection at CT20. Each animal was injected at CT6 or CT20 (arrowheads) and returned to constant darkness. D, Mean phase advances induced by 8-OH DPAT (5.0 mg/kg, i.p.) administration at CT1, CT6, CT8, CT14, and CT20. Numbers in parentheses indicate the number of experiments. Injection of 8-OH DPAT at CT6 or CT8 induced a significant phase advance (*p < 0.05, ##p < 0.001, Student's t test).

Effect of 8-OH DPAT on SCN Per mRNA

Administration of 8-OH DPAT (5.0 mg/kg) reduced the levels of Per1 in the entire SCN and Per2 preferentially in the ventrolateral part of the SCN (Fig. 4A,B). Four hours after drug injection, however, reduced Per1 and Per2 levels recovered to the control level of vehicle-treated animals. Injection of 8-OH DPAT at CT20 did not change the Per1 and Per2 levels in the SCN. (+) 8-OH DPAT (2.5 mg/kg)-induced reduction of Per1 and Per2 was similar to 8-OH DPAT (5.0 mg/kg)-induced reductions (Fig. 4A,B). Injection of 8-OH DPAT did not reduce the Per3 mRNA levels (Fig. 4C). For quantitative measurements of Per mRNA levels, in situ hybridizations using RI-labeled probes were performed. In Figure 5, the mean values for Per1, Per2, and Per3 in the hamster SCN of 8-OH DPAT and vehicle-treated groups at various CTs are shown. Vehicle-treated hamsters exhibit clear circadian rhythms of Per1 (ANOVA, F(2,12) = 9.363, p = 0.0032), Per2 (ANOVA, F(2,13) = 62.375, p = 0.0001), and Per3 (ANOVA, F(2,13) = 39.892, p = 0.0001) expression in the SCN. High expression of these genes was seen at CT6. Two hours after the administration of 8-OH DPAT (5.0 mg/kg) at CT6, the amount of both Per1 and Per2 mRNA was significantly reduced in comparison with the group receiving vehicle treatment (Fig. 5A,B). On the other hand, injection of 8-OH DPAT at CT1 or CT20 did not affect the amount of Per1 and Per2 mRNA. Interestingly, this drug did not change the Per3 mRNA of the SCN at any CTs. In the next experiment, we examined whether 8-OH DPAT reduced Per1 and Per2 mRNA in a dose-dependent manner (Fig. 6). Administration of 8-OH DPAT caused a phase advance in hamster wheel-running rhythm in a dose-dependent manner (Fig. 6A), and this compound also reduced the amount of both Per1 and Per2 mRNA in a dose-related fashion (Fig. 6B,C). Thus, the effective dose for behavioral phase shift induction and reduction of Per1 and Per2 was very similar. Amplitude of Per1 and Per2 reduction by (+) 8-OH DPAT (5.0 mg/kg) was similar to that of (+) 8-OH DPAT (2.5 mg/kg) (Fig. 6). Administration of triazolam (20 mg/kg), a central-type benzodiazepine receptor ligand, at CT 6 also reduced the amount of SCN Per1 and Per2 but not Per3 mRNA.



View larger version (68K):
[in this window]
[in a new window]
  		Figure 4.   Effects of 8-OH DPAT (5.0 mg/kg, i.p.) or (+) 8-OH DPAT (2.5 mg/kg, i.p.) on the expression of (A) Per1, (B) Per2, and (C) Per3 in the hamster suprachiasmatic nucleus. mRNA levels were demonstrated by DIG in situ hybridization. Drug was administered at CT6 or CT20, and Per mRNA levels were examined 60-240 min after drug injection. 8-OH DPAT reduced Per1 and Per2 mRNA levels in the SCN 120 min after injection at CT6, but mRNA levels returned to the control level 240 min after injection. Injection of 8-OH DPAT at CT20 did not affect Per1 or Per2 mRNA levels. The amount of Per3 mRNA was not affected by injection of 8-OH DPAT.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 5.   Effect of 8-OH DPAT at various CTs on Per1, Per2, and Per3 expression in the hamster suprachiasmatic nucleus. RI in situ hybridization was performed for the quantitative analysis. Circadian expression of these genes was observed at (A) Per1 (ANOVA, F(2,12) = 9.363, p = 0.0032), (B) Per2 (ANOVA, F(2,13) = 62.375, p = 0.0001), and (C) Per3 (ANOVA, F(2,13) = 39.892, p = 0.0001). 8-OH DPAT (5.0 mg/kg, i.p.) significantly reduced Per1 (#p < 0.005, Student's t test) and Per2 (∫∫p < 0.0001, Student's t test) but not Per3 mRNA levels 2 hr after drug injection at CT6. Numbers in parentheses indicate the number of experiments.



