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Orexin/Hypocretin and Organizing Principles for a Diversity of Wake-Promoting Neurons in the Brain

  • Cornelia Schöne
  • Denis Burdakov
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)

Abstract

An enigmatic feature of behavioural state control is the rich diversity of wake-promoting neural systems. This diversity has been rationalized as ‘robustness via redundancy’, wherein wakefulness control is not critically dependent on one type of neuron or molecule. Studies of the brain orexin/hypocretin system challenge this view by demonstrating that wakefulness control fails upon loss of this neurotransmitter system. Since orexin neurons signal arousal need, and excite other wake-promoting neurons, their actions illuminate nonredundant principles of arousal control. Here, we suggest such principles by reviewing the orexin system from a collective viewpoint of biology, physics and engineering. Orexin peptides excite other arousal-promoting neurons (noradrenaline, histamine, serotonin, acetylcholine neurons), either by activating mixed-cation conductances or by inhibiting potassium conductances. Ohm’s law predicts that these opposite conductance changes will produce opposite effects on sensitivity of neuronal excitability to current inputs, thus enabling orexin to differentially control input-output gain of its target networks. Orexin neurons also produce other transmitters, including glutamate. When orexin cells fire, glutamate-mediated downstream excitation displays temporal decay, but orexin-mediated excitation escalates, as if orexin transmission enabled arousal controllers to compute a time integral of arousal need. Since the anatomical and functional architecture of the orexin system contains negative feedback loops (e.g. orexin ➔ histamine ➔ noradrenaline/serotonin—orexin), such computations may stabilize wakefulness via integral feedback, a basic engineering strategy for set point control in uncertain environments. Such dynamic behavioural control requires several distinct wake-promoting modules, which perform nonredundant transformations of arousal signals and are connected in feedback loops.

Keywords

Arousal Brain state Control theory Hypocretin Hypothalamus Neurons Orexin 

Notes

Acknowledgements

This work was funded by The Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust.

