Skip to main content
Log in

Stress and arousal

The corticotrophin-releasing factor/hypocretin circuitry

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The hypocretins (also know as orexins) are two neuropeptides now commonly described as critical components for maintaining and regulating the stability of arousal. Several lines of evidence have raised the hypothesis that hypocretin-producing neurons are part of the circuitries that mediate the hypothalamic response to acute stress. New data indicate that the corticotrophin-releasing factor (CRF) peptidergic system directly innervates hypocretin-expressing neurons. CRF depolarizes hypocretin neurons, and this effect is blocked by a CRF-R1 antagonist. Furthermore, activation of hypocretinergic neurons by stress is impaired in CRF-R1 knockout mice. These data suggest that CRF-R1 receptor mediates the stress-induced activation of the hypocretinergic system. A significant amount of evidence also indicates that hypocretin cells connect reciprocally to the CRF system. We propose that upon stressor stimuli, CRF activates the hypocretin system, which relays these signals to brain stem nuclei involved in the modulation of arousal as well as to the extended amygdala, a structure involved in the negative motivational state that drives addiction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. de Lecea L., Kilduff T. S., Peyron C., et al. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. USA 95, 322–327.

    Article  PubMed  Google Scholar 

  2. Sakurai T., Amemiya A., Ishii M., et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585.

    Article  PubMed  CAS  Google Scholar 

  3. Marcus J. N., Aschkenasi C. J., Lee C. E., et al. (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25.

    Article  PubMed  CAS  Google Scholar 

  4. Peyron C., Tighe D. K., van den Pol A. N., et al. (1998) Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems. J. Neurosci. 18, 9996–10,015.

    PubMed  CAS  Google Scholar 

  5. Mignot E., Taheri S., and Nishino S. (2002) Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat. Neurosci. 5(Suppl), 1071–1075.

    Article  PubMed  CAS  Google Scholar 

  6. Willie J. T., Chemelli R. M., Sinton C. M., and Yanagisawa M. (2001) To eat or to sleep? orexin in the regulation of feeding and wakefulness. Annu. Rev. Neurosci. 24, 429–458.

    Article  PubMed  CAS  Google Scholar 

  7. Sutcliffe J. G. and de Lecea L. (2002) The hypocretins: setting the arousal threshold. Nat. Rev. Neurosci. 3, 339–349.

    Article  PubMed  CAS  Google Scholar 

  8. Scammell T. E. (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann. Neurol. 53, 154–166.

    Article  PubMed  Google Scholar 

  9. Lin L., Faraco J., Li R., et al. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376.

    Article  PubMed  CAS  Google Scholar 

  10. Chemelli R. M., Willie J. T., Sinton C. M., et al. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451.

    Article  PubMed  CAS  Google Scholar 

  11. Willie J. T., Chemelli R. M., Sinton C. M., et al. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron 38, 715–730.

    Article  PubMed  CAS  Google Scholar 

  12. Hara J., Beuckmann C. T., Nambu T., et al. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345–354.

    Article  PubMed  CAS  Google Scholar 

  13. Beuckmann C. T., Sinton C. M., Williams S. C., et al. (2004) Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J. Neurosci. 24, 4469–4477.

    Article  PubMed  CAS  Google Scholar 

  14. Mieda M., Willie J. T., Hara J., Sinton C. M., Sakurai T., and Yanagisawa M. (2004) Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc. Natl. Acad. Sci. USA 101, 4649–4654.

    Article  PubMed  CAS  Google Scholar 

  15. Yamanaka A., Beuckmann C. T., Willie J. T., et al. (2003) Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713.

    Article  PubMed  CAS  Google Scholar 

  16. Owens M. J. and Nemeroff C. B. (1991) Physiology and pharmacology of corticotropin-releasing factor. Pharmacol. Rev. 43, 425–473.

    PubMed  CAS  Google Scholar 

  17. Lubkin M. and Stricker-Krongrad A. (1998) Independent Feeding and Metabolic Actions of Orexins in Mice. Biochem. Biophys. Res. Commun. 253, 241–245.

    Article  PubMed  CAS  Google Scholar 

  18. Dube M. G., Kalra S. P., and Kalra P. S. (1999) Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. Brain Res. 842, 473–477.

    Article  PubMed  CAS  Google Scholar 

  19. Haynes A. C., Jackson B., Overend P., et al. (1999) Effects of single and chronic intracere-broventricular administration of the orexins on feeding in the rat [In Process Citation]. Peptides 20, 1099–1105.

    Article  PubMed  CAS  Google Scholar 

  20. Sweet D. C., Levine A. S., Billington C. J., and Kotz C. M. (1999) Feeding response to central orexins. Brain Res. 821, 535–538.

    Article  PubMed  CAS  Google Scholar 

  21. Espana R. A., Plahn S., and Berridge C. W. (2002) Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin. Brain Res. 943, 224–236.