View larger version (69K):
[in this window]
[in a new window]
  		Figure 6.   Dose-dependent advance of behavioral rhythms (A) and dose-dependent reduction of Per1 (B), Per2 (C), and Per3 (D) mRNA levels by 8-OH DPAT (1.0 or 5.0 mg/kg, i.p.), (+) 8-OH DPAT (2.5 mg/kg, i.p.), or triazolam (20 mg/kg, i.p.). mRNA levels were quantified using RI in situ hybridization. **p < 0.01, #p < 0.005, ##p < 0.001, ∫p < 0.0005, ∫∫p < 0.0001, $p < 0.00005 versus vehicle alone, Student's t test. Numbers in parentheses indicate the number of experiments. DPAT, 8-OH DPAT; (+)D, (+) 8-OH DPAT; TRZ, triazolam.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In situ hybridizations using digoxigenin-labeled probes of hamster Per genes revealed clear circadian expressions of Per1, Per2, and Per3 in the hamster SCN. The pattern of expression of these genes is very similar to that observed in the mouse (Albrecht et al., 1997; Shearman et al., 1997; Sun et al., 1997; Tei et al., 1997; Takumi et al., 1998a,b; Zylka et al., 1998) and rat (Sakamoto et al., 1998; Yan et al., 1999) SCN, with peak expression of hamster Per1, Per2, and Per3 found at CT4, CT8, and CT8, respectively. Reportedly, light exposure during subjective night causes a rapid induction of mPer1 and mPer2 in the SCN (Albrecht et al., 1997; Shearman et al., 1997; Takumi et al., 1998a). In the hamster, we also observed that Per1 and Per2 have light-responsive characters similar to mouse period genes.

Anatomical subdivisions such as the ventrolateral and dorsomedial parts in the rat SCN have been well established (Moore, 1982). Recently, we reported that light exposure at CT16 induced the expression of rat Per1 and Per2 in SCN neurons of the ventrolateral part, although the circadian rat Per1 and Per2 mRNA oscillations in light/dark and constant dark conditions occurred strongly in neurons in the dorsomedial part but weakly in neurons in the ventrolateral part of the SCN (Yan et al., 1999). In the hamster SCN, light-induced expression of Per1 and Per2 was preferential to the ventrolateral part of the SCN. Although the basic compartment profile of Per gene expression may be preserved in the hamster SCN, however, anatomical subdivision of the hamster SCN is vague compared with the rat SCN. Therefore, further experiments are needed to elucidate the compartmentalization of circadian profiles in Per genes in the hamster in detail.

In the present experiment, we demonstrated that 8-OH DPAT reduces SCN Per1 and Per2 mRNA in a circadian time-dependent manner. Actually, 8-OH DPAT reduced these gene mRNAs when administered at CT6 but not at CT1 or CT20. This result relates to the behavioral result showing a large phase advance at CT6 and CT8 but not at CT1 or CT20. In addition, 8-OH DPAT reduced Per1 and Per2 in a dose-dependent fashion. The dose and threshold closely correlated with Per1 and Per2 reduction in the SCN. mPer1 and mPer2 transcription is rapidly induced by light in a time-of-day-dependent manner (Shigeyoshi et al., 1997; Takumi et al., 1998b). Gating is known to play a role in the light-induced phase shifts of behavioral rhythms. The responsiveness of mPer1 mRNA to light is closely related to behavioral phase delays induced by light (Shigeyoshi et al., 1997). In addition, we previously demonstrated that light-induced phase delays in locomotor activity at CT16 were significantly inhibited when the mice were pretreated with mPer1 antisense ODN before light exposure (Akiyama et al., 1999). Therefore, the gated induction of mPer1 is a step necessary for producing behavioral phase shifts. These results along with our present results suggest that gated inhibition of Per1 and/or Per2 expression by nonphotic stimulation may facilitate Per gene reduction resulting in the onset of the next circadian induction of Per gene expression.

