Skip to main content
SpringerLink
Log in

Hyperarousal and Post-Traumatic Stress Disorder: A Role for the Hypocretin System

  • Chapter
  • First Online:
Post-Traumatic Stress Disorder

  • 3129 Accesses

Abstract

The hypocretins are a pair of neuropeptides produced in a few thousand neurons in the lateral hypothalamus. Extensive evidence suggests that one of the main functions of hypocretin neurons is to stabilize arousal/alertness during periods of wakefulness and to increase arousal-related behaviors, including eating, drinking, grooming, and locomotor activity. The ability of hypocretin neurons to increase arousal-associated behaviors suggests the possibility that these neurons may play a role in the hyperarousal state observed when an animal is exposed to an acute stressor. Consistent with this hypothesis is a variety of observations indicating that centrally administered hypocretins mimic the behavioral and physiological response to stress. In addition, hypocretin neurons receive prominent input and are activated by terminals containing corticotropin-releasing factor (CRF), a neuropeptide that is secreted in response to an acute stressor. There is abundant evidence demonstrating a reciprocal connection between hypocretin and CRF neurons, which may be important in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the acute stress response. Given that CRF secretion and hyperarousal are both important symptoms of post-traumatic stress disorder (PTSD), hypocretin neurons may play a prominent role in causing many of the other physiological symptoms of the disease. We review the possible role of hypocretin neurons in the allostatic pathophysiology of PTSD, including dysregulation of the stress response, and in the circuitry that regulates sleep and wakefulness.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

REFERENCES

  1. Yehuda, R., and LeDoux, J. (2007) Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56(1), 19–32.

    Article  PubMed  CAS  Google Scholar 

  2. Newport, D. J., and Nemeroff, C. B. (2000) Neurobiology of posttraumatic stress disorder. Curr Opin Neurobiol 10(2), 211–18.

    Article  PubMed  CAS  Google Scholar 

  3. Risbrough, V. B., and Stein, M. B. (2006). Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. Horm Behav 50(4), 550–61.

    Article  Google Scholar 

  4. Shekhar, A., Truitt, W., Rainnie, D., and Sajdyk, T. (2005) Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety. Stress 8(4), 209–19.

    Article  PubMed  CAS  Google Scholar 

  5. Berridge, C. W., and Espana, R. A. (2005) Hypocretin/orexin in stress and arousal. In de Lecea, L., and Sutcliffe, J. G., Hypocretins: Integrators of Physiological Functions. New York: Springer-Verlag.

    Google Scholar 

  6. de Lecea, L., Kilduff, T. S., Peyron, C., et al. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95(1), 322–27.

    Article  PubMed  Google Scholar 

  7. 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(5), 573–85.

    Article  PubMed  CAS  Google Scholar 

  8. 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(23), 9996–10015.

    PubMed  CAS  Google Scholar 

  9. Sakurai, T. (2007) The neural circuit of orexin (hypocretin), maintaining sleep and wakefulness. Nat Rev Neurosci 8(3), 171–81.

    Article  PubMed  CAS  Google Scholar 

  10. Date, Y., Ueta, Y., Yamashita, H., et al. (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci U S A 96(2), 748–53.

    Article  PubMed  CAS  Google Scholar 

  11. 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(3), 365–76.

    Article  PubMed  CAS  Google Scholar 

  12. Chemelli, R. M., Willie, J. T., Sinton, C. M., et al. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98(4), 437–51.

    Article  PubMed  CAS  Google Scholar 

  13. Hara, J., Beuckmann, C. T., Willie, J. T., et al. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30(2), 345–54.

    Article  PubMed  CAS  Google Scholar 

  14. Nishino, S., Ripley, B., Overeem, S., Lammers, G. J., and Mignot, E. (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355(9197), 39–40.

    Article  PubMed  CAS  Google Scholar 

  15. Peyron, C., Faraco, J., Rogers, W., et al. (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6(9), 991–97.

    Article  PubMed  CAS  Google Scholar 

  16. Thannickal, T. C., Moore, R. Y., Nienhuis, R., et al. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3), 469–74.

    Article  PubMed  CAS  Google Scholar 

  17. Yokogawa, T., Marin, W., Faraco, J., et al. (2007) Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biol 5(10), 2379–97.

    Article  CAS  Google Scholar 

  18. Espana, R. A., Baldo, B. A., Kelley, A. E., and Berridge, C. W. (2001) Wake-promoting and sleep-suppressing actions of hypocretin (orexin), basal forebrain sites of action. Neuroscience 106(4), 699–715.

