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The role of co-neurotransmitters in sleep and wake regulation

Abstract

Sleep and wakefulness control in the mammalian brain requires the coordination of various discrete interconnected neurons. According to the most conventional sleep model, wake-promoting neurons (WPNs) and sleep-promoting neurons (SPNs) compete for network dominance, creating a systematic “switch” that results in either the sleep or awake state. WPNs and SPNs are ubiquitous in the brainstem and diencephalon, areas that together contain <1% of the neurons in the human brain. Interestingly, many of these WPNs and SPNs co-express and co-release various types of the neurotransmitters that often have opposing modulatory effects on the network. Co-transmission is often beneficial to structures with limited numbers of neurons because it provides increasing computational capability and flexibility. Moreover, co-transmission allows subcortical structures to bi-directionally control postsynaptic neurons, thus helping to orchestrate several complex physiological functions such as sleep. Here, we present an in-depth review of co-transmission in hypothalamic WPNs and SPNs and discuss its functional significance in the sleep–wake network.

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References

  1. 1.

    Ng MC. Orexin and epilepsy: potential role of REM sleep. Sleep. 2017;40.

  2. 2.

    Kroeger D, Ferrari LL, Petit G, Mahoney CE, Fuller PM, Arrigoni E, et al. Cholinergic, glutamatergic, and gabaergic neurons of the pedunculopontine tegmental nucleus have distinct effects on sleep/wake behavior in mice. J Neurosci. 2017;37:1352–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Jacobson LH, Chen S, Mir S, Hoyer D. Orexin OX2 receptor antagonists as sleep aids. Curr Top Behav Neurosci. 2017;33:105–36.

    PubMed  Google Scholar 

  4. 4.

    Khanday MA, Somarajan BI, Mehta R, Mallick BN. Noradrenaline from locus coeruleus neurons acts on pedunculo-pontine neurons to prevent rem sleep and induces its loss-associated effects in rats. eNeuro. 2016;3:ENEURO0108.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Gotter AL, Forman MS, Harrell CM, Stevens J, Svetnik V, Yee KL, et al. Orexin 2 receptor antagonism is sufficient to promote NREM and REM sleep from mouse to man. Sci Rep. 2016;6:27147.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Takahashi K, Kayama Y, Lin JS, Sakai K. Locus coeruleus neuronal activity during the sleep-waking cycle in mice. Neuroscience. 2010;169:1115–26.

    CAS  PubMed  Google Scholar 

  7. 7.

    Takahashi K, Lin JS, Sakai K. Neuronal activity of histaminergic tuberomammillary neurons during wake-sleep states in the mouse. J Neurosci. 2006;26:10292–8.

    CAS  PubMed  Google Scholar 

  8. 8.

    Zhao LZ, Zhang GL, Gao J, Zhang JX, Zhong MK, Zhang J. [Role of serotonergic neurons in dorsal raphe nuclei in regulation of sleep]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2003;19:175–8.

    PubMed  Google Scholar 

  9. 9.

    Anaclet C, Ferrari L, Arrigoni E, Bass CE, Saper CB, Lu J, et al. The GABAergic parafacial zone is a medullary slow wave sleep-promoting center. Nat Neurosci. 2014;17:1217–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Chung S, Weber F, Zhong P, Tan CL, Nguyen TN, Beier KT, et al. Identification of preoptic sleep neurons using retrograde labelling and gene profiling. Nature. 2017;545:477–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Gallopin T, Fort P, Eggermann E, Cauli B, Luppi PH, Rossier J, et al. Identification of sleep-promoting neurons in vitro. Nature. 2000;404:992–5.

    CAS  PubMed  Google Scholar 

  12. 12.

    Pelluru D, Konadhode R, Shiromani PJ. MCH neurons are the primary sleep-promoting group. Sleep. 2013;36:1779–81.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Alam MA, Kumar S, McGinty D, Alam MN, Szymusiak R. Neuronal activity in the preoptic hypothalamus during sleep deprivation and recovery sleep. J Neurophysiol. 2014;111:287–99.