(+) 8-OH DPAT exhibited a higher affinity for 5-HT7 receptors than for 5-HT1A receptors, and amplitude of Per1 and Per2 reduction by 8-OH DPAT (5 mg/kg) was similar to that of (+) 8-OH DPAT (2.5 mg/kg). Thus, we estimate that the potential effect of (+) 8-OH DPAT is two times higher than that of 8-OH DPAT. The present results suggest that 5-HT7 receptors, rather than 5-HT1A receptors, have a more important role in phase shifting, as pointed out by Ying and Rusak (1997) during investigation of the inhibitory effect of 5-HT7 receptors on light-sensitive SCN neurons. Challet et al. (1998) reported that bilateral 8-OH DPAT injections into either the SCN or the intergeniculate leaflet cause significant phase advances in hamster wheel-running activity. Additional studies proposed that perfusion of 8-OH DPAT at CT6-CT8 advances neuron activity rhythm of the SCN in vitro (Shibata et al., 1992; Prosser et al., 1993). These reports prefer the direct action of 8-OH DPAT on SCN Per gene expression. On the other hand, Schuhler et al. (1998) demonstrated that the 5-HT fibers connecting the median raphe to the SCN are essential for the phase-shifting action of peripheral 8-OH DPAT injections into the SCN using microinjections of 5-HT neurotoxin. The present results demonstrate that 8-OH DPAT reduces Per1 mRNA levels in the entire SCN and preferentially reduces Per2 mRNA in the ventrolateral part of the SCN. Because serotonergic fibers from the median raphe nucleus innervate the ventrolateral part of the hamster SCN (Meyer-Bernstein and Morin, 1996; Leander et al., 1998), the reduction of this SCN serotonergic input may be one of the possible outcomes of 8-OH DPAT-induced reductions of Per mRNA. It is interesting that triazolam (20 mg/kg) causes not only a big phase advance but also a strong inhibition of Per1 and Per2 mRNA. Thus, reduction of Per1 and Per2 mRNA correlates well with phase advances induced by 8-OH DPAT as well as triazolam.

The SCN entrains to the environmental light/dark cycle via a retinal projection called the retinohypothalamic tract (RHT). Glutamate, which acts as an RHT transmitter (de Vries et al., 1993), and glutamate and NMDA application to the rat SCN in vitro reportedly causes phase delays in SCN firing rhythms when applied during early subjective night (Ding et al., 1994; Shibata et al., 1994; Shirakawa and Moore, 1994; Ding et al., 1997). Excitation of glutamate receptors is reported to facilitate the phosphorylation of cAMP response element binding protein (CREB) (Ding et al., 1997; McNulty et al., 1998). Furthermore, light exposure at night is reported to produce mitogen-activated protein kinase phosphorylation and CREB phosphorylation (Obrietan et al., 1998). Thus, the signal cascade of photic entrainment is well documented, whereas the signal cascade of nonphotic entrainment is obscure at present. Currently, we do not know the mechanism of Per1 and Per2 reduction in the SCN by 8-OH DPAT or triazolam.

Treatments using pituitary adenylate cyclase-activating polypeptide or cAMP during subjective day are reported to induce the phase shift of circadian rhythm, apparently via activation of adenylate cyclase and PKA activity (Prosser and Gillette, 1989; Hannibal et al., 1997; Harrington et al., 1999). 5-HT7 receptors are positively coupled to adenylate cyclase (Lovenberg et al., 1993; Tsou AP et al., 1994), and activation of both PKA and K+ channels is necessary for 5-HT-induced phase advances of circadian rhythm (Prosser et al., 1994). Therefore, we speculate that activation of PKA may be involved in the 8-OH DPAT-induced phase advance and transient reduction of Per mRNA levels.

In this experiment, we demonstrated that administration of triazolam and 8-OH DPAT during subjective day reduces Per1 and Per2 mRNA in the hamster SCN. Nonphotic resetting by benzodiazepine or novel wheel-running requires neuropeptide Y innervation of the SCN from the thalamus (Biello et al., 1994; Maywood et al., 1997). Recently, Maywood et al. (1999) also demonstrated the acute downregulation of SCN Per1 and Per2, whereas there was no significant change in SCN PER1 immunoreactivity by novel wheel-running during the daytime under a light/dark cycle. Our present results are highly consistent with the data of Maywood et al. (1997, 1999). Although we do not know whether the signal transduction mechanism of benzodiazepine-GABA, 8-OH DPAT, and novel wheel-running are identical, it is strongly suggested that nonphotic stimuli presented during subjective day cause a phase advance through the reduction of Per1 and Per2 mRNA in the hamster SCN. However, further experiments are needed to investigate the response of other clock elements such as Clock, Bmal1, Cry1, Cry2 (Gekakis et al., 1998; Thresher et al., 1998; Griffin et al., 1999; Jin et al., 1999; Kume et al., 1999; Miyamoto and Sancar, 1999; Okamura et al., 1999; van der Horst et al., 1999; Vitaterna et al., 1999), or other Per proteins in the hamster SCN after nonphotic stimuli, because these assessments will better clarify the cascading effects of nonphotic stimuli on the clock loop.