References

  1. 1.
    Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms. Nature 437(7063):1257–1263Google Scholar
  2. 2.
    Scammell TE (2015) Narcolepsy. N Engl J Med 373(27):2654–2662PubMedPubMedCentralGoogle Scholar
  3. 3.
    Dauvilliers Y, Arnulf I, Mignot E (2007) Narcolepsy with cataplexy. Lancet 369(9560):499–511PubMedGoogle Scholar
  4. 4.
    Peyron C 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):991–997Google Scholar
  5. 5.
    Ripley B et al (2001) CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 57(12):2253–2258PubMedPubMedCentralGoogle Scholar
  6. 6.
    Nishino S et al (2001) Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 50(3):381–388Google Scholar
  7. 7.
    Thannickal TC et al (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3):469–474Google Scholar
  8. 8.
    Yamanaka A et al (2003) Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38(5):701–713Google Scholar
  9. 9.
    Hara J et al (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30(2):345–354Google Scholar
  10. 10.
    Mahler SV et al (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17(10):1298–1303PubMedPubMedCentralGoogle Scholar
  11. 11.
    Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437(7058):556–559Google Scholar
  12. 12.
    Boutrel B et al (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 102(52):19168–19173Google Scholar
  13. 13.
    Sakurai T (2014) The role of orexin in motivated behaviours. Nat Rev Neurosci 15(11):719–731Google Scholar
  14. 14.
    Williams RH et al (2008) Adaptive sugar sensors in hypothalamic feeding circuits. Proc Natl Acad Sci U S A 105(33):11975–11980Google Scholar
  15. 15.
    Williams RH et al (2007) Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci U S A 104(25):10685–10690Google Scholar
  16. 16.
    Karnani MM et al (2011) Activation of central orexin/hypocretin neurons by dietary amino acids. Neuron 72(4):616–629PubMedPubMedCentralGoogle Scholar
  17. 17.
    Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46(5):787–798PubMedPubMedCentralGoogle Scholar
  18. 18.
    Kosse C, Burdakov D (2014) A unifying computational framework for stability and flexibility of arousal. Front Syst Neurosci 8:192PubMedPubMedCentralGoogle Scholar
  19. 19.
    Li Y et al (2002) Hypocretin/orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron 36(6):1169–1181PubMedPubMedCentralGoogle Scholar
  20. 20.
    Yamanaka A et al (2003) Regulation of orexin neurons by the monoaminergic and cholinergic systems. Biochem Biophys Res Commun 303(1):120–129PubMedGoogle Scholar
  21. 21.
    Grivel J et al (2005) The wake-promoting hypocretin/orexin neurons change their response to noradrenaline after sleep deprivation. J Neurosci 25(16):4127–4130PubMedGoogle Scholar
  22. 22.
    Lin L et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98(3):365–376PubMedPubMedCentralGoogle Scholar
  23. 23.
    Chemelli RM et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98(4):437–451Google Scholar
  24. 24.
    Willie JT 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(5):715–730Google Scholar
  25. 25.
    Carter ME et al (2012) Mechanism for hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci U S A 109(39):E2635–E2644Google Scholar
  26. 26.
    Mieda M et al (2011) Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci 31(17):6518–6526PubMedGoogle Scholar
  27. 27.
    Eriksson KS et al (2001) Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 21(23):9273–9279PubMedGoogle Scholar
  28. 28.
    Peyron C et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18(23):9996–10015PubMedGoogle Scholar
  29. 29.
    Ciriello J, Caverson MM (2014) Hypothalamic orexin-A (hypocretin-1) neuronal projections to the vestibular complex and cerebellum in the rat. Brain Res 1579:20–34PubMedGoogle Scholar
  30. 30.
    Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8(3):171–181PubMedPubMedCentralGoogle Scholar
  31. 31.
    Adamantidis AR et al (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450(7168):420–424Google Scholar
  32. 32.
    Eggermann E et al (2001) Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience 108(2):177–181Google Scholar