    CAS  PubMed  Google Scholar 

  14. 14.

    Lu BS, Zee PC. Neurobiology of sleep. Clin Chest Med. 2010;31:309–18.

    PubMed  Google Scholar 

  15. 15.

    Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001;24:726–31.

    CAS  PubMed  Google Scholar 

  16. 16.

    Szymusiak R, McGinty D. Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci. 2008;1129:275–86.

    CAS  PubMed  Google Scholar 

  17. 17.

    Saper CB, Fuller PM. Wake-sleep circuitry: an overview. Curr Opin Neurobiol. 2017;44:186–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Hokfelt T. Neuropeptides in perspective: the last ten years. Neuron. 1991;7:867–79.

    CAS  PubMed  Google Scholar 

  19. 19.

    Apostolides PF, Trussell LO. Rapid, activity-independent turnover of vesicular transmitter content at a mixed glycine/GABA synapse. J Neurosci. 2013;33:4768–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Tritsch NX, Granger AJ, Sabatini BL. Mechanisms and functions of GABA co-release. Nat Rev Neurosci. 2016;17:139–45.

    CAS  PubMed  Google Scholar 

  21. 21.

    Lee S, Kim K, Zhou ZJ. Role of ACh-GABA cotransmission in detecting image motion and motion direction. Neuron. 2010;68:1159–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Wojcik SM, Katsurabayashi S, Guillemin I, Friauf E, Rosenmund C, Brose N, et al. A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron. 2006;50:575–87.

    CAS  PubMed  Google Scholar 

  23. 23.

    Gillespie DC, Kim G, Kandler K. Inhibitory synapses in the developing auditory system are glutamatergic. Nat Neurosci. 2005;8:332–8.

    CAS  PubMed  Google Scholar 

  24. 24.

    Noh J, Seal RP, Garver JA, Edwards RH, Kandler K. Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat Neurosci. 2010;13:232–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Chuhma N, Choi WY, Mingote S, Rayport S. Dopamine neuron glutamate cotransmission: frequency-dependent modulation in the mesoventromedial projection. Neuroscience. 2009;164:1068–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lapish CC, Seamans JK, Chandler LJ. Glutamate-dopamine cotransmission and reward processing in addiction. Alcohol Clin Exp Res. 2006;30:1451–65.

    CAS  PubMed  Google Scholar 

  27. 27.

    Mingote S, Chuhma N, Kalmbach A, Thomsen GM, Wang Y, Mihali A, et al. Dopamine neuron dependent behaviors mediated by glutamate cotransmission. eLife. 2017;6:e27566.

  28. 28.

    Panula P, Yang HY, Costa E. Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci USA. 1984;81:2572–6.

    CAS  PubMed  Google Scholar 

  29. 29.

    Airaksinen MS, Paetau A, Paljärvi L, Reinikainen K, Riekkinen P, Suomalainen R, et al. Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer diseased brains. Neuroscience. 1991;44:465–81.

    CAS  PubMed  Google Scholar 

  30. 30.

    Airaksinen MS, Alanen S, Szabat E, Visser TJ, Panula P. Multiple neurotransmitters in the tuberomammillary nucleus: comparison of rat, mouse, and guinea pig. J Comp Neurol. 1992;323:103–16.

    CAS  PubMed  Google Scholar 

  31. 31.

    Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88:1183–241.

    CAS  PubMed  Google Scholar 

  32. 32.

    Merickel A, Edwards RH. Transport of histamine by vesicular monoamine transporter-2. Neuropharmacology. 1995;34:1543–7.

    CAS  PubMed  Google Scholar 

  33. 33.

    Thakkar MM. Histamine in the regulation of wakefulness. Sleep Med Rev. 2011;15:65–74.

    PubMed  Google Scholar 

  34. 34.

    Monti JM, D’Angelo L, Jantos H, Pazos S. Effects of a-fluoromethylhistidine on sleep and wakefulness in the rat. Short note. J Neural Transm. 1988;72:141–5.