The levels of mPer3 mRNA are not affected by light exposure (Takumi et al., 1998b; Zylka et al., 1998). In the present experiment, Per3 mRNA levels in the hamster SCN were unresponsive to light exposure at CT20 or to administration of 8-OH DPAT at various CTs. Triazolam also did not affect Per3 mRNA levels. We do not know why Per3 mRNA levels in the SCN are insensitive to both photic and nonphotic stimuli. It could be that acute changing of the expression of Per3 is not required for phase shifts in mice and hamster circadian rhythms.

In summary, we found that the acute and circadian time-dependent reduction of Per1 or Per2 mRNA, or both, in the hamster SCN by 8-OH DPAT strongly correlates with the phase resetting in response to 8-OH DPAT. Therefore, the present findings suggest that nonphotic shifts involve alteration in Per1 or Per2 mRNA levels, or both, in the SCN.


    FOOTNOTES

Received Sept. 7, 1999; revised April 27, 2000; accepted May 11, 2000.

This study was partially supported by grants awarded to S.S. from the Research Project for the Future Program (RFTF96L00310), the Japanese Ministry of Education, Science, Sports, and Culture (11170248, 1123207, 11145240), and The Special Coordination Funds of the Japanese Science and Technology Agency.

Correspondence should be addressed to Shigenobu Shibata, Department of Pharmacology and Brain Science, School of Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan. E-mail address: shibata{at}human.waseda.ac.jp.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