    Article  PubMed  CAS  Google Scholar 

  19. Espana, R. A., Plahn, S., and Berridge, C. W. (2002) Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin. Brain Res 943(2), 224–36.

    Article  PubMed  CAS  Google Scholar 

  20. Piper, D. C., Upton, N., Smith, M. I., and Hunter, A. J. (2000) The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur J Neurosci 12(2), 726–30.

    Article  PubMed  CAS  Google Scholar 

  21. da Silva, E. S., Dos Santos, R. V., Hoeller, A. A., et al. (2008) Behavioral and metabolic effects of central injections of orexins/hypocretins in pigeons (Columba livia). Regul Pept 147, 9–18, Epub 2007 Dec 26.

    Article  PubMed  Google Scholar 

  22. Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K., and de Lecea, L. (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature. 450(7168), 420–424.

    Article  PubMed  CAS  Google Scholar 

  23. Winsky-Sommerer, R., Boutrel, B., and de Lecea, L. (2005) Stress and arousal: the corticotropin releasing factor/hypocretin circuitry. Mol Neurobiol 32(3), 285–94.

    Article  PubMed  CAS  Google Scholar 

  24. Ida, T., Nakahara, K., Katayama, T., Murakami, N., and Nakazato, M. (1999) Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res 821(2), 526–29.

    Article  PubMed  CAS  Google Scholar 

  25. Ida, T., Nakahara, K., Murakami, T., Hanada, R., Makazato, M., and Murakami, N. (2000) Possible involvement of orexin in the stress reaction in rats. Biochem Biophys Res Commun 270(1), 318–23.

    Article  PubMed  CAS  Google Scholar 

  26. Espana, R. A., Valentino, R. J., and Berridge, C. W. (2003) Fos immunoreactivity in hypocretin-synthesizing and hypocretin-1 receptor-expressing neurons: effects of diurnal and nocturnal spontaneous waking, stress, and hypocretin-1 administration. Neuroscience 121(1), 201–17.

    Article  PubMed  CAS  Google Scholar 

  27. 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(3), 155–58.

    Article  PubMed  CAS  Google Scholar 

  28. Chen, C. T., Hwang, L. L., Chang, J. K., and Dun, N. J. (2000) Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of anesthetized rats. Am J Physiol Regul Integr Comp Physiol 278(3), R692–97.

    PubMed  CAS  Google Scholar 

  29. Lubkin, M., and Stricker-Krongrad, A. (1998) Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun 253(2), 241–45.

    Article  PubMed  CAS  Google Scholar 

  30. Samson, W. K., Gosnell, B., Chang, J. K., Resch, Z. T., and Murphy, T. C. (1999) Cardiovascular regulatory actions of the hypocretins in brain. Brain Res 831(1–2), 248–53.

    Article  PubMed  CAS  Google Scholar 

  31. 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(2), R1780–85.

    PubMed  CAS  Google Scholar 

  32. Yoshimichi, G., Yoshimatsu, H., Masaki, T., and Sakata, T. (2001) Orexin-A regulates body temperature in coordination with arousal status. Exp Biol Med 226(5), 468–476.

    CAS  Google Scholar 

  33. Brown, M. R., and Koob, G. F. (2005). In Brown, M. R., and Koob, G. F., Stress Neurobiology and Neuroendocrinology. New York: Rivier Marcel Dekker.

    Google Scholar 

  34. Chrousos, G. P., and Gold, P. W. (1992) The concepts of stress and stress system disorders: Overview of physical and behavioral homeostasis. JAMA 267, 1244–52.

    Article  PubMed  CAS  Google Scholar 

  35. McEwen, B.S. (2000). In: Fink, G., , Encyclopedia of Stress. San Diego, CA: Academic.

    Google Scholar 

  36. McEwen, B. S. (2003) Mood disorders and alalostatic load. Biol Psychiatry 54(3), 200–7.

    Article  PubMed  Google Scholar 

  37. Van Praag, H. M. (2004) de Kloet, E. R., , Stress, the Brain and Depression. Cambridge: Cambridge University Press.

    Chapter  Google Scholar 

  38. Yehuda, R. (2002) Post-traumatic stress disorder. N Engl J Med 346(2), 108–14.

    Article  PubMed  CAS  Google Scholar 

  39. 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(3), 183–91.

    Article  PubMed  CAS  Google Scholar 

  40. Sakurai, T., Moriguchi, T., Furuya, K., et al. (1999) Structure and function of human prepro-orexin gene. J Biol Chem 27425, 17771–76.

    Article  PubMed  CAS  Google Scholar 

  41. Zhu, L., Onaka, T., Sakurai, T., and Yada, T. (2002) Activation of orexin neurons after noxious but not conditioned fear stimuli in rats. Neuroreport 13(10), 1351–53.