    CAS  PubMed  Google Scholar 

  35. 35.

    Yu X, Ye Z, Houston CM, Zecharia AY, Ma Y, Zhang Z, et al. Wakefulness is governed by GABA and histamine cotransmission. Neuron. 2015;87:164–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kukko-Lukjanov TK, Panula P. Subcellular distribution of histamine, GABA and galanin in tuberomamillary neurons in vitro. J Chem Neuroanat. 2003;25:279–92.

    CAS  PubMed  Google Scholar 

  37. 37.

    Kjaer A, Knigge U, Rouleau A, Garbarg M, Warberg J. Dehydration-induced release of vasopressin involves activation of hypothalamic histaminergic neurons. Endocrinology. 1994;135:675–81.

    CAS  PubMed  Google Scholar 

  38. 38.

    Ookuma K, Sakata T, Fukagawa K, Yoshimatsu H, Kurokawa M, Machidori H, et al. Neuronal histamine in the hypothalamus suppresses food intake in rats. Brain Res. 1993;628:235–42.

    CAS  PubMed  Google Scholar 

  39. 39.

    Sakata T, Kurokawa M, Oohara A, Yoshimatsu H. A physiological role of brain histamine during energy deficiency. Brain Res Bull. 1994;35:135–9.

    CAS  PubMed  Google Scholar 

  40. 40.

    Lundius EG, Sanchez-Alavez M, Ghochani Y, Klaus J, Tabarean IV. Histamine influences body temperature by acting at H1 and H3 receptors on distinct populations of preoptic neurons. J Neurosci. 2010;30:4369–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci. 2003;4:121–30.

    CAS  PubMed  Google Scholar 

  42. 42.

    Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012;287:40224–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Kamondi A, Reiner PB. Hyperpolarization-activated inward current in histaminergic tuberomammillary neurons of the rat hypothalamus. J Neurophysiol. 1991;66:1902–11.

    CAS  PubMed  Google Scholar 

  44. 44.

    Liu S, Plachez C, Shao Z, Puche A, Shipley MT. Olfactory bulb short axon cell release of GABA and dopamine produces a temporally biphasic inhibition-excitation response in external tufted cells. J Neurosci. 2013;33:2916–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Wu J, Hablitz JJ. Cooperative activation of D1 and D2 dopamine receptors enhances a hyperpolarization-activated inward current in layer I interneurons. J Neurosci. 2005;25:6322–8.

    CAS  PubMed  Google Scholar 

  46. 46.

    Liu S, Shipley MT. Intrinsic conductances actively shape excitatory and inhibitory postsynaptic responses in olfactory bulb external tufted cells. J Neurosci. 2008;28:10311–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Williams RH, Chee MJ, Kroeger D, Ferrari LL, Maratos-Flier E, Scammell TE, et al. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J Neurosci. 2014;34:6023–9.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Saras A, Gisselmann G, Vogt-Eisele AK, Erlkamp KS, Kletke O, Pusch H, et al. Histamine action on vertebrate GABAA receptors: direct channel gating and potentiation of GABA responses. J Biol Chem. 2008;283:10470–5.

    CAS  PubMed  Google Scholar 

  49. 49.

    Bianchi MT, Clark AG, Fisher JL. The wake-promoting transmitter histamine preferentially enhances alpha-4 subunit-containing GABAA receptors. Neuropharmacology. 2011;61:747–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Hoerbelt P, Ramerstorfer J, Ernst M, Sieghart W, Thomson JL, Hough LB, et al. Mutagenesis and computational docking studies support the existence of a histamine binding site at the extracellular beta3 + beta3- interface of homooligomeric beta3 GABAA receptors. Neuropharmacology. 2016;108:252–63.

    CAS  PubMed  Google Scholar 

  51. 51.

    Thiel U, Platt SJ, Wolf S, Hatt H, Gisselmann G. Identification of amino acids involved in histamine potentiation of GABA A receptors. Front Pharmacol. 2015;6:106.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Hatton GI, Yang QZ. Ionotropic histamine receptors and H2 receptors modulate supraoptic oxytocin neuronal excitability and dye coupling. J Neurosci. 2001;21:2974–82.