  • Akiyama M, Kouzu Y, Takahashi S, Wakamatsu H, Moriya T, Maetani M, Watanabe S, Tei H, Sakaki Y, Shibata S (1999) Inhibition of light- or glutamate-induced mPer1 expression represses the phase shifts into the mouse circadian locomotor and suprachiasmatic firing rhythms. J Neurosci 19:1115-1121[Abstract/Free Full Text].
  • Albrecht U, Sun ZS, Eichele G, Lee CC (1997) A differential response of two putative mammalian circadian regulators, mPer1 and mPer2, to light. Cell 91:1055-1064[Web of Science][Medline].
  • Biello SM, Janik D, Mrosovsky N (1994) Neuropeptide Y and behaviorally induced phase shifts. Neuroscience 62:273-279[Web of Science][Medline].
  • Challet E, Scarbrough K, Penev PD, Turek FW (1998) Roles of suprachiasmatic nuclei and intergeniculate leaflets in mediating the phase-shifting effects of a serotonergic agonist and their photic modulation during subjective day. J Biol Rhythms 13:410-421[Abstract/Free Full Text].
  • Cutrera RA, Saboureau M, Pevet P (1996) Phase-shifting effect of 8-OH DPAT, a 5-HT1A/5-HT7 receptor agonist, on locomotor activity in golden hamster in constant darkness. Neurosci Lett 210:1-4[Web of Science][Medline].
  • Daan S, Pittendrigh C (1976) A functional analysis of circadian pacemakers in nocturnal rodents II. The variability of phase response curves. J Comp Physiol [A] 106:253-266.
  • de Vries MJ, Nunes Cardozo B, van der Want J, de Wolf A, Meijer JH (1993) Glutamate immunoreactivity in terminals of the retinohypothalamic tract of the brown Norwegian rat. Brain Res 612:231-237[Web of Science][Medline].
  • Ding JM, Chen D, Weber ET, Faiman LE, Rea MA, Gillette MU (1994) Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science 266:1713-1717[Abstract/Free Full Text].
  • Ding JM, Faiman LE, Hurst WJ, Kuriashkina LR, Gillette MU (1997) Resetting the biological clock: mediation of nocturnal CREB phosphorylation via light, glutamate, and nitric oxide. J Neurosci 17:667-675[Abstract/Free Full Text].
  • Dunlap JC (1999) Molecular bases for circadian clocks. Cell 96:271-290[Web of Science][Medline].
  • Edgar DM, Miller JD, Prosser R, Dean RR, Dement WC (1993) Serotonin and the mammalian circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists. J Biol Rhythms 8:17-31[Abstract/Free Full Text].
  • Eriksson H, Evrin K (1996) An evaluation of the 5-HT7 receptor mediated signal transduction pathway in a transfected cell line by using the cytosensor microphysiometer. Soc Neurosci Abstr 22:1782.
  • Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ (1998) Role of the CLOCK protein in the mammalian circadian mechanism. Science 280:1564-1569[Abstract/Free Full Text].
  • Griffin Jr EA, Staknis D, Weitz CJ (1999) Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286:768-771[Abstract/Free Full Text].
  • Hannibal J, Ding JM, Chen D, Fahrenkrug J, Larsen PJ, Gillette MU, Mikkelsen JD (1997) Pituitary adenylate cyclase-activating peptide (PACAP) in the retinohypothalamic tract: a potential daytime regulator of the biological clock. J Neurosci 17:2637-2644[Abstract/Free Full Text].
  • Harrington ME, Hoque S, Hall A, Golombek D, Biello S (1999) Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light. J Neurosci 19:6637-6642[Abstract/Free Full Text].
  • Hastings MH (1997) Central clocking. Trends Neurosci 20:459-464[Web of Science][Medline].
  • Jin X, Shearman LP, Weaver DR, Zylka MJ, de Vries GJ, Reppert SM (1999) A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96:57-68[Web of Science][Medline].
  • Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM (1999) mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98:193-205[Web of Science][Medline].
  • Leander P, Vrang N, Moller M (1998) Neuronal projections from the mesencephalic raphe nuclear complex to the suprachiasmatic nucleus and the deep pineal gland of the golden hamster (Mesocricetus auratus). J Comp Neurol 14:73-93.
  • Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW, Danielson PE, Sutcliffe JG, Erlander MG (1993) A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron 11:449-458[Web of Science][Medline].
  • Maywood ES, Smith E, Hall SJ, Hastings MH (1997) A thalamic contribution to arousal-induced, non-photic entrainment of the circadian clock of the Syrian hamster. Eur J Neurosci 9:1739-1747[Web of Science][Medline].
  • Maywood ES, Mrosovsky N, Field MD, Hastings MH (1999) Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock. Proc Natl Acad Sci USA 96:15211-15216[Abstract/Free Full Text].
  • McNulty S, Schurov IL, Sloper PJ, Hastings MH (1998) Stimuli which entrain the circadian clock of the neonatal Syrian hamster in vivo regulate the phosphorylation of the transcription factor CREB in the suprachiasmatic nucleus in vitro. Eur J Neurosci 10:1063-1072[Web of Science][Medline].
  • Mead S, Ebling FJ, Maywood ES, Humby T, Herbert J, Hastings MH (1992) A nonphotic stimulus causes instantaneous phase advances of the light-entrainable circadian oscillator of the Syrian hamster but does not induce the expression of c-fos in the suprachiasmatic nuclei. J Neurosci 12:2516-2522[Abstract].
  • Meyer-Bernstein EL, Morin LP (1996) Differential serotonergic innervation of the suprachiasmatic nucleus and the intergeniculate leaflet and its role in circadian rhythm modulation. J Neurosci 16:2097-2111[Abstract/Free Full Text].
  • Miller JD, Liu ZW, Tenner T (1996) Activity of 8-OH-DPAT enantiomers at the 5-HT7 receptor in SCN and transfected CHO cells. Soc Neurosci Abstr 22:1142.
  • Mintz EM, Gillespie CF, Marvel CL, Huhman KL, Albers HE (1997) Serotonergic regulation of circadian rhythms in syrian hamsters. Neuroscience 79:563-569[Web of Science][Medline].
