Hitoshi Okamura

Last updated
Hitoshi Okamura
Born (1952-12-02) December 2, 1952 (age 71)
Nationality Japanese
Scientific career
Fields Chronobiology, Physiology
Website Okamura Lab

Hitoshi Okamura (born December 2, 1952) [1] is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. [2] His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension. [3]

Contents

Education

Hitoshi Okamura received his undergraduate, medical, and doctorate in science degrees from the Kyoto Prefectural University of Medicine. After training as a pediatrician at the Children's Medical Center of the Okayama National Hospital (1979-1981), he worked on neuroanatomy at the Kyoto Prefectural University of Medicine (1981-1995). He was then a professor of Brain Sciences at the Kobe University School of Medicine from 1995 to 2008. [4] Since 2007, he has worked as a professor of Systems Biology at the Kyoto University Graduate School of Pharmaceutical Sciences. [5] Since 2014, he has worked as the Research Director of the Japan Science Technology Institute, CREST. His work has focused on understanding mammalian circadian rhythms.

Awards and honors

Scientific contributions

Suprachiasmatic Nucleus research

Okamura began his study of circadian rhythms in 1982 with the peptide work in the suprachiasmatic nucleus (SCN) using the technique of histochemistry in Yasuhiko Ibata's laboratory in the Kyoto Prefectural University of Medicine. He established quantitative histochemistry of the suprachiasmatic nucleus (SCN) in the 1980s, and together with Shin-Ichi Inouye, established in vitro slice cultures of the SCN in the early 1990s. [6]

Discovery of Mammalian Period Genes

In 1997, Hajime Tei, Yoshiyuki Sakaki, and Hitoshi Okamura discovered the mammalian period gene PER1 in mice and humans. They also discovered PER2, PER3, and the mammalian homolog of the Drosophila gene timeless. [7] They found that Per1 is light-inducible and can phase shift the circadian clock by light. [8] Okamura worked with Jay Dunlap, a chronobiologist specializing in circadian rhythms in Neurospora, to show that mammalian clocks are similar to neurospora clocks in their use of induction to phase shift. This is in contrast to the drosophila clock, which phase shift via protein degradation rather than induction. [9]

Protein Level Regulation of Mammalian Per

Okamura's team discovered that mammalian PER proteins made in the cytoplasm translocate into the nucleus of the cell and form a complex composed of CRY1, CRY2, PER1, PER2, PER3, and TIM. [10] This negative complex suppresses the transcription of mRNA activated by CLOCK and BMAL1. [11] Okamura has also done research on mPER1 and mPER2 degradation. They found that PER and CRY form a dimer that inhibits PER degradation and that the inhibition of PER degradation suppresses Per1 and Per2 transcription. [10] This negative feedback loop appears to be found in all clocks. [12]

Core clock loop of clock genes is universal among mammalian cells

Okamura became interested in the possible differences of autonomously rhythmic clock genes in fibroblast cell lines and those in the SCN. His team discovered that in mice, both types of cells showed temporal expression of profiles of all known clock genes, [13] the phases of various mRNA rhythms, the delay between maximum mRNA levels and appearance of nuclear PER1 and PER2 protein, the inability to produce circadian oscillations in the absence of functional Cry genes, and the control of period length by CRY proteins.

Total Loss of Oscillation in mCry1/mCry2-double knockout mice

Okamura collaborated with Gijsbertus T.J. van der Horst and found that both peripheral and central clocks are stopped in Cry deficient mice. [11] Okamura also collaborated with Shin-Ichi Inouye to find that behavioral circadian rhythmicity was recovered when the SCN from wild-type mice was transplanted into Cry deficient mice. This suggests that the suprachiasmatic nucleus (SCN) synchronizes and generates behavioral rhythms. [14]

Restoration of Circadian Rhythms Using Mammalian Per

Okamura collaborated with Amita Sehgal to determine if the mPer1 and mPer2 genes were able to generate circadian oscillations. [5] They transplanted Per1 and Per2 genes from mice into arrhythmic per0 mutants of Drosophila and found that transplantation restored circadian rhythms. [15]