    CAS  PubMed  Google Scholar 

  53. 53.

    Yang QZ, Hatton GI. Histamine mediates fast synaptic inhibition of rat supraoptic oxytocin neurons via chloride conductance activation. Neuroscience. 1994;61:955–64.

    CAS  PubMed  Google Scholar 

  54. 54.

    Sittig N, Davidowa H. Histamine reduces firing and bursting of anterior and intralaminar thalamic neurons and activates striatal cells in anesthetized rats. Behav Brain Res. 2001;124:137–43.

    CAS  PubMed  Google Scholar 

  55. 55.

    Lee KH, Broberger C, Kim U, McCormick DA. Histamine modulates thalamocortical activity by activating a chloride conductance in ferret perigeniculate neurons. Proc Natl Acad Sci USA. 2004;101:6716–21.

    CAS  PubMed  Google Scholar 

  56. 56.

    Fleck MW, Thomson JL, Hough LB. Histamine-gated ion channels in mammals? Biochem Pharmacol. 2012;83:1127–35.

    CAS  PubMed  Google Scholar 

  57. 57.

    Gerashchenko D, Wisor JP, Burns D, Reh RK, Shiromani PJ, Sakurai T, et al. Identification of a population of sleep-active cerebral cortex neurons. Proc Natl Acad Sci USA. 2008;105:10227–32.

    CAS  PubMed  Google Scholar 

  58. 58.

    Kilduff TS, Cauli B, Gerashchenko D. Activation of cortical interneurons during sleep: an anatomical link to homeostatic sleep regulation? Trends Neurosci. 2011;34:10–19.

    CAS  PubMed  Google Scholar 

  59. 59.

    Chen L, Majde JA, Krueger JM. Spontaneous sleep in mice with targeted disruptions of neuronal or inducible nitric oxide synthase genes. Brain Res. 2003;973:214–22.

    CAS  PubMed  Google Scholar 

  60. 60.

    Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature. 2007;450:420–4.

    CAS  PubMed  Google Scholar 

  61. 61.

    Tsunematsu T, Kilduff TS, Boyden ES, Takahashi S, Tominaga M, Yamanaka A. Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. J Neurosci. 2011;31:10529–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Tsunematsu T, Tabuchi S, Tanaka KF, Boyden ES, Tominaga M, Yamanaka A. Long-lasting silencing of orexin/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice. Behav Brain Res. 2013;255:64–74.

    CAS  PubMed  Google Scholar 

  63. 63.

    Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98:437–51.

    CAS  PubMed  Google Scholar 

  64. 64.

    Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2011;51:243–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Hoang QV, Bajic D, Yanagisawa M, Nakajima S, Nakajima Y. Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol. 2003;90:693–702.

    CAS  PubMed  Google Scholar 

  66. 66.

    Burdakov D, Liss B, Ashcroft FM. Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium--calcium exchanger. J Neurosci. 2003;23:4951–7.

    CAS  PubMed  Google Scholar 

  67. 67.

    Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, et al. Orexin (hypocretin) neurons contain dynorphin. J Neurosci. 2001;21:RC168.

    CAS  PubMed  Google Scholar 

  68. 68.

    Shukla VK, Lemaire S. Non-opioid effects of dynorphins: possible role of the NMDA receptor. Trends Pharmacol Sci. 1994;15:420–4.

    CAS  PubMed  Google Scholar 

  69. 69.

    Tejeda HA, Shippenberg TS, Henriksson R. The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci. 2012;69:857–96.

    CAS  PubMed  Google Scholar 

  70. 70.

    Bruijnzeel AW. kappa-Opioid receptor signaling and brain reward function. Brain Res Rev. 2009;62:127–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Crain SM, Shen KF. Modulatory effects of Gs-coupled excitatory opioid receptor functions on opioid analgesia, tolerance, and dependence. Neurochem Res. 1996;21:1347–51.