  • Miyamoto Y, Sancar A (1999) Circadian regulation of cryptochrome genes in the mouse. Brain Res Mol Brain Res 71:238-243[Medline].
  • Moore RY (1982) The suprachiasmatic nucleus and the organization of a circadian system. Trends Neurosci 5:404-407[Web of Science].
  • Mrosovsky N (1988) Phase response curves for social entrainment. J Comp Physiol [A] 162:35-46[Medline].
  • Obrietan K, Impey S, Storm DR (1998) Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nat Neurosci 1:693-700[Web of Science][Medline].
  • Okamura H, Miyake S, Sumi Y, Yamaguchi S, Yasui A, Muijtjens M, Hoeijmakers JH, van der Horst GT (1999) Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 286:2531-2534[Abstract/Free Full Text].
  • Prosser RA, Gillette MU (1989) The mammalian circadian clock in the suprachiasmatic nuclei is reset in vitro by cAMP. J Neurosci 9:1073-1081[Abstract].
  • Prosser RA, Dean RR, Edgar DM, Heller HC, Miller JD (1993) Serotonin and the mammalian circadian system: I. In vitro phase shifts by serotonergic agonists and antagonists. J Biol Rhythms 8:1-16[Abstract/Free Full Text].
  • Prosser RA, Heller HC, Miller JD (1994) Serotonergic phase advances of the mammalian circadian clock involve protein kinase A and K+ channel opening. Brain Res 644:67-73[Web of Science][Medline].
  • Reebs SG, Mrosovsky N (1989) Effects of induced wheel running on the circadian activity rhythm of Syrian hamsters: entrainment and phase response curve. J Biol Rhythms 4:39-48[Abstract/Free Full Text].
  • Sakamoto K, Nagase T, Fukui H, Horikawa K, Okada T, Tanaka H, Sato K, Miyake Y, Ohara O, Kako K, Ishida N (1998) Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain. J Biol Chem 273:27039-27042[Abstract/Free Full Text].
  • Schuhler S, Saboureau M, Pitrosky B, Pevet P (1998) In Syrian hamsters, 5-HT fibres within the suprachiasmatic nuclei are necessary for the expression of 8-OH-DPAT induced phase-advance of locomotor activity rhythm. Neurosci Lett 256:33-36[Web of Science][Medline].
  • Shearman LP, Zylka MJ, Weaver DR, Kolakowski Jr LF, Reppert SM (1997) Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19:1261-1269[Web of Science][Medline].
  • Shibata S, Tsuneyoshi A, Hamada T, Tominaga K, Watanabe S (1992) Phase-resetting effect of 8-OH DPAT, a serotonin 1A receptor agonist, on the circadian rhythm of firing rate in the rat suprachiasmatic nuclei in vitro. Brain Res 582:353-356[Web of Science][Medline].
  • Shibata S, Watanabe A, Hamada T, Ono M, Watanabe S (1994) N-methyl-D-aspartate induces phase shifts in circadian rhythm of neuronal activity of rat SCN in vitro. Am J Physiol 267:R360-R364[Abstract/Free Full Text].
  • Shigeyoshi Y, Taguchi K, Yamamoto S, Takekida S, Yan L, Tei H, Moriya T, Shibata S, Loros JJ, Dunlap JC, Okamura H (1997) Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell 91:1043-1053[Web of Science][Medline].
  • Shirakawa T, Moore RY (1994) Glutamate shifts the phase of the circadian neuronal firing rhythm in the rat suprachiasmatic nucleus in vitro. Neurosci Lett 178:47-50[Web of Science][Medline].
  • Sun ZS, Albrecht U, Zhuchenko O, Bailey J, Eichele G, Lee CC (1997) RIGUI, a putative mammalian ortholog of the Drosophila period gene. Cell 19:1003-1011.
  • Takumi T, Matsubara C, Shigeyoshi Y, Taguchi K, Yagita K, Maebayashi Y, Sakakida Y, Okumura K, Takashima N, Okamura H (1998a) A new mammalian period gene predominantly expressed in the suprachiasmatic nucleus. Genes Cells 3:167-176[Abstract].
  • Takumi T, Taguchi K, Miyake S, Sakakida Y, Takashima N, Matsubara C, Maebayashi Y, Okumura K, Takekida S, Yamamoto S, Yagita K, Yan L, Young MW, Okamura H (1998b) A light-independent oscillatory gene mPer3 in mouse SCN and OVLT. EMBO J 17:4753-4759[Web of Science][Medline].
  • Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose M, Sakaki Y (1997) Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389:512-516[Medline].
  • Thresher RJ, Vitaterna MH, Miyamoto Y, Kazantsev A, Hsu DS, Petit C, Selby CP, Dawut L, Smithies O, Takahashi JS, Sancar A (1998) Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282:1490-1494[Abstract/Free Full Text].
  • Tominaga K, Shibata S, Ueki S, Watanabe S (1992) Effects of 5-HT1A receptor agonists on the circadian rhythm of wheel-running activity in hamsters. Eur J Pharmacol 214:79-84[Web of Science][Medline].
  • Tsou AP, Kosaka A, Bach C, Zuppan P, Yee C, Tom L, Alvarez R, Ramsey S, Bonhaus DW, Stefanich E (1994) Cloning and expression of a 5-hydroxytryptamine7 receptor positively coupled to adenylyl cyclase. J Neurochem 63:456-464[Web of Science][Medline].
  • van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D, Buijs R, Bootsma D, Hoeijmakers JH, Yasui A (1999) Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398:627-630[Medline].
  • Vitaterna MH, Selby CP, Todo T, Niwa H, Thompson C, Fruechte EM, Hitomi K, Thresher RJ, Ishikawa T, Miyazaki J, Takahashi JS, Sancar A (1999) Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc Natl Acad Sci USA 96:12114-12119[Abstract/Free Full Text].
  • Yan L, Takekida S, Shigeyoshi Y, Okamura H (1999) Per1 and Per2 gene expression in the rat suprachiasmatic nucleus: circadian profile and the compartment-specific response to light. Neuroscience 94:141-150[Web of Science][Medline].
  • Ying SW, Rusak B (1997) 5-HT7 receptors mediate serotonergic effects on light-sensitive suprachiasmatic nucleus neurons. Brain Res 755:246-254[Web of Science][Medline].
  • Zylka MJ, Shearman LP, Weaver DR, Reppert SM (1998) Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20:1103-1110[Web of Science][Medline].