    Article  PubMed  CAS  Google Scholar 

  22. Estabrooke I. V., McCarthy M. T., Ko E., et al. (2001) Fos expression in orexin neurons varies with behavioral state. J. Neurosci. 21, 1656–1662.

    PubMed  CAS  Google Scholar 

  23. Zeitzer J. M., Buckmaster C. L., Lyons D. M., and Mignot E. (2004) Locomotor-dependent and -independent components to hypocretin-1 (orexin A) regulation in sleep-wake consolidating monkeys. J. Physiol. 557, 1045–1053.

    Article  PubMed  CAS  Google Scholar 

  24. Balasko M., Szelenyi Z., and Szekely M. (1999) Central thermoregulatory effects of neuropeptide Y and orexin A in rats. Acta. Physiol. Hung. 86, 219–222.

    PubMed  CAS  Google Scholar 

  25. Yoshimichi G., Yoshimatsu H., Masaki T., and Sakata T. (2001) Orexin-A regulates body temperature in coordination with arousal status. Exp. Biol. Med. (Maywood) 226, 468–476.

    CAS  Google Scholar 

  26. Dun N. J., Le Dun S., Chen C. T., Hwang L. L., Kwok E. H., and Chang J. K. (2000) Orexins: a role in medullary sympathetic outflow. Regul. Pept. 96, 65–70.

    Article  PubMed  CAS  Google Scholar 

  27. Shirasaka T., Nakazato M., Matsukura S., Takasaki M., and Kannan H. (1999) Sympathetic and cardiovascular actions of orexins in conscious rats. Am. J. Physiol. 277, R1780-R1785.

    PubMed  CAS  Google Scholar 

  28. Kayaba Y., Nakamura A., Kasuya Y., et al. (2003) Attenuated defense response and low basal blood pressure in orexin knockout mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R581-R593.

    PubMed  Google Scholar 

  29. Blanco M., Garcia-Caballero T., Fraga M., et al. (2002) Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas. Regul. Pept. 104, 161–165.

    Article  PubMed  CAS  Google Scholar 

  30. Lopez M., Senaris R., Gallego R., et al. (1999) Orexin receptors are expressed in the adrenal medulla of the rat. Endocrinology 140, 5991–5994.

    Article  PubMed  CAS  Google Scholar 

  31. Nanmoku T., Isobe K., Sakurai T., et al. (2002) Effects of orexin on cultured porcine adrenal medullary and cortex cells. Regul. Pept. 104, 125–130.

    Article  PubMed  CAS  Google Scholar 

  32. Sakamoto F., Yamada S., and Ueta Y. (2004) Centrally administered orexin-A activates corticotropin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons. Regul. Pept. 118, 183–191.

    Article  PubMed  CAS  Google Scholar 

  33. Samson W. K., Taylor M. M., Follwell M., and Ferguson A. V. (2002) Orexin actions in hypothalamic paraventricular nucleus: physiological consequences and cellular correlates. Regul. Pept. 104, 97–103.

    Article  PubMed  CAS  Google Scholar 

  34. Kuru M., Ueta Y., Serino R., et al. (2000) Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 11, 1977–1980.

    Article  PubMed  CAS  Google Scholar 

  35. Ida T., Nakahara K., Murakami T., Hanada R., Nakazato M., and Murakami N. (2000) Possible involvement of orexin in the stress reaction in rats. Biochem. Biophys. Res. Commun. 270, 318–323.

    Article  PubMed  CAS  Google Scholar 

  36. Ida T., Nakahara K., Kuroiwa T., et al. (2000) Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats. Neurosci. Lett. 293, 119–122.

    Article  PubMed  CAS  Google Scholar 

  37. Jaszberenyi M., Bujdoso E., Pataki I.. and Telegdy G. (2000) Effects of orexins on the hypothalamic-pituitary-adrenal system. J. Neuroendocrinol. 12, 1174–1178.

    Article  PubMed  CAS  Google Scholar 

  38. Espana R. A., Valentino R. J., and Berridge C. W. (2002) Fos expression in hypocretin-1 receptor-bearing and hypocretin-synthesizing neurons: effects of diurnal and nocturnal waking, stress and hcrt-1 administration. Abstract Viewer/Itinerary Planner. Society for Neuroscience., Program No. 776.5.

  39. Martins P. J., D’Almeida V., Pedrazzoli M., Lin L., Mignot E., and Tufik S. (2004) Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity. Regul. Pept. 117, 155–158.

    Article  PubMed  CAS  Google Scholar 

  40. Reyes T. M., Walker J. R., DeCino C., Hogenesch J. B., and Sawchenko P. E. (2003) Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus. J. Neurosci. 23, 5607–5616.