SCN as the Central Clock

Okamura's team also analyzed the SCN at the cellular level. They succeeded in monitoring the rhythmic transcription of genes at the single cell level in real-time. This work was achieved by combining the SCN slice-culture technique, transgenic mice carrying the luciferase gene driven by the Per1 promoter (Per1-luc), and the cryogenic high resolution CCD camera. They have demonstrated that a stable ensemble SCN rhythm is orchestrated within an assembly of cellular clocks that are differentially phased and that sit in a distinct topographic order in the SCN. Tetrodotoxin, which blocks action potentials, not only desynchronizes the cell population, but also suppresses the level of clock gene expression, demonstrating that neuronal networks play a dominant role in oscillation of rhythms in the SCN. Using the same Per-luc mice with the optical fiber inserted to the brain, Okamura's team succeeded in monitoring the rhythmic gene expression of the clock gene in real-time in freely moving mice, demonstrating that the Per gene is activated in the daytime and rests in the nighttime in the SCN. Okamura discovered that flashing NMDA, which is analogous to light stimuli, instantly altered the phase of the core clock oscillation of a slice of SCN. [16] This proved that there is rhythmic transcription of genes at the single cell level. It has been shown that the SCN regulates peripheral clocks by regulating melatonin in the sympathetic nervous system. [17] Okamura's team also demonstrated that the light can activate genes and corticosterone secretion in the adrenal gland through the SCN-sympathetic nerve routes. So, the sympathetic nerve conveys the time signal of the core central clock (SCN) to peripheral organs, and the adrenal gland is the key organ in transforming circadian signals from nerve signals to the endocrine signals. [14]

Cell Clock and Cell Cycle

Okamura's team has also looked into the relationship between the circadian clock and the cell cycle. They performed DNA arrays and Northern blots to characterize the molecular differences in M-phase entry and found that cyclin B1 and cdc2 were positively correlated. They also found that wee1, the gene for a kinase that inhibits mitosis by inactivating CDC2/cyclin B, was negatively correlated to M-phase. [18] Their research showed that mouse hepatocyte proliferation is under circadian control. [19]

Current research pursuits

In more recent years, Okamura and his team extended their molecular clock work to posttranscriptional, intercellular, and systemic levels. [20] They found the mRNA methylation alters the speed of circadian rhythms [3] and heterogeneity of G protein signaling is necessary for time-keeping in the SCN. [21] Moreover, they found the dysregulated clock induces salt-sensitive hypertension through the inappropriate secretion of aldosterone. [22] Another discovery was that clock regulation of gap junction protein in the urinary bladder was a cause of abnormal urination. [23] Very recently, they found that vasopressin signaling in the SCN is crucial for jet lag. [24] [25]

Now, Okamura continues investigations of biological clocks, fascinated with the integrational characteristics of "time" in a vertical arrangement, providing a bridge between single genes and the living organism as a whole.

Comprehensive timeline

Name [1] [5] Year
Born1952
Becomes a professor in the Department of Anatomy II/Lab at Kobe University1995
Discovery of mammalian Per1, Per2, Per3, Timeless1997, 1998
Found that mPer is light-inducible1998
Discovery that clock proteins form complexes and prevent degradation2000, 2002, 2005
Work on fibroblasts and the universality of the core clock loop among mammalian cells2001
Loss of oscillations in Cry deficient mice2001
SCN transplantation restored circadian rhythms2003
Core clock regulates cell cycle2003
Light activates the adrenal gland via SCN-sympathetic nerves2005
Received Medal of Honor with Purple Ribbon2007
Became Professor of Systems Biology at Kyoto University/Pharmaceutical Sciences2007
Received Aschoff's Ruler2009
The role of dysregulated clocks in salt-sensitive hypertension2010
Circadian G protein signaling RGS16 in the SCN2011
mRNA methylation in regulation of circadian period length2013
Vasopressin is critical for jet lag2013
Became Research Director of the Japan Science Technology Institute, CREST2014

Related Research Articles

<span class="mw-page-title-main">Suprachiasmatic nucleus</span> Part of the brains hypothalamus

The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is the principal circadian pacemaker in mammals, responsible for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow it to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.