    Article  PubMed  CAS  Google Scholar 

  42. Owens, M. J., and Nemeroff, C. B. (1990) Physiology and pharmacology of corticotropin-releasing factor. Pharmacol Rev 43, 425–73.

    Google Scholar 

  43. Dunn, A. J., and Berridge, C. W. (1990) Is corticotropin-releasing factor a mediator of stress responses? Ann NY Acad Sci 579, 183–91.

    Article  PubMed  CAS  Google Scholar 

  44. Dunn, A. J., and Berridge, C. W. (1990) Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res Brain Res Rev 15(2), 71–100.

    Article  PubMed  CAS  Google Scholar 

  45. Chang, F. C., and Opp, M. R. (2001) Corticotropin releasing hormone (CRF) as a regulator of waking. Neurosci Biobehav Rev 25, 445–53.

    Article  PubMed  CAS  Google Scholar 

  46. Chang, F. C., and Opp, M. R. (2005) A corticotropin-releasing hormone antisense oligodeoxynucleotide reduces spontaneous waking in the rat. Regul Pept 117(1), 43–52.

    Article  Google Scholar 

  47. Koob, G. F., and Bloom, F. E. (1985) Corticotropin-releasing factor and behavior. Fed Proc 44, 259–63.

    PubMed  CAS  Google Scholar 

  48. Sapolsky, R. M., Romero, L. M., and Munck, A. U. (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, simulatory, and preparative actions. Endocr Rev 21, 55–89.

    Article  PubMed  CAS  Google Scholar 

  49. Lu, X. Y., Bagnol, D., Burke, S., Akil, H., and Watson, S. J. (2000) Differential distribution and regulation of OC1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav 37(4), 335–44.

    Article  PubMed  CAS  Google Scholar 

  50. Shirasaka, T., Miyahara, S., Kunitake, T., et al. (2001) Orexin depolarizes rat hypothalamic paraventricular nucleus neurons. Am J Physiol Regul Integr Comp Physiol 281(4), R1114–18.

    PubMed  CAS  Google Scholar 

  51. Follwell, M. J., and Ferguson, A. V. (2002) Cellular mechanisms of orexin actions on paraventricular nucleus neurons in rat hypothalamus. J Physiol 545(pt 3), 855–67.

    Article  PubMed  CAS  Google Scholar 

  52. Al-Barazanji, K. A., Wilson, S., Baker, J., Jessop, D. S., and Harbuz, M. S. (2001) Central orexin-A activates hypothalamic-pituitary-adrenal axis and stimulates hypothalamic corticotropin releasing factor and arginine vasopressin neurons in conscious rats. J Neuroendocrinol 13(5), 421–24.

    Article  PubMed  CAS  Google Scholar 

  53. Jaszberenyi, M., Bujdoso, E., Pataki, I., and Telegdy, G. (2000) Effects of orexins on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol 12(12), 1174–78.

    Article  PubMed  CAS  Google Scholar 

  54. Kuro, M., Ueta, Y., Serino, R., et al. (2000) Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 11(9), 1977–80.

    Article  Google Scholar 

  55. 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(50), 11439–48.

    Article  PubMed  CAS  Google Scholar 

  56. Mochizuki, T., and Scammell, T. E. (2003) Orexin/hypocretin: wired for wakefulness. Curr Biol 13(14), R563–64.

    Article  PubMed  CAS  Google Scholar 

  57. Campeau, S., and Davis, M. (1995) Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J Neurosci 15(3), 2301–11.

    PubMed  CAS  Google Scholar 

  58. Sanders, S. K., and Shekhar, A. (1991) Blockade of GABAA receptors in the region of the anterioir basolateral amygdala of rats elicits increases in heart rate and blood pressure. Brain Res 567(1), 101–10.

    Article  PubMed  CAS  Google Scholar 

  59. Sanders, S. K., and Shekhar, A. (1995) Anxiolytic effects of chlordiazepoxide blocked by injection of GABAA and benzodiazepine receptor antagonists in the region of the anterior basolateral amygdala of rats. Biol Psychiatry 37(7), 473–76.

    Article  PubMed  CAS  Google Scholar 

  60. Shekhar, A., Sajdyk, T. S., Keim, S. R., Yoder, K. K., and Sanders, S. K. (1999) Role of the basolateral amygdala in panic disorder. Ann N Y Acad Sci 877:747–50.

    Article  PubMed  CAS  Google Scholar 

  61. Sajdyk, T. J., and Shekhar, A. (2000) Sodium lactate elicits anxiety in rats after repeated GABA receptor blockade in the basolateral amygdala. Eur J Pharmacol 394(2–3), 265–73.