    CAS  PubMed  Google Scholar 

  72. 72.

    Muschamp JW, Hollander JA, Thompson JL, Voren G, Hassinger LC, Onvani S. et al. Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci USA. 2014;111:E1648–55.

    CAS  PubMed  Google Scholar 

  73. 73.

    McFadzean I, Lacey MG, Hill RG, Henderson G. Kappa opioid receptor activation depresses excitatory synaptic input to rat locus coeruleus neurons in vitro. Neuroscience. 1987;20:231–9.

    CAS  PubMed  Google Scholar 

  74. 74.

    Kreibich A, Reyes BA, Curtis AL, Ecke L, Chavkin C, Van Bockstaele EJ, et al. Presynaptic inhibition of diverse afferents to the locus ceruleus by kappa-opiate receptors: a novel mechanism for regulating the central norepinephrine system. J Neurosci. 2008;28:6516–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Pinnock RD. Activation of kappa-opioid receptors depresses electrically evoked excitatory postsynaptic potentials on 5-HT-sensitive neurones in the rat dorsal raphe nucleus in vitro. Brain Res. 1992;583:237–46.

    CAS  PubMed  Google Scholar 

  76. 76.

    Tao R, Auerbach SB. Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system. J Pharmacol Exp Ther. 2002;303:549–56.

    CAS  PubMed  Google Scholar 

  77. 77.

    Ferrari LL, Agostinelli LJ, Krashes MJ, Lowell BB, Scammell TE, Arrigoni E. Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms. J Physiol. 2016;594:1069–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Matzeu A, Kallupi M, George O, Schweitzer P, Martin-Fardon R. Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence. Neuropsychopharmacology. 2017;43.

  79. 79.

    Baimel C, Lau BK, Qiao M, Borgland SL. Projection-target-defined effects of orexin and dynorphin on VTA dopamine neurons. Cell Rep. 2017;18:1346–55.

    CAS  PubMed  Google Scholar 

  80. 80.

    Sun HX, Wang DR, Ye CB, Hu ZZ, Wang CY, Huang ZL, et al. Activation of the ventral tegmental area increased wakefulness in mice. Sleep Biol Rhythms. 2017;15:107–15.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Monti JM, Monti D. The involvement of dopamine in the modulation of sleep and waking. Sleep Med Rev. 2007;11:113–33.

    PubMed  Google Scholar 

  82. 82.

    Yamanaka A, Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M. Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci. 2010;30:12642–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Li Y, van den Pol AN. Differential target-dependent actions of coexpressed inhibitory dynorphin and excitatory hypocretin/orexin neuropeptides. J Neurosci. 2006;26:13037–47.

    CAS  PubMed  Google Scholar 

  84. 84.

    Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci. 1998;18:4705–21.

    CAS  PubMed  Google Scholar 

  85. 85.

    Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Activation of ventrolateral preoptic neurons during sleep. Science. 1996;271:216–9.

    CAS  PubMed  Google Scholar 

  86. 86.

    Eriksson KS, Sergeeva OA, Selbach O, Haas HL. Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons. Eur J Neurosci. 2004;19:1278–84.

    PubMed  Google Scholar 

  87. 87.

    Apergis-Schoute J, Iordanidou P, Faure C, Jego S, Schone C, Aitta-Aho T, et al. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J Neurosci. 2015;35:5435–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Robinson JD, McDonald PH. The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism. Cell Signal. 2015;27:1449–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Chen J, Zhang R, Chen X, Wang C, Cai X, Liu H, et al. Heterodimerization of human orexin receptor 1 and kappa opioid receptor promotes protein kinase A/cAMP-response element binding protein signaling via a Galphas-mediated mechanism. Cell Signal. 2015;27:1426–38.

    CAS  PubMed  Google Scholar 

  90. 90.

    Rosin DL, Weston MC, Sevigny CP, Stornetta RL, Guyenet PG. Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. J Comp Neurol. 2003;465:593–603.

    CAS  PubMed  Google Scholar 

  91. 91.

