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Gene Review

Hcrt  -  hypocretin

Mus musculus

Synonyms: Hypocretin, Orexin, Ox, Ppox, orexin A, ...
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Disease relevance of Hcrt


Psychiatry related information on Hcrt


High impact information on Hcrt


Chemical compound and disease context of Hcrt

  • We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 +/- 8 mmHg in wild type and 92 +/- 3 in knockout) and conscious (125 +/- 6 mmHg in wild type and 109 +/- 2 in knockout) conditions. alpha-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP [10].
  • Here we provide several lines of evidence that orexin A induces wakefulness by means of the TMN and histamine H(1) receptor (H1R) [11].
  • Calcium imaging using orexin/YC2.1 transgenic mouse brain revealed that NA-induced inhibition of orexin neurons is not altered by sleep deprivation or circadian time in mice [12].
  • Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates [13].
  • We thus compared the effects of orexin A and some established secretagogues on duodenal HCO3- secretion in fed rats with effects in rats exposed to short (overnight) food deprivation [14].

Biological context of Hcrt


Anatomical context of Hcrt

  • Prepro-Hcrt/OX mRNA expression, measured by in situ hybridization was restricted to the lateral hypothalamus area [18].
  • Acute third ventricle (i3vt) injections of Hcrt/OX peptides in ob/ob mice transiently increased their metabolic rate and stimulated lipid substrate utilization [18].
  • Hcrt-2 actions were stronger than those of Hcrt-1, and the action persisted in TTX and in low calcium/high magnesium artificial cerebrospinal fluid, consistent with direct actions mediated by Hcrt receptor-2 [19].
  • Collectively, our findings indicate that Hcrt/Orx signaling in the reticular activating system involves elevation of [Ca(2+)](i) by a PKC-involved influx of Ca(2+) across the plasma membrane, in part, via L-type calcium channels [20].
  • The paraventricular thalamic nucleus (PVT) receives one of the most dense innervations by hypothalamic hypocretin/orexin (Hcrt) neurons, which play important roles in sleep-wakefulness, attention, and autonomic function [19].

Associations of Hcrt with chemical compounds

  • Activity of isolated orexin neurons is inhibited by glucose and leptin and stimulated by ghrelin [6].
  • We also found a decrease in basal orexin mRNA levels in the lateral hypothalamus of the D3-/- mice, which was unaltered by acute "binge" cocaine [21].
  • The robust excitation evoked by Hcrt-2 on cortically projecting glutamate PVT neurons could generate substantial excitation in multiple layers of the mPFC, adding to the more selective direct excitatory actions of Hcrt in the mPFC and potentially increasing cortical arousal and attention to limbic or visceral states [19].
  • In contrast, Hcrt/Orx responses were strongly attenuated by lowering extracellular Ca(2+) ( approximately 20 microM) but were not inhibited by concentrations of KB-R7943 (10 microM) selective for blockade of sodium/calcium exchange [20].
  • Nifedipine (10 microM), inhibited Hcrt/Orx responses but was more effective at abolishing spiking than plateau responses [20].
  • Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age [22].
  • These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA [23].

Physical interactions of Hcrt


Regulatory relationships of Hcrt


Other interactions of Hcrt

  • The expression of gastric ghrelin and hypothalamic orexin was decreased in PP-overexpressing mice [28].
  • There are two phylogenetically conserved regions located 287 bp (orexin regulatory element (OE) 1) and 2.5 kb (OE2) upstream of the transcription initiation site of the human prepro-orexin gene [3].
  • Adult mutants display increased hypothalamic CRH and NPY levels, but peptide levels of melanin concentrating hormone and Orexin A and B are unchanged [29].
  • However, RF shifted the peak of Fos expression of the orexin neurons from night to day [30].
  • The expression of mNpas2 mRNA, a transcription factor thought to be involved in regulation of the food entrainable oscillator as well as mPer1 and mBmal1 mRNA, was reduced in the forebrain of orexin/ataxin-3 mice [30].