    PubMed  CAS  Google Scholar 

  41. Stricker-Krongrad A., Richy S., and Beck B. (2002) Orexins/hypocretins in the ob/ob mouse: hypothalamic gene expression, peptide content and metabolic effects. Regul. Pept. 104, 11–20.

    Article  PubMed  CAS  Google Scholar 

  42. Winsky-Sommerer R., Yamanaka A., Diano S., et al. (2004) Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J. Neurosci. 24, 11,439–11,448.

    Article  CAS  Google Scholar 

  43. Samson W. K. and Taylor M. M. (2001) Hypocretin/orexin suppresses corticotroph responsiveness in vitro. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1140–1145.

    PubMed  CAS  Google Scholar 

  44. Lu X. Y., Bagnol D., Burke S., Akil H., and Watson S. J. (2000) Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm. Behav. 37, 335–344.

    Article  PubMed  CAS  Google Scholar 

  45. Shirasaka T., Miyahara S., Kunitake T., et al. (2001) Orexin depolarizes rat hypothalamic paraventricular nucleus neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1114-R1118.

    PubMed  CAS  Google Scholar 

  46. Follwell M. J. and Ferguson A. V. (2002) Cellular mechanisms of orexin actions on paraventricular nucleus neurones in rat hypothalamus. J. Physiol. 545, 855–867.

    Article  PubMed  CAS  Google Scholar 

  47. Horvath T. L., Diano S., and van den Pol A. N. (1999) Synaptic interaction between hypocretin (Orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: A novel circuit implicated in metabolic and endocrine regulations. J. Neurosci. 19, 1072–1087.

    PubMed  CAS  Google Scholar 

  48. Heilig M. (2004) The NPY system in stress, anxiety and depression. Neuropeptides 38, 213–224.

    Article  PubMed  CAS  Google Scholar 

  49. Adrian T. E., Allen J. M., Bloom S. R., et al. (1983) Neuropeptide Y distribution in human brain. Nature 306, 584–586.

    Article  PubMed  CAS  Google Scholar 

  50. Baldo B. A., Daniel R. A., Berridge C. W., and Kelley A. E. (2003) Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J. Comp. Neurol. 464, 220–237.

    Article  PubMed  Google Scholar 

  51. Naveilhan P., Canals J. M., Valjakka A., Vartiainen J., Arenas E., and Ernfors P. (2001) Neuropeptide Y alters sedation through a hypothalamic Y1-mediated mechanism. Eur. J. Neurosci. 13, 2241–2246.

    Article  PubMed  CAS  Google Scholar 

  52. Bannon A. W., Seda J., Carmouche M., et al. (2000) Behavioral characterization of neuropeptide Y knockout mice. Brain Res. 868, 79–87.

    Article  PubMed  CAS  Google Scholar 

  53. Palmiter R. D., Erickson J. C., Hollopeter G., Baraban S. C., and Schwartz M. W. (1998) Life without neuropeptide Y. Rec. Prog. Horm. Res. 53, 163–199.

    PubMed  CAS  Google Scholar 

  54. Karlsson R. M., Holmes A., Heilig M., and Crawley J. N. (2005) Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL/6J mice. Pharmacol. Biochem. Behav. 80, 427–436.

    Article  PubMed  CAS  Google Scholar 

  55. Fu L. Y., Acuña-Goycolea C.. and van den Pol A. N. (2004) Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J. Neurosci. 24, 8741–8751.

    Article  PubMed  CAS  Google Scholar 

  56. Kalivas P. W. and McFarland K. (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl.) 168, 44–56.

    Article  CAS  Google Scholar 

  57. Koob G. F. (1999) Stress, corticotropin-releasing factor, and drug addiction. Ann. NY Acad. Sci. 897, 27–45.

    Article  PubMed  CAS  Google Scholar 

  58. Koob G. F., Sanna P. P., and Bloom F. E. (1998) Neuroscience of addiction. Neuron 21, 467–476.

    Article  PubMed  CAS  Google Scholar 

  59. Koob G. F. (2000) Neurobiology of addiction. Toward the development of new therapies. Ann. NY Acad. Sci. 909, 170–185.

    Article  PubMed  CAS  Google Scholar 

  60. Koob G. F. (1999) The role of the striatopallidal and extended amygdala systems in drug addiction. Ann. NY Acad. Sci. 877, 445–460.

    Article  PubMed  CAS  Google Scholar 

  61. Korotkova T. M., Eriksson K. S., Haas H. L., and Brown R. E. (2002) Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul. Pept. 104, 83–89.

    Article  PubMed  CAS  Google Scholar 

  62. Martin G., Fabre V., Siggins G. R., and de Lecea L. (2002) Interaction of the hypocretins with neurotransmitters in the nucleus accumbens. Regul. Pept. 104, 111–117.