    Mickelsen LE, Kolling FWt, Chimileski BR, Fujita A, Norris C, Chen K, et al. Neurochemical heterogeneity among lateral hypothalamic hypocretin/orexin and melanin-concentrating hormone neurons identified through single-cell gene expression analysis. eNeuro. 2017;4:ENEURO0013.

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Henny P, Brischoux F, Mainville L, Stroh T, Jones BE. Immunohistochemical evidence for synaptic release of glutamate from orexin terminals in the locus coeruleus. Neuroscience. 2010;169:1150–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Torrealba F, Yanagisawa M, Saper CB. Colocalization of orexin a and glutamate immunoreactivity in axon terminals in the tuberomammillary nucleus in rats. Neuroscience. 2003;119:1033–44.

    CAS  PubMed  Google Scholar 

  94. 94.

    van den Pol AN. Neuropeptide transmission in brain circuits. Neuron. 2012;76:98–115.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Baimel C, Borgland SL. Hypocretin/orexin and plastic adaptations associated with drug abuse. Curr Top Behav Neurosci. 2017;33:283–304.

    CAS  PubMed  Google Scholar 

  96. 96.

    Sudhof TC. The presynaptic active zone. Neuron. 2012;75:11–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Schone C, Apergis-Schoute J, Sakurai T, Adamantidis A, Burdakov D. Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep. 2014;7:697–704.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Sudhof TC. Calcium control of neurotransmitter release. Cold Spring Harb Perspect Biol. 2012;4:a011353.

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Chen L, Gu Y, Huang LY. The mechanism of action for the block of NMDA receptor channels by the opioid peptide dynorphin. J Neurosci. 1995;15:4602–11.

    CAS  PubMed  Google Scholar 

  100. 100.

    Sita LV, Elias CF, Bittencourt JC. Connectivity pattern suggests that incerto-hypothalamic area belongs to the medial hypothalamic system. Neuroscience. 2007;148:949–69.

    CAS  PubMed  Google Scholar 

  101. 101.

    Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, et al. The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J Comp Neurol. 1992;319:218–45.

    CAS  PubMed  Google Scholar 

  102. 102.

    Bittencourt JC. Anatomical organization of the melanin-concentrating hormone peptide family in the mammalian brain. Gen Comp Endocrinol. 2011;172:185–97.

    CAS  PubMed  Google Scholar 

  103. 103.

    Diniz GB, Bittencourt JC. The Melanin-Concentrating Hormone as an Integrative Peptide Driving Motivated Behaviors. Front Syst Neurosci. 2017;11:32.

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Casatti CA, Elias CF, Sita LV, Frigo L, Furlani VC, Bauer JA, et al. Distribution of melanin-concentrating hormone neurons projecting to the medial mammillary nucleus. Neuroscience. 2002;115:899–915.

    CAS  PubMed  Google Scholar 

  105. 105.

    Adamantidis A, de Lecea L. A role for melanin-concentrating hormone in learning and memory. Peptides. 2009;30:2066–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Smith DG, Davis RJ, Rorick-Kehn L, Morin M, Witkin JM, McKinzie DL, et al. Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice. Neuropsychopharmacology. 2006;31:1135–45.

    CAS  PubMed  Google Scholar 

  107. 107.

    Glick M, Segal-Lieberman G, Cohen R, Kronfeld-Schor N. Chronic MCH infusion causes a decrease in energy expenditure and body temperature, and an increase in serum IGF-1 levels in mice. Endocrine. 2009;36:479–85.

    CAS  PubMed  Google Scholar 

  108. 108.

    Yoon YS, Lee HS. Projections from melanin-concentrating hormone (MCH) neurons to the dorsal raphe or the nuclear core of the locus coeruleus in the rat. Brain Res. 2013;1490:72–82.

    CAS  PubMed  Google Scholar 

  109. 109.

    Torterolo P, Sampogna S, Chase MH. MCHergic projections to the nucleus pontis oralis participate in the control of active (REM) sleep. Brain Res. 2009;1268:76–87.