Analytical, diagnostic and therapeutic context of Hcrt

  • Whole-cell recordings revealed that Hcrt/Orx had actions on both presynaptic neurons and at postsynaptic sites [17].
  • To characterize the physiological role(s) of orexins in the mouse, we cloned and characterized the mouse orexin receptor(s), mOX1R and mOX2R, using rapid amplification of cDNA (mouse brain) ends, RT-PCR, and gene structure analysis [31].
  • After depriving mice of sleep for 2-8 hr, orexin KO mice recovered their NREM and rapid eye movement sleep deficits at comparable rates and to the same extent as WT mice, with similar increases in EEG delta power, suggesting that their homeostatic control of sleep is normal [32].
  • Microdialysis studies showed that application of orexin A to the TMN increased histamine release from both the medial preoptic area and the frontal cortex by approximately 2-fold over the baseline for 80 to 160 min in a dose-dependent manner [11].
  • Perfusion of orexin A (5 and 25 pmol/min) for 1 hr into the TMN of rats through a microdialysis probe promptly increased wakefulness for 2 hr after starting the perfusion by 2.5- and 4-fold, respectively, concomitant with a reduction in rapid eye movement (REM) and non-REM sleep [11].


  1. Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models. Fujiki, N., Yoshida, Y., Zhang, S., Sakurai, T., Yanagisawa, M., Nishino, S. Peptides (2006) [Pubmed]
  2. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Willie, J.T., Chemelli, R.M., Sinton, C.M., Yanagisawa, M. Annu. Rev. Neurosci. (2001) [Pubmed]
  3. The human prepro-orexin gene regulatory region that activates gene expression in the lateral region and represses it in the medial regions of the hypothalamus. Moriguchi, T., Sakurai, T., Takahashi, S., Goto, K., Yamamoto, M. J. Biol. Chem. (2002) [Pubmed]
  4. High level of orexin A observed in the phenylketonuria mouse brain is due to the abnormal expression of prepro-orexin. Surendran, S., Rady, P.L., Szucs, S., Michals-Matalon, K., Tyring, S.K., Matalon, R. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  5. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Willie, J.T., Chemelli, R.M., Sinton, C.M., Tokita, S., Williams, S.C., Kisanuki, Y.Y., Marcus, J.N., Lee, C., Elmquist, J.K., Kohlmeier, K.A., Leonard, C.S., Richardson, J.A., Hammer, R.E., Yanagisawa, M. Neuron (2003) [Pubmed]
  6. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Yamanaka, A., Beuckmann, C.T., Willie, J.T., Hara, J., Tsujino, N., Mieda, M., Tominaga, M., Yagami, K., Sugiyama, F., Goto, K., Yanagisawa, M., Sakurai, T. Neuron (2003) [Pubmed]
  7. GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. Xie, X., Crowder, T.L., Yamanaka, A., Morairty, S.R., Lewinter, R.D., Sakurai, T., Kilduff, T.S. J. Physiol. (Lond.) (2006) [Pubmed]
  8. Age-related decline in hypocretin (orexin) receptor 2 messenger RNA levels in the mouse brain. Terao, A., Apte-Deshpande, A., Morairty, S., Freund, Y.R., Kilduff, T.S. Neurosci. Lett. (2002) [Pubmed]
  9. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Richardson, J.A., Williams, S.C., Xiong, Y., Kisanuki, Y., Fitch, T.E., Nakazato, M., Hammer, R.E., Saper, C.B., Yanagisawa, M. Cell (1999) [Pubmed]
  10. Attenuated defense response and low basal blood pressure in orexin knockout mice. Kayaba, Y., Nakamura, A., Kasuya, Y., Ohuchi, T., Yanagisawa, M., Komuro, I., Fukuda, Y., Kuwaki, T. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2003) [Pubmed]
  11. Arousal effect of orexin A depends on activation of the histaminergic system. Huang, Z.L., Qu, W.M., Li, W.D., Mochizuki, T., Eguchi, N., Watanabe, T., Urade, Y., Hayaishi, O. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  12. Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. Yamanaka, A., Muraki, Y., Ichiki, K., Tsujino, N., Kilduff, T.S., Goto, K., Sakurai, T. J. Neurophysiol. (2006) [Pubmed]
  13. Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates. Willie, J.T., Renthal, W., Chemelli, R.M., Miller, M.S., Scammell, T.E., Yanagisawa, M., Sinton, C.M. Neuroscience (2005) [Pubmed]