  33. 33.
    Arrigoni E, Mochizuki T, Scammell TE (2010) Activation of the basal forebrain by the orexin/hypocretin neurones. Acta Physiol (Oxf) 198(3):223–235Google Scholar
  34. 34.
    Hoang QV et al (2014) Orexin (hypocretin) effects on constitutively active inward rectifier K+ channels in cultured nucleus basalis neurons. J Neurophysiol 92(6):3183–3191PubMedGoogle Scholar
  35. 35.
    Ferrari LL et al (2015) Dynorphin inhibits basal forebrain cholinergic neurons by pre- and post-synaptic mechanisms. J Physiol 594(4):1069–1085PubMedPubMedCentralGoogle Scholar
  36. 36.
    Wu M (2004) Hypocretin/orexin innervation and excitation of identified septohippocampal cholinergic neurons. J Neurosci 24(14):3527–3536PubMedPubMedCentralGoogle Scholar
  37. 37.
    Wu M et al (2002) Hypocretin increases impulse flow in the septohippocampal GABAergic pathway: implications for arousal via a mechanism of hippocampal disinhibition. J Neurosci 22(17):7754–7765PubMedGoogle Scholar
  38. 38.
    Mukai K et al (2009) Electrophysiological effects of orexin/hypocretin on nucleus accumbens shell neurons in rats: an in vitro study. Peptides 30(8):1487–1496PubMedPubMedCentralGoogle Scholar
  39. 39.
    Martin G et al (2002) Interaction of the hypocretins with neurotransmitters in the nucleus accumbens. Regul Pept 104(1-3):111–117PubMedGoogle Scholar
  40. 40.
    Lambe EK, Aghajanian GK (2003) Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron 40(1):139–150PubMedGoogle Scholar
  41. 41.
    Lambe EK et al (2005) Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J Neurosci 25(21):5225–5229PubMedGoogle Scholar
  42. 42.
    Marcus JN et al (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435(1):6–25PubMedGoogle Scholar
  43. 43.
    Bayer L et al (2004) Exclusive postsynaptic action of hypocretin-orexin on sublayer 6b cortical neurons. J Neurosci 24(30):6760–6764PubMedGoogle Scholar
  44. 44.
    Hay YA et al (2015) Orexin-dependent activation of layer VIb enhances cortical network activity and integration of non-specific thalamocortical inputs. Brain Struct Funct 220:3497–3512PubMedGoogle Scholar
  45. 45.
    Akbari E et al (2011) Orexin-1 receptor mediates long-term potentiation in the dentate gyrus area of freely moving rats. Behav Brain Res 216(1):375–380PubMedGoogle Scholar
  46. 46.
    Wayner MJ et al (2004) Orexin-A (hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo. Peptides 25(6):991–996PubMedGoogle Scholar
  47. 47.
    Selbach O et al (2010) Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases. Acta Physiol (Oxf) 198(3):277–285PubMedGoogle Scholar
  48. 48.
    Bayer L et al (2002) Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. J Neurosci 22(18):7835–7839PubMedGoogle Scholar
  49. 49.
    Lungwitz EA et al (2012) Orexin-A induces anxiety-like behavior through interactions with glutamatergic receptors in the bed nucleus of the stria terminalis of rats. Physiol Behav 107(5):726–732Google Scholar
  50. 50.
    Conrad KL et al (2012) Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes. Neuropsychopharmacology 37(10):2253–2266PubMedPubMedCentralGoogle Scholar
  51. 51.
    Ishibashi M et al (2005) Effects of orexins/hypocretins on neuronal activity in the paraventricular nucleus of the thalamus in rats in vitro. Peptides 26(3):471–481Google Scholar
  52. 52.
    Huang H, Ghosh P, Pol AN (2006) Prefrontal cortex-projecting glutamatergic thalamic paraventricular nucleus-excited by hypocretin: a feedforward circuit that may enhance cognitive arousal. J Neurophysiol 95(3):1656–1668PubMedPubMedCentralGoogle Scholar
  53. 53.
    Kolaj M et al (2007) Orexin-induced modulation of state-dependent intrinsic properties in thalamic paraventricular nucleus neurons attenuates action potential patterning and frequency. Neuroscience 147(4):1066–1075PubMedPubMedCentralGoogle Scholar
  54. 54.
    Palus K, Chrobok L, Lewandowski MH (2015) Orexins/hypocretins modulate the activity of NPY-positive and -negative neurons in the rat intergeniculate leaflet via OX1 and OX2 receptors. Neuroscience 300:370–380PubMedPubMedCentralGoogle Scholar
  55. 55.