    CAS  PubMed  Google Scholar 

  110. 110.

    Fraigne JJ, Peever JH. Melanin-concentrating hormone neurons promote and stabilize sleep. Sleep. 2013;36:1767–8.

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Whiddon BB, Palmiter RD. Ablation of neurons expressing melanin-concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling. J Neurosci. 2013;33:2009–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Fort P, Salvert D, Hanriot L, Jego S, Shimizu H, Hashimoto K, et al. The satiety molecule nesfatin-1 is co-expressed with melanin concentrating hormone in tuberal hypothalamic neurons of the rat. Neuroscience. 2008;155:174–81.

    CAS  PubMed  Google Scholar 

  113. 113.

    Elias CF, Lee CE, Kelly JF, Ahima RS, Kuhar M, Saper CB, et al. Characterization of CART neurons in the rat and human hypothalamus. J Comp Neurol. 2001;432:1–19.

    CAS  PubMed  Google Scholar 

  114. 114.

    Hawes BE, Kil E, Green B, O’Neill K, Fried S, Graziano MP. The melanin-concentrating hormone receptor couples to multiple G proteins to activate diverse intracellular signaling pathways. Endocrinology. 2000;141:4524–32.

    CAS  PubMed  Google Scholar 

  115. 115.

    Gao XB, van den Pol AN. Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons. J Physiol. 2002;542(Pt 1):273–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Gao XB, van den Pol AN. Melanin concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus. J Physiol. 2001;533(Pt 1):237–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Tan CP, Sano H, Iwaasa H, Pan J, Sailer AW, Hreniuk DL, et al. Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. Genomics. 2002;79:785–92.

    CAS  PubMed  Google Scholar 

  118. 118.

    Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong SS, et al. Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc Natl Acad Sci USA. 2001;98:7564–9.

    CAS  PubMed  Google Scholar 

  119. 119.

    Konadhode RR, Pelluru D, Blanco-Centurion C, Zayachkivsky A, Liu M, Uhde T, et al. Optogenetic stimulation of MCH neurons increases sleep. J Neurosci. 2013;33:10257–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Blanco-Centurion C, Liu M, Konadhode RP, Zhang X, Pelluru D, van den Pol AN, et al. Optogenetic activation of melanin-concentrating hormone neurons increases non-rapid eye movement and rapid eye movement sleep during the night in rats. Eur J Neurosci. 2016;44:2846–57.

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Jego S, Glasgow SD, Herrera CG, Ekstrand M, Reed SJ, Boyce R, et al. Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nat Neurosci. 2013;16:1637–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Tsunematsu T, Ueno T, Tabuchi S, Inutsuka A, Tanaka KF, Hasuwa H, et al. Optogenetic manipulation of activity and temporally controlled cell-specific ablation reveal a role for MCH neurons in sleep/wake regulation. J Neurosci. 2014;34:6896–909.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Fujimoto M, Fukuda S, Sakamoto H, Takata J, Sawamura S. Neuropeptide glutamic acid-isoleucine (NEI)-induced paradoxical sleep in rats. Peptides. 2017;87:28–33.

    CAS  PubMed  Google Scholar 

  124. 124.

    Verret L, Goutagny R, Fort P, Cagnon L, Salvert D, Leger L, et al. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci. 2003;4:19.

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Ahnaou A, Drinkenburg WH, Bouwknecht JA, Alcazar J, Steckler T, Dautzenberg FM. Blocking melanin-concentrating hormone MCH1 receptor affects rat sleep-wake architecture. Eur J Pharmacol. 2008;579:177–88.

    CAS  PubMed  Google Scholar 

  126. 126.

    Vetrivelan R, Kong D, Ferrari LL, Arrigoni E, Madara JC, Bandaru SS, et al. Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience. 2016;336:102–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Naganuma F, Bandaru SS, Absi G, Mahoney CE, Scammell TE, Vetrivelan R. Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy. Neurobiol Dis. 2018;120:12–20.

    CAS  PubMed  Google Scholar 

  128. 128.