Copyright © 2000 Society for Neuroscience  0270-6474/00/20155867-07$05.00/0


This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. J. Legan, K. M. Donoghue, K. M. Franklin, and M. J. Duncan
Phenobarbital blockade of the preovulatory luteinizing hormone surge: association with phase-advanced circadian clock and altered suprachiasmatic nucleus Period1 gene expression
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1620 - R1630.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
A. M. Vosko, M. H. Hagenauer, D. L. Hummer, and T. M. Lee
Period gene expression in the diurnal degu (Octodon degus) differs from the nocturnal laboratory rat (Rattus norvegicus)
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2009; 296(2): R353 - R361.
[Abstract] [Full Text] [PDF]

Home page
 J Biol RhythmsHome page
J. C. Ehlen, C. M. Novak, M. C. Karom, K. L. Gamble, and H. E. Albers
Interactions of GABAA Receptor Activation and Light on Period mRNA Expression in the Suprachiasmatic Nucleus
J Biol Rhythms, February 1, 2008; 23(1): 16 - 25.
[Abstract] [PDF]

Home page
 EndocrinologyHome page
E. Challet
Minireview: Entrainment of the Suprachiasmatic Clockwork in Diurnal and Nocturnal Mammals
Endocrinology, December 1, 2007; 148(12): 5648 - 5655.
[Abstract] [Full Text] [PDF]

Home page
 Cold Spring Harb Symp Quant BiolHome page
U. Albrecht, A. Bordon, I. Schmutz, and J. Ripperger
The Multiple Facets of Per2
Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 95 - 104.
[Abstract] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
H. Abe, S. Honma, and K.-i. Honma
Daily restricted feeding resets the circadian clock in the suprachiasmatic nucleus of CS mice
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R607 - R615.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. E. Knoch, D. Siegel, M. J. Duncan, and J. D. Glass
Serotonergic mediation of constant light-potentiated nonphotic phase shifting of the circadian locomotor activity rhythm in Syrian hamsters
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2006; 291(1): R180 - R188.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. E. Mistlberger
Illuminating serotonergic gateways for strong resetting of the mammalian circadian clock
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2006; 291(1): R177 - R179.
[Full Text] [PDF]

Home page
 EndocrinologyHome page
C.-X. Yi, J. van der Vliet, J. Dai, G. Yin, L. Ru, and R. M. Buijs
Ventromedial Arcuate Nucleus Communicates Peripheral Metabolic Information to the Suprachiasmatic Nucleus
Endocrinology, January 1, 2006; 147(1): 283 - 294.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. Ushijima, H. Sakaguchi, Y. Sato, H. To, S. Koyanagi, S. Higuchi, and S. Ohdo
Chronopharmacological Study of Antidepressants in Forced Swimming Test of Mice
J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 764 - 770.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
T. Akagi, K. Ushinohama, S. Ikesue, E. Yukawa, S. Higuchi, K. Hamase, K. Zaitsu, and S. Ohdo
Chronopharmacology of Melatonin in Mice to Maximize the Antitumor Effect and Minimize the Rhythm Disturbance Effect
J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 378 - 384.
[Abstract] [Full Text] [PDF]

Home page
 J Biol RhythmsHome page
M. J. Vansteensel, T. Deboer, A. Dahan, and J. H. Meijer
Differential Responses of Circadian Activity Onset and Offset Following GABA-ergic and Opioid Receptor Activation
J Biol Rhythms, August 1, 2003; 18(4): 297 - 306.
[Abstract] [PDF]

Home page
 J Biol RhythmsHome page
M. C. Antle, D. K. Foley, N. C. Foley, and R. Silver
Gates and Oscillators: A Network Model of the Brain Clock
J Biol Rhythms, August 1, 2003; 18(4): 339 - 350.
[Abstract] [PDF]

Home page
 J Biol RhythmsHome page
K. Bae and D. R. Weaver
Light-Induced Phase Shifts in Mice Lacking mPER1 or mPER2
J Biol Rhythms, April 1, 2003; 18(2): 123 - 133.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
T. Hirota, T. Okano, K. Kokame, H. Shirotani-Ikejima, T. Miyata, and Y. Fukada
Glucose Down-regulates Per1 and Per2 mRNA Levels and Induces Circadian Gene Expression in Cultured Rat-1 Fibroblasts
J. Biol. Chem., November 8, 2002; 277(46): 44244 - 44251.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Z. Travnickova-Bendova, N. Cermakian, S. M. Reppert, and P. Sassone-Corsi
Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity
PNAS, May 28, 2002; 99(11): 7728 - 7733.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
D. E. Kolker, S. Losee Olson, J. Dutton-Boilek, K. M. Bennett, E. P. Wallen, T. H. Horton, and F. W. Turek
Feeding melatonin enhances the phase shifting response to triazolam in both young and old golden hamsters
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1382 - R1388.
[Abstract] [Full Text] [PDF]