  14. Short fasting dramatically decreases rat duodenal secretory responsiveness to orexin A but not to VIP or melatonin. Flemström, G., Sjöblom, M., Jedstedt, G., Akerman, K.E. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  15. A commentary on the neurobiology of the hypocretin/orexin system. Mignot, E. Neuropsychopharmacology (2001) [Pubmed]
  16. Down regulation of the prepro-orexin gene expression in genetically obese mice. Yamamoto, Y., Ueta, Y., Date, Y., Nakazato, M., Hara, Y., Serino, R., Nomura, M., Shibuya, I., Matsukura, S., Yamashita, H. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  17. Direct and indirect excitation of laterodorsal tegmental neurons by Hypocretin/Orexin peptides: implications for wakefulness and narcolepsy. Burlet, S., Tyler, C.J., Leonard, C.S. J. Neurosci. (2002) [Pubmed]
  18. Orexins/hypocretins in the ob/ob mouse: hypothalamic gene expression, peptide content and metabolic effects. Stricker-Krongrad, A., Richy, S., Beck, B. Regul. Pept. (2002) [Pubmed]
  19. Prefrontal cortex-projecting glutamatergic thalamic paraventricular nucleus-excited by hypocretin: a feedforward circuit that may enhance cognitive arousal. Huang, H., Ghosh, P., van den Pol, A.N. J. Neurophysiol. (2006) [Pubmed]
  20. Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. Kohlmeier, K.A., Inoue, T., Leonard, C.S. J. Neurophysiol. (2004) [Pubmed]
  21. Effects of acute "binge" cocaine on mRNA levels of mu opioid receptor and neuropeptides in dopamine D1 or D3 receptor knockout mice. Zhou, Y., Adomako-Mensah, J., Yuferov, V., Ho, A., Zhang, J., Xu, M., Kreek, M.J. Synapse (2007) [Pubmed]
  22. Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice. Tsuneki, H., Murata, S., Anzawa, Y., Soeda, Y., Tokai, E., Wada, T., Kimura, I., Yanagisawa, M., Sakurai, T., Sasaoka, T. Diabetologia (2008) [Pubmed]
  23. Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia. Xie, X., Wisor, J.P., Hara, J., Crowder, T.L., LeWinter, R., Khroyan, T.V., Yamanaka, A., Diano, S., Horvath, T.L., Sakurai, T., Toll, L., Kilduff, T.S. J. Clin. Invest. (2008) [Pubmed]
  24. Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions. Hara, J., Yanagisawa, M., Sakurai, T. Neurosci. Lett. (2005) [Pubmed]
  25. Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. Fu, L.Y., Acuna-Goycolea, C., van den Pol, A.N. J. Neurosci. (2004) [Pubmed]
  26. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. Winsky-Sommerer, R., Yamanaka, A., Diano, S., Borok, E., Roberts, A.J., Sakurai, T., Kilduff, T.S., Horvath, T.L., de Lecea, L. J. Neurosci. (2004) [Pubmed]
  27. Ghrelin-induced food intake is mediated via the orexin pathway. Toshinai, K., Date, Y., Murakami, N., Shimada, M., Mondal, M.S., Shimbara, T., Guan, J.L., Wang, Q.P., Funahashi, H., Sakurai, T., Shioda, S., Matsukura, S., Kangawa, K., Nakazato, M. Endocrinology (2003) [Pubmed]
  28. Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Asakawa, A., Inui, A., Yuzuriha, H., Ueno, N., Katsuura, G., Fujimiya, M., Fujino, M.A., Niijima, A., Meguid, M.M., Kasuga, M. Gastroenterology (2003) [Pubmed]
  29. Inactivation of the GR in the nervous system affects energy accumulation. Kellendonk, C., Eiden, S., Kretz, O., Schütz, G., Schmidt, I., Tronche, F., Simon, E. Endocrinology (2002) [Pubmed]
  30. Reduced food anticipatory activity in genetically orexin (hypocretin) neuron-ablated mice. Akiyama, M., Yuasa, T., Hayasaka, N., Horikawa, K., Sakurai, T., Shibata, S. Eur. J. Neurosci. (2004) [Pubmed]
  31. Genomic organization of mouse orexin receptors: characterization of two novel tissue-specific splice variants. Chen, J., Randeva, H.S. Mol. Endocrinol. (2004) [Pubmed]
  32. Behavioral state instability in orexin knock-out mice. Mochizuki, T., Crocker, A., McCormack, S., Yanagisawa, M., Sakurai, T., Scammell, T.E. J. Neurosci. (2004) [Pubmed]
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