<span class="mw-page-title-main">CREB</span> Class of proteins

CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.

A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">PER3</span> Protein and coding gene in humans

The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.

Michael Menaker, was an American chronobiologist who was Commonwealth Professor of Biology at University of Virginia. His research focused on circadian rhythmicity of vertebrates, including contributing to an understanding of light input pathways on extra-retinal photoreceptors of non-mammalian vertebrates, discovering a mammalian mutation for circadian rhythmicity, and locating a circadian oscillator in the pineal gland of bird. He wrote almost 200 scientific publications.

Hajime Tei is a Japanese neuroscientist specializing in the study of chronobiology. He currently serves as a professor at the Kanazawa University Graduate School of Natural Science & Technology. He is most notable for his contributions to the discovery of the mammalian period genes, which he discovered alongside Yoshiyuki Sakaki and Hitoshi Okamura.

In the field of chronobiology, the dual circadian oscillator model refers to a model of entrainment initially proposed by Colin Pittendrigh and Serge Daan. The dual oscillator model suggests the presence of two coupled circadian oscillators: E (evening) and M (morning). The E oscillator is responsible for entraining the organism’s evening activity to dusk cues when the daylight fades, while the M oscillator is responsible for entraining the organism’s morning activity to dawn cues, when daylight increases. The E and M oscillators operate in an antiphase relationship. As the timing of the sun's position fluctuates over the course of the year, the oscillators' periods adjust accordingly. Other oscillators, including seasonal oscillators, have been found to work in conjunction with circadian oscillators in order to time different behaviors in organisms such as fruit flies.

<span class="mw-page-title-main">Sato Honma</span>

Sato Honma is a Japanese chronobiologist who researches the biological mechanisms of circadian rhythms. She mainly collaborates with Ken-Ichi Honma on publications, and both of their primary research focuses are the human circadian clock under temporal isolation and the mammalian suprachiasmatic nucleus (SCN), its components, and associates. Honma is a retired professor at the Hokkaido University School of Medicine in Sapporo, Japan. She received her Ph.D. in physiology from Hokkaido University. She taught physiology at the School of Medicine and then at the Research and Education Center for Brain Science at Hokkaido University. She is currently the director at the Center for Sleep and Circadian Rhythm Disorders at Sapporo Hanazono Hospital and works as a somnologist.

The food-entrainable oscillator (FEO) is a circadian clock that can be entrained by varying the time of food presentation. It was discovered when a rhythm was found in rat activity. This was called food anticipatory activity (FAA), and this is when the wheel-running activity of mice decreases after feeding, and then rapidly increases in the hours leading up to feeding. FAA appears to be present in non-mammals (pigeons/fish), but research heavily focuses on its presence in mammals. This rhythmic activity does not require the suprachiasmatic nucleus (SCN), the central circadian oscillator in mammals, implying the existence of an oscillator, the FEO, outside of the SCN, but the mechanism and location of the FEO is not yet known. There is ongoing research to investigate if the FEO is the only non-light entrainable oscillator in the body.

Martha Ulbrick Gillette is a chronobiologist and neurobiologist with research focusing on the effects of circadian clocks on integrative brain functions metabolism and the molecular mechanisms involved in signaling pathways. She is a fellow of the American Association for the Advancement of Science.