    Article  PubMed  CAS  Google Scholar 

  63. Fadel J. and Deutch A. Y. (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111, 379–387.

    Article  PubMed  CAS  Google Scholar 

  64. Olds J. and Milner P. (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427.

    Article  PubMed  CAS  Google Scholar 

  65. Anand B. K. and Brobeck J. R. (1951) Localization of a feeding center in the hypothalamus of the rat. Proc. Soc. Exp. Biol. Med. 77, 323,324.

    PubMed  CAS  Google Scholar 

  66. Gallistel C. R., Shizgal P., and Yeomans J. S. (1981) A portrait of the substrate for self-stimulation. Psychol. Rev. 88, 228–273.

    Article  PubMed  CAS  Google Scholar 

  67. Sarnyai Z., Shaham Y., and Heinrichs S. C. (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol. Rev. 53, 209–243.

    PubMed  CAS  Google Scholar 

  68. Stricker-Krongrad A. and Beck B. (2002) Modulation of hypothalamic hypocretin/orexin mRNA expression by glucocorticoids. Biochem. Biophys. Res. Commun. 296, 129–133.

    Article  PubMed  CAS  Google Scholar 

  69. Boutrel B., Kenny P. J., Winsky-Sommerer R., Markou A., Koob G. F., and de Lecea L. (2003) Soc. Neurosci. Abstr. 879.7.

  70. Macey D. J., Koob G. F. and Markou A. (2000) CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist. Brain Res. 866, 82–91.

    Article  PubMed  CAS  Google Scholar 

  71. Georgescu D., Zachariou V., Barrot M., et al. (2003) Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J. Neurosci. 23, 3106–3111.

    PubMed  CAS  Google Scholar 

  72. Heinrichs S. C. and Koob G. F. (2004) Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J. Pharmacol. Exp. Ther. 311, 427–440.

    Article  PubMed  CAS  Google Scholar 

  73. Aston-Jones G. and Harris G. C. (2004) Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology 47(Suppl 1), 167–179.

    Article  PubMed  CAS  Google Scholar 

  74. Shalev U., Morales M., Hope B., Yap J. and Shaham Y. (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology (Berl.) 156, 98–107.

    Article  CAS  Google Scholar 

  75. Lopez M., Seoane L., Garcia M. C., et al. (2000) Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus. Biochem. Biophys. Res. Commun. 269, 41–45.

    Article  PubMed  CAS  Google Scholar 

  76. Yamamoto Y., Ueta Y., Date Y., et al. (1999) Down regulation of the prepro-orexin gene expression in genetically obese mice. Brain Res. Mol. Brain Res. 65, 14–22.

    Article  PubMed  CAS  Google Scholar 

  77. Cai X. J., Lister C. A., Buckingham R. E., et al. (2000) Down-regulation of orexin gene expression by severe obesity in the rats: studies in Zucker fatty and zucker diabetic fatty rats and effects of rosiglitazone. Brain Res. Mol. Brain Res. 77, 131–137.

    Article  PubMed  CAS  Google Scholar 

  78. Komaki G., Matsumoto Y., Nishikata H., et al. (2001) Orexin-A and leptin change inversely in fasting non-obese subjects. Eur. J. Endocrinol. 144, 645–651.

    Article  PubMed  CAS  Google Scholar 

  79. Rauch M., Riediger T., Schmid H. A., and Simon E. (2000) Orexin A activates leptin-responsive neurons in the arcuate nucleus. Pflugers Arch. 440, 699–703.

    Article  PubMed  CAS  Google Scholar 

  80. Thiele T. E., Sparta D. R., Hayes D. M., and Fee J. R. (2004) A role for neuropeptide Y in neurobiological responses to ethanol and drugs of abuse. Neuropeptides 38, 235–243.

    Article  PubMed  CAS  Google Scholar 

  81. Valdez G. R. and Koob G. F. (2004) Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism. Pharmacol. Biochem. Behav. 79, 671–689.

    Article  PubMed  CAS  Google Scholar 

  82. Koob G. F. (2003) Alcoholism: allostasis and beyond. Alcohol Clin. Exp. Res. 27, 232–243.

    Article  PubMed  CAS  Google Scholar 

  83. Roy A. and Pandey S. C. (2002) The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic ethanol exposure. Alcohol Clin. Exp. Res. 26, 796–803.

    PubMed  CAS  Google Scholar 

  84. Thiele T. E., Marsh D. J., Ste Marie L., Bernstein I. L., and Palmiter R. D. (1998) Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396, 366–369.

    Article  PubMed  CAS  Google Scholar 

  85. Koob G. F., Ahmed S. H., Boutrel B., et al. (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci. Biobehav. Rev. 27, 739–749.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Winsky-Sommerer, R., Boutrel, B. & de Lecea, L. Stress and arousal. Mol Neurobiol 32, 285–294 (2005). https://doi.org/10.1385/MN:32:3:285

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:32:3:285

Index Entries

Navigation