    Chrobok L, Palus K, Lewandowski MH (2015) Orexins excite ventrolateral geniculate nucleus neurons predominantly via OX2 receptors. Neuropharmacology 103:236–246PubMedGoogle Scholar
  56. 56.
    Govindaiah G, Cox CL (2006) Modulation of thalamic neuron excitability by orexins. Neuropharmacology 51(3):414–425PubMedGoogle Scholar
  57. 57.
    Yamanaka A et al (2002) Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem Biophys Res Commun 290(4):1237–1245PubMedGoogle Scholar
  58. 58.
    Schöne C et al (2014) Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep 7(3):697–704PubMedPubMedCentralGoogle Scholar
  59. 59.
    Hoang QV et al (2003) Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol 90(2):693–702PubMedGoogle Scholar
  60. 60.
    Eriksson KS et al (2004) Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons. Eur J Neurosci 19(5):1278–1284PubMedGoogle Scholar
  61. 61.
    Schöne C et al (2012) Optogenetic probing of fast glutamatergic transmission from hypocretin/orexin to histamine neurons in situ. J Neurosci 32(36):12437–12443PubMedGoogle Scholar
  62. 62.
    Belle MD et al (2014) Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock. J Neurosci 34(10):3607–3621PubMedGoogle Scholar
  63. 63.
    Kohlmeier KA, Inoue T, Leonard CS (2004) Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol 92(1):221–235PubMedGoogle Scholar
  64. 64.
    Burlet S, Tyler CJ, Leonard CS (2002) Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy. J Neurosci 22(7):2862–2872Google Scholar
  65. 65.
    Kim J et al (2009) Orexin-A and ghrelin depolarize the same pedunculopontine tegmental neurons in rats: an in vitro study. Peptides 30(7):1328–1335PubMedPubMedCentralGoogle Scholar
  66. 66.
    Horvath TL et al (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415(2):145–159PubMedGoogle Scholar
  67. 67.
    Soffin EM et al (2002) SB-334867-A antagonises orexin mediated excitation in the locus coeruleus. Neuropharmacology 42(1):127–133PubMedGoogle Scholar
  68. 68.
    Soffin EM et al (2004) Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus. Neuropharmacology 46(8):1168–1176PubMedGoogle Scholar
  69. 69.
    Murai Y, Akaike T (2005) Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons. Neurosci Res 51(1):55–65PubMedPubMedCentralGoogle Scholar
  70. 70.
    Kreibich A et al (2008) Presynaptic inhibition of diverse afferents to the locus ceruleus by kappa-opiate receptors: a novel mechanism for regulating the central norepinephrine system. J Neurosci 28(25):6516–6525PubMedGoogle Scholar
  71. 71.
    Henny P et al (2010) Immunohistochemical evidence for synaptic release of glutamate from orexin terminals in the locus coeruleus. Neuroscience 169(3):1150–1157PubMedPubMedCentralGoogle Scholar
  72. 72.
    Brown RE et al (2002) Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 22(20):8850–8859PubMedGoogle Scholar
  73. 73.
    Liu RJ, Pol AN, Aghajanian GK (2002) Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 22(21):9453–9464Google Scholar
  74. 74.
    Haj-Dahmane S, Shen RY (2005) The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signaling. J Neurosci 25(4):896–905PubMedPubMedCentralGoogle Scholar
  75. 75.
    Bisetti A et al (2006) Excitatory action of hypocretin/orexin on neurons of the central medial amygdala. Neuroscience 142(4):999–1004Google Scholar
  76. 76.
    Pol AN et al (2004) Physiological properties of hypothalamic MCH neurons identified with selective expression of reporter gene after recombinant virus infection. Neuron 42(4):635–652PubMedGoogle Scholar
  77. 77.
    Li Y, Pol AN (2006) Differential target-dependent actions of coexpressed inhibitory dynorphin and excitatory hypocretin/orexin neuropeptides. J Neurosci 26(50):13037–13047PubMedPubMedCentralGoogle Scholar
  78. 78.
    Burdakov D, Liss B, Ashcroft FM (2003) Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium--calcium exchanger. J Neurosci 23(12):4951–4957Google Scholar
  79. 79.
    Muroya S et al (2004) Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 19(6):1524–1534PubMedGoogle Scholar
  80. 80.
    Top M et al (2004) Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci 7(5):493–494PubMedGoogle Scholar
  81. 81.