Home page
 J Biol RhythmsHome page
A. Jovanovska and R. A. Prosser
Translational and Transcriptional Inhibitors Block Serotonergic Phase Advances of the Suprachiasmatic Nucleus Circadian Pacemaker In Vitro
J Biol Rhythms, April 1, 2002; 17(2): 137 - 146.
[Abstract] [PDF]

Home page
 J. Appl. Physiol.Home page
U. Albrecht
Functional Genomics of Sleep and Circadian Rhythm: Invited Review: Regulation of mammalian circadian clock genes
J Appl Physiol, March 1, 2002; 92(3): 1348 - 1355.
[Abstract] [Full Text] [PDF]

Home page
 J Biol RhythmsHome page
J. M. Brewer, P. C. Yannielli, and M. E. Harrington
Neuropeptide Y Differentially Suppresses per1 and per2 mRNA Induced by Light in the Suprachiasmatic Nuclei of the Golden Hamster
J Biol Rhythms, February 1, 2002; 17(1): 28 - 39.
[Abstract] [PDF]

Home page
 J. Appl. Physiol.Home page
E. D. Herzog and W. J. Schwartz
Functional Genomics of Sleep and Circadian Rhythm: Invited Review: A neural clockwork for encoding circadian time
J Appl Physiol, January 1, 2002; 92(1): 401 - 408.
[Abstract] [Full Text] [PDF]

Home page
 J Biol RhythmsHome page
N. Mrosovsky, K. Edelstein, M. H. Hastings, and E. S. Maywood
Cycle of period Gene Expression in a Diurnal Mammal (Spermophilus tridecemlineatus): Implications for Nonphotic Phase Shifting
J Biol Rhythms, October 1, 2001; 16(5): 471 - 478.
[Abstract] [PDF]

Home page
 J. Neurosci.Home page
T. Hamada, J. LeSauter, J. M. Venuti, and R. Silver
Expression of Period Genes: Rhythmic and Nonrhythmic Compartments of the Suprachiasmatic Nucleus Pacemaker
J. Neurosci., October 1, 2001; 21(19): 7742 - 7750.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
J. C. Ehlen, G. H. Grossman, and J. D. Glass
In Vivo Resetting of the Hamster Circadian Clock by 5-HT7 Receptors in the Suprachiasmatic Nucleus
J. Neurosci., July 15, 2001; 21(14): 5351 - 5357.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Doi, Y. Nakajima, T. Okano, and Y. Fukada
Light-induced phase-delay of the chicken pineal circadian clock is associated with the induction of cE4bp4, a potential transcriptional repressor of cPer2 gene
PNAS, June 20, 2001; (2001) 141090998.
[Abstract] [Full Text] [PDF]

Home page
 J Biol RhythmsHome page
U. Albrecht, B. Zheng, D. Larkin, Z. S. Sun, and C. C. Lee
mPer1 and mPer2 Are Essential for Normal Resetting of the Circadian Clock
J Biol Rhythms, April 1, 2001; 16(2): 100 - 104.
[Abstract] [PDF]

Home page
 Mol. Pharmacol.Home page
T. Nikaido, M. Akiyama, T. Moriya, and S. Shibata
Sensitized Increase of Period Gene Expression in the Mouse Caudate/Putamen Caused by Repeated Injection of Methamphetamine
Mol. Pharmacol., April 1, 2001; 59(4): 894 - 900.
[Abstract] [Full Text]

Home page
 J Biol RhythmsHome page
B. N. Smith, P. J. Sollars, F. E. Dudek, and G. E. Pickard
Serotonergic Modulation of Retinal Input to the Mouse Suprachiasmatic Nucleus Mediated by 5-HT1B and 5-HT7 Receptors
J Biol Rhythms, February 1, 2001; 16(1): 25 - 38.
[Abstract] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Doi, Y. Nakajima, T. Okano, and Y. Fukada
Light-induced phase-delay of the chicken pineal circadian clock is associated with the induction of cE4bp4, a potential transcriptional repressor of cPer2 gene
PNAS, July 3, 2001; 98(14): 8089 - 8094.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an eLetter
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (99)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Horikawa, K.
Right arrow Articles by Shibata, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Horikawa, K.
Right arrow Articles by Shibata, S.

-
-

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help
-
Copyright 2009 by Society for Neuroscience ONLINE ISSN: 1529-2401
-