    Jancsik V, Bene R, Sotonyi P, Zachar G. Sub-cellular organization of the melanin-concentrating hormone neurons in the hypothalamus. Peptides. 2017;99:56–60.

    CAS  PubMed  Google Scholar 

  129. 129.

    Chee MJ, Arrigoni E, Maratos-Flier E. Melanin-concentrating hormone neurons release glutamate for feedforward inhibition of the lateral septum. J Neurosci. 2015;35:3644–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Blanco-Centurion C, Bendell E, Zou B, Sun Y, Shiromani PJ, Liu M. VGAT and VGLUT2 expression in MCH and orexin neurons in double transgenic reporter mice. IBRO Rep. 2018;4:44–9.

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Tuominen L, Nummenmaa L, Keltikangas-Jarvinen L, Raitakari O, Hietala J. Mapping neurotransmitter networks with PET: an example on serotonin and opioid systems. Hum Brain Mapp. 2014;35:1875–84.

    PubMed  Google Scholar 

  132. 132.

    Liu ZY, Liu FT, Zuo CT, Koprich JB, Wang J. Update on molecular imaging in Parkinson’s disease. Neurosci Bull. 2018;34:330–40.

    CAS  PubMed  Google Scholar 

  133. 133.

    Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009;513:532–41.

    PubMed  Google Scholar 

  134. 134.

    Schwarz LA, Luo L. Organization of the locus coeruleus-norepinephrine system. Curr Biol. 2015;25:R1051–6.

    CAS  PubMed  Google Scholar 

  135. 135.

    Liu Z, Zhou J, Li Y, Hu F, Lu Y, Ma M, et al. Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron. 2014;81:1360–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Sengupta A, Bocchio M, Bannerman DM, Sharp T, Capogna M. Control of amygdala circuits by 5-HT neurons via 5-HT and glutamate cotransmission. J Neurosci. 2017;37:1785–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Le Maitre E, Barde SS, Palkovits M, Diaz-Heijtz R, Hokfelt TG. Distinct features of neurotransmitter systems in the human brain with focus on the galanin system in locus coeruleus and dorsal raphe. Proc Natl Acad Sci USA. 2013;110:E536–545.

    PubMed  Google Scholar 

  138. 138.

    Wagatsuma A, Okuyama T, Sun C, Smith LM, Abe K, Tonegawa S. Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context. Proc Natl Acad Sci USA. 2018;115:E310–E316.

    CAS  PubMed  Google Scholar 

  139. 139.

    Kempadoo KA, Mosharov EV, Choi SJ, Sulzer D, Kandel ER. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci USA. 2016;113:14835–40.

    CAS  PubMed  Google Scholar 

  140. 140.

    Eser RA, Ehrenberg AJ, Petersen C, Dunlop S, Mejia MB, Suemoto CK, et al. Selective vulnerability of brainstem nuclei in distinct tauopathies: a postmortem study. J Neuropathol Exp Neurol. 2018;77:149–61.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We gratefully acknowledge support from the Tau Consortium/Rainwater Charitable Foundation and NIH grants: K24AG053435 (LTG), R56MH107042 (TCN). The Grants that support JCB came from the Fundação de Amparo à Pesquisa do Estado de São Paulo [São Paulo Research Foundation - FAPESP] grant #2016/02224-1 [JCB], the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior [Agency for the Advancement of Higher Education – CAPES grant #848/15], and the Conselho Nacional de Desenvolvimento Científico e Tecnológico [National Council for Scientific and Technological Development - CNPq] with grant #426378/2016-4. JCB is an investigator with the CNPq. JYO is a Tau Consortium Fellow. We also thank Dulce Morales for histology and Evan T. Keum and Brian Hitchin for manuscript editing.

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Correspondence to Lea T. Grinberg.

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Oh, J., Petersen, C., Walsh, C.M. et al. The role of co-neurotransmitters in sleep and wake regulation. Mol Psychiatry 24, 1284–1295 (2019). https://doi.org/10.1038/s41380-018-0291-2

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