    Ma X et al (2007) Electrical inhibition of identified anorexigenic POMC neurons by orexin/hypocretin. J Neurosci 27(7):1529–1533PubMedGoogle Scholar
  82. 82.
    Shirasaka T et al (2001) Orexin depolarizes rat hypothalamic paraventricular nucleus neurons. Am J Physiol Regul Integr Comp Physiol 281(4):R1114–R1118PubMedGoogle Scholar
  83. 83.
    Muschamp JW et al (2014) Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci U S A 111(16):E1648–E1655Google Scholar
  84. 84.
    Uramura K et al (2001) Orexin-a activates phospholipase C- and protein kinase C-mediated Ca2+ signaling in dopamine neurons of the ventral tegmental area. Neuroreport 12(9):1885–1889Google Scholar
  85. 85.
    Borgland SL, Storm E, Bonci A (2008) Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur J Neurosci 28(8):1545–1556Google Scholar
  86. 86.
    Korotkova TM et al (2003) Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 23(1):7–11PubMedGoogle Scholar
  87. 87.
    Li A, Nattie E (2014) Orexin, cardio-respiratory function, and hypertension. Front Neurosci 8:22–22PubMedPubMedCentralGoogle Scholar
  88. 88.
    Kohlmeier KA et al (2008) Dual orexin actions on dorsal raphe and laterodorsal tegmentum neurons: noisy cation current activation and selective enhancement of Ca2+ transients mediated by L-type calcium channels. J Neurophysiol 100(4):2265–2281PubMedPubMedCentralGoogle Scholar
  89. 89.
    Dias MB, Li A, Nattie EE (2009) Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness. J Physiol 587(Pt 9):2059–2067PubMedPubMedCentralGoogle Scholar
  90. 90.
    Shahid IZ, Rahman AA, Pilowsky PM (2012) Orexin and central regulation of cardiorespiratory system. Vitam Horm 89:159–184PubMedGoogle Scholar
  91. 91.
    Lazarenko RM et al (2011) Orexin A activates retrotrapezoid neurons in mice. Respir Physiol Neurobiol 175(2):283–287Google Scholar
  92. 92.
    Young JK et al (2005) Orexin stimulates breathing via medullary and spinal pathways. J Appl Physiol (1985) 98(4):1387–1395PubMedGoogle Scholar
  93. 93.
    Smith BN et al (2002) Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2. Neuroscience 115(3):707–714Google Scholar
  94. 94.
    Yang B, Ferguson AV (2003) Orexin-A depolarizes nucleus tractus solitarius neurons through effects on nonselective cationic and K+ conductances. J Neurophysiol 89(4):2167–2175PubMedPubMedCentralGoogle Scholar
  95. 95.
    Azhdari-Zarmehri H, Semnanian S, Fathollahi Y (2015) Orexin-a modulates firing of rat rostral ventromedial medulla neurons: an in vitro study. Cell J 17(1):163–170PubMedPubMedCentralGoogle Scholar
  96. 96.
    Huang SC et al (2010) Orexins depolarize rostral ventrolateral medulla neurons and increase arterial pressure and heart rate in rats mainly via orexin 2 receptors. J Pharmacol Exp Ther 334(2):522–529PubMedGoogle Scholar
  97. 97.
    Antunes VR et al (2001) Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro. Am J Physiol Regul Integr Comp Physiol 281(6):R1801–R1807PubMedGoogle Scholar
  98. 98.
    Top M et al (2003) Orexins induce increased excitability and synchronisation of rat sympathetic preganglionic neurones. J Physiol 549(3):809–821Google Scholar
  99. 99.
    Zhang GH et al (2014) Orexin A activates hypoglossal motoneurons and enhances genioglossus muscle activity in rats. Br J Pharmacol 171(18):4233–4246PubMedPubMedCentralGoogle Scholar
  100. 100.
    Corcoran A, Richerson G, Harris M (2010) Modulation of respiratory activity by hypocretin-1 (orexin A) in situ and in vitro. Adv Exp Med Biol 669:109–113PubMedGoogle Scholar
  101. 101.
    Ivanov A, Aston-Jones G (2000) Hypocretin/orexin depolarizes and decreases potassium conductance in locus coeruleus neurons. Neuroreport 11(8):1755–1758PubMedPubMedCentralGoogle Scholar
  102. 102.
    Peever JH, Lai Y-Y, Siegel JM (2003) Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism. J Neurophysiol 89(5):2591–2600Google Scholar
  103. 103.
    Yu L et al (2015) Orexin excites rat inferior vestibular nuclear neurons via co-activation of OX1 and OX 2 receptors. J Neural Transm (Vienna) 122(6):747–755PubMedGoogle Scholar
  104. 104.
    Korotkova TM et al (2002) Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul Pept 104(1-3):83–89PubMedGoogle Scholar
