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Motivational activation: a unifying hypothesis of orexin/hypocretin function

Abstract

Orexins (hypocretins) are two peptides (orexin A and B) produced from the pre-pro-orexin precursor and expressed in a limited region of dorsolateral hypothalamus. Orexins were originally thought to specifically mediate feeding and promote wakefulness, but it is now clear that they participate in a wide range of behavioral and physiological processes under select circumstances. Orexins primarily mediate behavior under situations of high motivational relevance, such as during physiological need states, exposure to threats or reward opportunities. We hypothesize that many behavioral functions of orexins (including regulation of sleep/wake cycling) reflect a fundamentally integrated function for orexins in translating motivational activation into organized suites of psychological and physiological processes supporting adaptive behaviors. We also discuss how numerous forms of neural heterogeneity modulate this function, allowing orexin neurons to organize diverse, adaptive responses in a variety of motivationally relevant situations. Thus, the involvement of orexins in diverse behaviors may reflect a common underlying function for this peptide system.

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Figure 1: Model of orexins' functions in sleep/wake regulation.

References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Alexandre, C., Andermann, M.L. & Scammell, T.E. Control of arousal by the orexin neurons. Curr. Opin. Neurobiol. 23, 752–759 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sakurai, T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat. Rev. Neurosci. 8, 171–181 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Kilduff, T.S. & Peyron, C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci. 23, 359–365 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Mignot, E. Sleep, sleep disorders and hypocretin (orexin). Sleep Med. 5 (suppl. 1), S2–S8 (2004).

    Article  PubMed  Google Scholar 

  7. Li, J., Hu, Z. & de Lecea, L. The hypocretins/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171, 332–350 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Siegel, J.M. Narcolepsy: a key role for hypocretins (orexins). Cell 98, 409–412 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fadel, J. & Burk, J.A. Orexin/hypocretin modulation of the basal forebrain cholinergic system: role in attention. Brain Res. 1314, 112–123 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Berridge, C.W., Espana, R.A. & Vittoz, N.M. Hypocretin/orexin in arousal and stress. Brain Res. 1314, 91–102 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Saper, C.B., Fuller, P.M., Pedersen, N.P., Lu, J. & Scammell, T.E. Sleep state switching. Neuron 68, 1023–1042 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mileykovskiy, B.Y., Kiyashchenko, L.I. & Siegel, J.M. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46, 787–798 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lee, M.G., Hassani, O.K. & Jones, B.E. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J. Neurosci. 25, 6716–6720 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bromberg-Martin, E.S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive and alerting. Neuron 68, 815–834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Aston-Jones, G. & Cohen, J.D. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28, 403–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Mochizuki, T. et al. Behavioral state instability in orexin knock-out mice. J. Neurosci. 24, 6291–6300 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bayard, S. & Dauvilliers, Y.A. Reward-based behaviors and emotional processing in human with narcolepsy-cataplexy. Front. Behav. Neurosci. 7, 50 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Takahashi, K., Lin, J.S. & Sakai, K. Neuronal activity of orexin and non-orexin waking-active neurons during wake-sleep states in the mouse. Neuroscience 153, 860–870 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Chase, M.H. A unified survival theory of the functioning of the hypocretinergic system. J. Appl. Physiol. 115, 954–971 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Wu, M.F., Nienhuis, R., Maidment, N., Lam, H.A. & Siegel, J.M. Cerebrospinal fluid hypocretin (orexin) levels are elevated by play but are not raised by exercise and its associated heart rate, blood pressure, respiration or body temperature changes. Arch. Ital. Biol. 149, 492–498 (2011).