References

  1. 1 2 "Kyoto University Activity Database on Education and Research".
  2. ↑ "Prize Winners of Aschoff's Ruler". EBRS. Archived from the original on 2016-10-21. Retrieved 2015-04-09.
  3. 1 2 Fustin, Jean-Michael; Doi, Masao; Yamaguchi, Yoshiaka; Nishimura, Shinichi; Yoshia, Minoru; Isagawa, Takayuki; Morioka, Masaki; Kayeka, Hideaki; Manabe, Ichiro; Okamura, Hitoshi (November 7, 2013). "RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock". Cell. 155 (4): 793–806. doi: 10.1016/j.cell.2013.10.026 . PMID   24209618.
  4. ↑ "Prof Hitoshi Okamura". ISH 2012.
  5. 1 2 3 "Okamura Laboratory". Kyoto University Graduate School of Pharmaceutical Sciences, Department of Systems Biology.
  6. ↑ Tanaka, Masani; Ichitani, Yukio; Hitoshi, Okamura; Tanaka, Yoshifumi; Ibata, Yasuhiko (14 December 1992). "The direct retinal projection to VIP neuronal elements in the rat SCN". Brain Research Bulletin. 31 (6): 637–640. doi:10.1016/0361-9230(93)90134-w. PMID   8518955. S2CID   4762448.
  7. ↑ Reppert, Steven M; Weaver, David R (2001). "Molecular Analysis of Mammalian Circadian Rhythms". Annual Review of Physiology. 63 (1): 647–676. doi:10.1146/annurev.physiol.63.1.647. ISSN   0066-4278. PMID   11181971.
  8. ↑ Albrecht, Urs; Zheng, Binhai; Larkin, David; Sun, Zhong; Lee, Cheng (April 2001). "mPer1 and mPer2 Are Essential for Normal Resetting of the Circadian Clock". Journal of Biological Rhythms. 16 (2): 100–104. doi: 10.1177/074873001129001791 . PMID   11302552. S2CID   9067400.
  9. ↑ Liu, Yi (June 2003). "Molecular Mechanisms of Entrainment in the Neurospora Circadian Clock". Journal of Biological Rhythms. 18 (3): 195–205. doi:10.1177/0748730403018003002. PMID   12828277. S2CID   29200514.
  10. 1 2 Preitner, Nicolas; Damiola, Francesca; Lopez-Molina, Luis; Zakany, Joszef; Duboule, Denis; Albrecht, Urs; Schibler, Ueli (26 July 2002). "The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator". Cell. 110 (2): 251–260. doi: 10.1016/S0092-8674(02)00825-5 . PMID   12150932. S2CID   15224136.
  11. 1 2 Reppert, Steven M.; Weaver, David R. (2002). "Coordination of circadian timing in mammals". Nature. 418 (6901): 935–941. Bibcode:2002Natur.418..935R. doi:10.1038/nature00965. ISSN   0028-0836. PMID   12198538. S2CID   4430366.
  12. ↑ Balsalobre, Aurélio (24 January 2014). "Clock genes in mammalian peripheral tissues". Cell and Tissue Research. 309 (1): 193–199. doi:10.1007/s00441-002-0585-0. PMID   12111549. S2CID   27600488.
  13. ↑ Hastings, Michael; Reddy, Akhilesh; Maywood, Elizabeth (August 2003). "A clockwork web: circadian timing in brain and periphery, in health and disease". Nature Reviews Neuroscience. 4 (8): 649–661. doi:10.1038/nrn1177. PMID   12894240. S2CID   205499642.
  14. 1 2 Dibner, Charna; Schibler, Ueli; Albrecht, Urs (2010). "The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks" (PDF). Annual Review of Physiology. 72 (1): 517–549. doi:10.1146/annurev-physiol-021909-135821. ISSN   0066-4278. PMID   20148687.
  15. ↑ Hendricks, Joan C. (2003). "Invited Review: Sleeping flies don't lie: the use of Drosophila melanogaster to study sleep and circadian rhythms". Journal of Applied Physiology. 94 (4): 1660–1672. doi:10.1152/japplphysiol.00904.2002. ISSN   8750-7587. PMID   12626480.