  105. 105.
    Yu L et al (2010) Orexins excite neurons of the rat cerebellar nucleus interpositus via orexin 2 receptors in vitro. Cerebellum 9(1):88–95Google Scholar
  106. 106.
    Dergacheva O et al (2012) Orexinergic modulation of GABAergic neurotransmission to cardiac vagal neurons in the brain stem nucleus ambiguus changes during development. Neuroscience 209:12–20PubMedPubMedCentralGoogle Scholar
  107. 107.
    Lecea L et al (2006) Addiction and arousal: alternative roles of hypothalamic peptides. J Neurosci 26(41):10372–10375PubMedGoogle Scholar
  108. 108.
    Patyal R, Woo EY, Borgland SL (2012) Local hypocretin-1 modulates terminal dopamine concentration in the nucleus accumbens shell. Front Behav Neurosci 6:82PubMedPubMedCentralGoogle Scholar
  109. 109.
    Gonzalez JA et al (2016) Inhibitory interplay between orexin neurons and eating. Curr Biol 26(18):2486–2491PubMedPubMedCentralGoogle Scholar
  110. 110.
    Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117(4):500–544PubMedPubMedCentralGoogle Scholar
  111. 111.
    Koch C (1999) Biophysics of computation. Oxford Universtiy Press, New YorkGoogle Scholar
  112. 112.
    Salinas E, Thier P (2000) Gain modulation: a major computational principle of the central nervous system. Neuron 27(1):15–21PubMedGoogle Scholar
  113. 113.
    Mochizuki T et al (2011) Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci U S A 108(11):4471–4476Google Scholar
  114. 114.
    Hasegawa E et al (2014) Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest 124(2):604–616PubMedGoogle Scholar
  115. 115.
    Sakurai T (2013) Orexin deficiency and narcolepsy. Curr Opin Neurobiol 23(5):760–766PubMedGoogle Scholar
  116. 116.
    Kayaba Y et al (2003) Attenuated defense response and low basal blood pressure in orexin knockout mice. Am J Physiol Regul Integr Comp Physiol 285(3):R581–R593PubMedGoogle Scholar
  117. 117.
    Meletti S et al (2015) The brain correlates of laugh and cataplexy in childhood narcolepsy. J Neurosci 35(33):11583–11594Google Scholar
  118. 118.
    Burgess CR et al (2013) Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci 33(23):9734–9742PubMedGoogle Scholar
  119. 119.
    DiStefano J Stubberud A, Williams I (2012) Feedback and control systems, 2nd ed. McGrawHillGoogle Scholar
  120. 120.
    Csete ME, Doyle JC (2002) Reverse engineering of biological complexity. Science 295:1664–1669PubMedGoogle Scholar
  121. 121.
    Aström K, Hagglund T (1995) PID controllers: theory, design, and tuning. Intrument Society of America (ISA). ISBN-10: 1556175167Google Scholar
  122. 122.
    Uschakov A et al (2011) Sleep-deprivation regulates alpha-2 adrenergic responses of rat hypocretin/orexin neurons. PLoS One 6(2):e16672PubMedPubMedCentralGoogle Scholar
  123. 123.
    Yamanaka A et al (2010) Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci 30(38):12642–12652PubMedGoogle Scholar
  124. 124.
    Ohno K, Sakurai T (2008) Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front Neuroendocrinol 29(1):70–87PubMedGoogle Scholar
  125. 125.
    Lu J et al (2006) A putative flip-flop switch for control of REM sleep. Nature 441(7093):589–594PubMedGoogle Scholar
  126. 126.
    Sakurai T et al (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46(2):297–308Google Scholar
  127. 127.
    Yoshida K et al (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494(5):845–861Google Scholar
  128. 128.
    Tsujino N et al (2005) Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor. J Neurosci 25(32):7459–7469PubMedGoogle Scholar
  129. 129.
    Gonzalez JA et al (2016) Awake dynamics and brain-wide direct inputs of hypothalamic MCH and orexin networks. Nat Commun 7:11395PubMedPubMedCentralGoogle Scholar
  130. 130.
    Schöne C, Burdakov D (2012) Glutamate and GABA as rapid effectors of hypothalamic “peptidergic” neurons. Front Behav Neurosci 6:81PubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Department of NeurologyUniversity of BernBernSwitzerland
  2. 2.The Francis Crick Institute, Mill Hill LaboratoryLondonUK

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