    PubMed  PubMed Central  Google Scholar 

  21. Appelbaum, L. et al. Circadian and homeostatic regulation of structural synaptic plasticity in hypocretin neurons. Neuron 68, 87–98 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thompson, J.L. & Borgland, S.L. A role for hypocretin/orexin in motivation. Behav. Brain Res. 217, 446–453 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Tsujino, N. & Sakurai, T. Role of orexin in modulating arousal, feeding and motivation. Front. Behav. Neurosci. 7, 28 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gao, X.B. & Horvath, T. Function and dysfunction of hypocretin/orexin: an energetics point of view. Annu. Rev. Neurosci. 37, 101–116 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Borbély, A.A. A two process model of sleep regulation. Hum. Neurobiol. 1, 195–204 (1982).

    PubMed  Google Scholar 

  26. Zeitzer, J.M. et al. Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness. J. Neurosci. 23, 3555–3560 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Overeem, S., Lammers, G.J. & van Dijk, J.G. Cataplexy: 'tonic immobility' rather than 'REM-sleep atonia'? Sleep Med. 3, 471–477 (2002).

    Article  PubMed  Google Scholar 

  28. Oishi, Y. et al. Role of the medial prefrontal cortex in cataplexy. J. Neurosci. 33, 9743–9751 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Burgess, C.R., Oishi, Y., Mochizuki, T., Peever, J.H. & Scammell, T.E. Amygdala lesions reduce cataplexy in orexin knock-out mice. J. Neurosci. 33, 9734–9742 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Borgland, S.L. et al. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J. Neurosci. 29, 11215–11225 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Harris, G.C., Wimmer, M. & Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Berthoud, H.R. & Munzberg, H. The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics. Physiol. Behav. 104, 29–39 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Burdakov, D., Karnani, M.M. & Gonzalez, A. Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control. Physiol. Behav. 121, 117–124 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cason, A.M. et al. Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol. Behav. 100, 419–428 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sheng, Z., Santiago, A.M., Thomas, M.P. & Routh, V.H. Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry. Mol. Cell. Neurosci. published online, 10.1016/j.mcn.2014.08.001 (6 August 2014).

  36. Mahler, S.V., Smith, R.J., Moorman, D.E., Sartor, G.C. & Aston-Jones, G. Multiple roles for orexin/hypocretin in addiction. Prog. Brain Res. 198, 79–121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yamanaka, A. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Perello, M. et al. Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol. Psychiatry 67, 880–886 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Calipari, E.S. & Espana, R.A. Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms. Front. Behav. Neurosci. 6, 54 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mahler, S.V., Smith, R.J. & Aston-Jones, G. Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl.) 226, 687–698 (2013).