  16. ↑ Colwell, Christopher (20 December 2001). "NMDA-evoked calcium transients and currents in the suprachiasmatic nucleus: gating by the circadian system". European Journal of Neuroscience. 13 (7): 1420–1428. doi:10.1046/j.0953-816x.2001.01517.x. PMC   2577309 . PMID   11298803.
  17. ↑ Bartness, Timothy; Demas, Gregory; Song, C. Kay (2002). "Seasonal Changes in Adiposity: the Roles of the Photoperiod, Melatonin and Other Hormones, and Sympathetic Nervous System". Experimental Biology and Medicine. 227 (6): 363–376. doi:10.1177/153537020222700601. PMID   12037125. S2CID   26813489.
  18. ↑ Mitra, Jayashree; Schultz, Richard (1 September 1996). "Regulation of the acquisition of meiotic competence in the mouse: changes in the subcellular localization of cdc2, cyclin B1, cdc25C and wee1, and in the concentration of these proteins and their transcripts". Journal of Cell Science. 109 (9): 2407–2415. doi:10.1242/jcs.109.9.2407. PMID   8886990.
  19. ↑ Fausto, Nelson; Campbell, Jean S.; Riehle, Kimberly J. (2006). "Liver regeneration". Hepatology. 43 (S1): S45–S53. doi:10.1002/hep.20969. ISSN   0270-9139. PMID   16447274. S2CID   39302882.
  20. ↑ "Raku-Yu" (PDF). Kyoto University Newsletter (Autumn 2014). 2014. Retrieved 2015-04-23.
  21. ↑ Doi, Masao; Ishida, Atsushi; Miyake, Akiko; Sato, Miho; Komatsu, Rie; Yamazaki, Fumiyoshi; Kimura, Ikuo; Tsuchiya, Soken; Kori, Hiroshi; Seo, Kazuyuki; Yamaguchi, Yoshiaki; Matsuo, Masahiro; Fustin, Jean-Michel; Tanaka, Rina; Santo, Yasuko; Yamada, Hiroyuki; Takahashi, Yukari; Araki, Michihiro; Nakao, Kazuki; Aizawa, Shinichi; Kobayashi, Masaki; Obrietan, Karl; Tsujimoto, Gozoh; Okamura, Hitoshi (2011). "Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus". Nature Communications. 2: 327. Bibcode:2011NatCo...2..327D. doi:10.1038/ncomms1316. ISSN   2041-1723. PMC   3112533 . PMID   21610730.
  22. ↑ Nikolaeva, S.; Pradervand, S.; Centeno, G.; Zavadova, V.; Tokonami, N.; Maillard, M.; Bonny, O.; Firsov, D. (2012). "The Circadian Clock Modulates Renal Sodium Handling". Journal of the American Society of Nephrology. 23 (6): 1019–1026. doi:10.1681/ASN.2011080842. ISSN   1046-6673. PMC   3358761 . PMID   22440902.
  23. ↑ Timóteo, M. Alexandrina; Carneiro, Inês; Silva, Isabel; Noronha-Matos, José Bernardo; Ferreirinha, Fátima; Silva-Ramos, Miguel; Correia-de-Sá, Paulo (2014). "ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors". Biochemical Pharmacology. 87 (2): 371–379. doi:10.1016/j.bcp.2013.11.007. ISSN   0006-2952. PMID   24269631.
  24. ↑ Sporns, Olaf; Ananthasubramaniam, Bharath; Herzog, Erik D.; Herzel, Hanspeter (2014). "Timing of Neuropeptide Coupling Determines Synchrony and Entrainment in the Mammalian Circadian Clock". PLOS Computational Biology. 10 (4): e1003565. Bibcode:2014PLSCB..10E3565A. doi: 10.1371/journal.pcbi.1003565 . ISSN   1553-7358. PMC   3990482 . PMID   24743470.
  25. ↑ Yamaguchi, Yoshiaki; Suzuki, Toru; Mizoro, Yasutaka; Kori, Hiroshi (October 2013). "Mice Genetically Deficient in Vasopressin V1a and V1b Receptors Are Resistant to Jet Lag". Science. 342 (6154): 85–90. Bibcode:2013Sci...342...85Y. doi:10.1126/science.1238599. PMID   24092737. S2CID   2681988.
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