    Article  PubMed  CAS  Google Scholar 

  62. Shekhar, A., Sajdyk, T. J., Gehlert, D. R., and Rainnie, D. G. (2003) The amygdala, panic disorder, and cardiovascular responses. Ann N Y Acad Sci 985:308–25.

    Article  PubMed  CAS  Google Scholar 

  63. Rainnie, D. G., Bergeron, R., Sajdyk, T. J., Patil, M., Hehlert, D. R., and Shekhar, A. (2004) Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. J Neurosci 24(14), 3471–79.

    Article  PubMed  CAS  Google Scholar 

  64. Vyas, A., Mitra, R., Shankaranarayana Rao, B. S., and Chattarji, S. (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22, 6810–18.

    PubMed  CAS  Google Scholar 

  65. Rauch, S. L., Whalen, P. J., Shin, L. M., et al. (2000) Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 47(9), 769–76.

    Article  PubMed  CAS  Google Scholar 

  66. Williams, L. M., Kemp, A. H., Felmingham, K., et al. (2006) Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. Neuroimage 29(2), 347–57.

    Article  PubMed  Google Scholar 

  67. Liberzon, I., and Sripada, C. S. (2008) The functional neuroanatomy of PTSD: a critical review. Prog Brain Res 167, 151–69.

    Article  PubMed  Google Scholar 

  68. Herringa, R. J., Nanda, S. A., Hsu, D. T., Roseboom, P. H., and Kalin, N. H. (2004) The effects of acute stress on the regulation of central and basolateral amygdala CRF-binding protein gene expression. Brain Res Mol Brain Res 131, 17–25.

    Article  PubMed  CAS  Google Scholar 

  69. Merlo Pich, E., Lorang, M., Yeganeh, M., et al. (1995) Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15(8), 5439–47.

    PubMed  CAS  Google Scholar 

  70. Cratty, M. S., Ward, H. E., Johnson, E. A., Azzaro, A. J., and Birkle, D. L. (1995) Prenatal stress increases corticotropin-releasing factor (CRF) content and release in rat amygdala minces. Brain Res 675(1–2), 297–302.

    Article  PubMed  CAS  Google Scholar 

  71. Maher, M. J., Rego, S. A., and Asnis, G. M. (2006) Sleep disturbances in patients with post-traumatic stress disorder: epidemiology, impact, and approaches to management. CNS Drugs 20(7), 567–90.

    Article  PubMed  CAS  Google Scholar 

  72. Inman, D., Silver, S., and Doghramji, K. (1990) Sleep disturbances in patients with post-traumatic stress disorder: a comparison with non-PTSD insomnia. J Trauma Stress 3, 429–37.

    Article  Google Scholar 

  73. Ross, R. J., Ball, W. A., Sullivan, K. A., and Caroff, S. N. (1989) Sleep disturbance as the hallmark of posttraumatic stress disorder. Am J Psychiatry 146(6), 697–707.

    PubMed  CAS  Google Scholar 

  74. Mellman, T. A., Kumar, A., Kulick-Bell, R., Kumar, M., and Nolan, B. (1995) Nocturnal/daytime urine noradrenergic measures and sleep in combat-related PTSD. Biol Psychiatry 38(3), 174–79.

    Article  PubMed  CAS  Google Scholar 

  75. Lamarche, L. J., and De Koninck, J. (2007) Sleep disturbance in adults with posttraumatic stress disorder: a review. J Clin Psychiatry 68(8), 1257–70.

    Article  PubMed  Google Scholar 

  76. Brisbare-Roch, C., Dingemanse, J., Koberstein, R., et al. (2007) Promotion of sleep by targeting the orexin system in rats, dogs, and humans. Nat Med 13, 150–55.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University, 701B Welch Road, Palo Alto, CA 94304

    Matt Carter & Luis de Lecea

Authors
  1. Matt Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis de Lecea
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Carter, M., de Lecea, L. (2009). Hyperarousal and Post-Traumatic Stress Disorder: A Role for the Hypocretin System. In: LeDoux, J., Keane, T., Shiromani, P. (eds) Post-Traumatic Stress Disorder. Humana Press. https://doi.org/10.1007/978-1-60327-329-9_9

    Download citation

    • DOI: https://doi.org/10.1007/978-1-60327-329-9_9

    • Published:

    • Publisher Name: Humana Press

    • Print ISBN: 978-1-60327-328-2

    • Online ISBN: 978-1-60327-329-9

    • eBook Packages: MedicineMedicine (R0)

    Publish with us

    Policies and ethics

    Search

    Navigation