    Article  CAS  Google Scholar 

  41. Yeoh, J.W., Campbell, E.J., James, M.H., Graham, B.A. & Dayas, C.V. Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Front. Neurosci. 8, 36 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Boutrel, B., Steiner, N. & Halfon, O. The hypocretins and the reward function: what have we learned so far? Front. Behav. Neurosci. 7, 59 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Marchant, N.J., Millan, E.Z. & McNally, G.P. The hypothalamus and the neurobiology of drug seeking. Cell. Mol. Life Sci. 69, 581–597 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Kuwaki, T. & Zhang, W. Orexin neurons as arousal-associated modulators of central cardiorespiratory regulation. Respir. Physiol. Neurobiol. 174, 43–54 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Carrive, P. Orexin, orexin receptor antagonists and central cardiovascular control. Front. Neurosci. 7, 257 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Johnson, P.L., Molosh, A., Fitz, S.D., Truitt, W.A. & Shekhar, A. Orexin, stress and anxiety/panic states. Prog. Brain Res. 198, 133–161 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Winsky-Sommerer, R. et al. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J. Neurosci. 24, 11439–11448 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, R.J. & Aghajanian, G.K. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc. Natl. Acad. Sci. USA 105, 359–364 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Salomon, R.M. et al. Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol. Psychiatry 54, 96–104 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Lutter, M. et al. Orexin signaling mediates the antidepressant-like effect of calorie restriction. J. Neurosci. 28, 3071–3075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. James, M.H. et al. Exercise reverses the effects of early life stress on orexin cell reactivity in male but not female rats. Front. Behav. Neurosci. 8, 244 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tupone, D., Madden, C.J., Cano, G. & Morrison, S.F. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J. Neurosci. 31, 15944–15955 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wheeler, D.S. et al. Role of lateral hypothalamus in two aspects of attention in associative learning. Eur. J. Neurosci. 40, 2359–2377 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lambe, E.K., Olausson, P., Horst, N.K., Taylor, J.R. & Aghajanian, G.K. Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J. Neurosci. 25, 5225–5229 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Muschamp, J.W. et al. Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc. Natl. Acad. Sci. USA 111, E1648–E1655 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sears, R.M. et al. Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc. Natl. Acad. Sci. USA 110, 20260–20265 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Akbari, E., Naghdi, N. & Motamedi, F. Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task. Behav. Brain Res. 173, 47–52 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Smith, R.J., See, R.E. & Aston-Jones, G. Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking. Eur. J. Neurosci. 30, 493–503 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Harris, G.C. & Aston-Jones, G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 29, 571–577 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Yoshida, K., McCormack, S., Espana, R.A., Crocker, A. & Scammell, T.E. Afferents to the orexin neurons of the rat brain. J. Comp. Neurol. 494, 845–861 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Deutch, A.Y. & Bubser, M. The orexins/hypocretins and schizophrenia. Schizophr. Bull. 33, 1277–1283 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Chou, T.C. et al. Orexin (hypocretin) neurons contain dynorphin. J. Neurosci. 21, RC168 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kukkonen, J.P. & Leonard, C.S. Orexin/hypocretin receptor signaling cascades. Br. J. Pharmacol. 171, 314–331 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Schöne, C. & Burdakov, D. Glutamate and GABA as rapid effectors of hypothalamic “peptidergic” neurons. Front. Behav. Neurosci. 6, 81 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gao, X.B. & Horvath, T. Function and dysfunction of hypocretin/orexin: an energetics point of view. Annu. Rev. Neurosci. 37, 101–116 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Belle, M.D. et al. Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock. J. Neurosci. 34, 3607–3621 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Borgland, S.L., Ungless, M.A. & Bonci, A. Convergent actions of orexin/hypocretin and CRF on dopamine neurons: emerging players in addiction. Brain Res. 1314, 139–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Tabuchi, S. et al. Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J. Neurosci. 34, 6495–6509 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mahlios, J., De la Herran-Arita, A.K. & Mignot, E. The autoimmune basis of narcolepsy. Curr. Opin. Neurobiol. 23, 767–773 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Khatami, R., Birkmann, S. & Bassetti, C.L. Amygdala dysfunction in narcolepsy-cataplexy. J. Sleep Res. 16, 226–229 (2007).

    Article  PubMed  Google Scholar 

  71. Ponz, A. et al. Reduced amygdala activity during aversive conditioning in human narcolepsy. Ann. Neurol. 67, 394–398 (2010).

    Article  PubMed  Google Scholar 

  72. Morein-Zamir, S., Turner, D.C. & Sahakian, B.J. A review of the effects of modafinil on cognition in schizophrenia. Schizophr. Bull. 33, 1298–1306 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Blouin, A.M. et al. Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. Nat. Commun. 4, 1547 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Siegel, J.M. et al. Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla. Science 252, 1315–1318 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank E. Vought for assistance with figure art and design, and A. Koller for helpful comments. Funding was provided by US National Institutes of Health grants F32 DA026692, K99 DA035251, R01-DA006214, P50 DA015369, R21 DA037744, R21 DA032005 and C06 RR015455, and National Health and Medical Research Council CJ Martin Fellowship 1072706.

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Correspondence to Gary Aston-Jones.

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Mahler, S., Moorman, D., Smith, R. et al. Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17, 1298–1303 (2014). https://doi.org/10.1038/nn.3810

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