Projections of the MCH System to Structures Involved in the Regulation of Sleep and Wakefulness

  • Hyun Sook LeeEmail author


Although glutamatergic sublaterodorsal tegmental nucleus (SLD) constitutes a core of rapid eye movement (REM) sleep circuits, recent reports assert that REM sleep generation is under hypothalamic control of melanin-concentrating hormone (MCH) neurons. GABAergic MCH cells control the onset and maintenance of REM sleep via direct inhibitory projection to REM-off GABAergic neurons in ventrolateral periaqueductal gray matter which exert a potent inhibitory influence on REM-on SLD cells. It is generally accepted that cholinergic neurons in the pedunculopontine tegmental (PPT) and laterodorsal tegmental (LDT) nuclei serve as supplementary REM-on cells, while noradrenergic locus coeruleus (LC) and serotoninergic dorsal raphe (DR) cells contribute to REM-off circuitry. MCH neurons project heavily to the PPT and LDT, where cholinergic neurons might play a role in the strengthening of non-REM (NREM) to REM transitions once initiated. They also project to the LC and DR; the microinjection of MCH into these nuclei increases REM sleep duration. Likewise, MCH neurons send efferent fibers to the tuberomammillary nucleus (TMN); the activation of these fibers prolongs REM sleep episodes. Among monoaminergic nuclei, the TMN is unique in that (1) histaminergic neurons are active in cataplexy, implying their role in the maintenance of arousal state during the period, and (2) it contains a substantial number of MCH somata within its boundary, whose physiological function remains to be established.


Melanin-concentrating hormone (MCH) Ventrolateral periaqueductal gray (vlPAG) Sublaterodorsal tegmental nucleus (SLD) Pedunculopontine tegmental nucleus (PPT) Laterodorsal tegmental nucleus (LDT) Dorsal raphe (DR) Locus coeruleus (LC) Amygdala Tuberomammillary nucleus (TMN) 



The author thanks warmly Dr. Pierre H. Luppi from University Lyon 1, France, for critical reading of the manuscript.


  1. Bäckberg M, Hervieu G, Wilson S, Meister B (2002) Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Eur J Neurosci 15:315–328CrossRefGoogle Scholar
  2. Barson JR, Morganstern I, Leibowitz SF (2013) Complementary roles of orexin and melanin-concentrating hormone in feeding behavior. Int J Endocrinol 2013:1–10CrossRefGoogle Scholar
  3. Bisetti A, Cvetkovic V, Bayer L, Jones BE, Serafin M, Muhlethaler M (2009) Melanin concentrating hormone antagonizes the hypocretin/orexin-induced depolarization of neurons in the locus coeruleus and ventral tuberomammillary nuclei. Abstr Soc Neurosci 277.6/EE18Google Scholar
  4. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL et al (1992) The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J Comp Neurol 319:218–245CrossRefGoogle Scholar
  5. Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, Luppi PH (2002) The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur J Neurosci 16:1959–1973CrossRefGoogle Scholar
  6. Boucetta S, Cissé Y, Mainville L, Morales M, Jones BE (2014) Discharge profiles across the sleep–waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. J Neurosci 26:4708–4727CrossRefGoogle Scholar
  7. Bruinstroop E, Cano G, Vanderhorst VG, Cavalcante JC, Wirth J, Sena-Esteves M, Saper CB (2011) Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats. J Comp Neurol 520:1985–2001CrossRefGoogle Scholar
  8. Burgess CR, Peever JH (2013) A noradrenergic mechanism functions to couple motor behavior with arousal state. Curr Biol 23:1719–1725CrossRefGoogle Scholar
  9. Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE (2013) Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci 33:9734–9742CrossRefGoogle Scholar
  10. Casatti CA, Elias CF, Sita LV, Frigo L, Furiani VC, Bauer JA, Bittencourt JC (2002) Distribution of melanin-concentrating hormone neurons projecting to the medial mammillary nucleus. Neuroscience 115:899–915CrossRefGoogle Scholar
  11. Chometton S, Franchi G, Houdayer C, Mariot A, Poncet F, Fellmann D, Tillet Y, Risold PY (2014) Different distributions of preproMCH and hypocretin/orexin in the forebrain of the pig (Sus scrofa domesticus). J Chem Neuroanat 61:72–82CrossRefGoogle Scholar
  12. Clément O, Sapin E, Libourel PA, Arthaud S, Brischoux F, Fort P, Luppi PH (2012) The lateral hypothalamic area controls paradoxical (REM) sleep by means of descending projections to brainstem GABAergic neurons. J Neurosci 32:16763–16774CrossRefGoogle Scholar
  13. Del Cid-Pellitero E, Jones BE (2012) Immunohistochemical evidence for synaptic release of GABA from melanin-concentrating hormone containing varicosities in the locus coeruleus. Neuroscience 223:269–276CrossRefGoogle Scholar
  14. Ford B, Holmes CJ, Mainville L, Jones BE (1995) GABAergic neurones in the rat pontomesencephalic tegmentum: codistribution with cholinergic and other tegmental neurones projecting to the posterior lateral hypothalamus. J Comp Neurol 363:177–196CrossRefGoogle Scholar
  15. Fraigne JJ, Torontali ZA, Snow MB, Peever JH (2015) REM sleep at its core – circuits, neurotransmitters, and pathophysiology. Front Neurol 6(123):1–9Google Scholar
  16. Garcia SV, Libourel PA, Lazarus M, Grassi D, Luppi PH, Fort P (2017) Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder. Brain 140:414–428CrossRefGoogle Scholar
  17. Grace KP, Vanstone LE, Horner RL (2014) Endogenous cholinergic input to the pontine REM sleep generator is not required for REM sleep to occur. J Neurosci 34:14198–14209CrossRefGoogle Scholar
  18. Guan JL, Uehara K, Lu S, Wang QP, Funahashi H, Sakurai T, Yanagizawa M, Shioda S (2002) Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation. Int J Obes Relat Metab Disord 26:1523–1532CrossRefGoogle Scholar
  19. Gulyani S, Wu MF, Nienhuis R, John J, Siegel JM (2002) Cataplexy-related neurons in the amygdala of the narcoleptic dog. Neuroscience 112:355–365CrossRefGoogle Scholar
  20. Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA (2000) The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat. Eur J Neurosci 12:1194–1216CrossRefGoogle Scholar
  21. Hong EY, Yoon YS, Lee HS (2011) Differential distribution of melanin-concentrating hormone (MCH)- and hypocretin (Hcrt)-immunoreactive neurons projecting to the mesopontine cholinergic complex in the rat. Brain Res 1424:20–31CrossRefGoogle Scholar
  22. Jego S, Glasgow SD, Herrera CG, Ekstrand M, Reed SJ, Boyce R, Friedman J, Burdakov D, Adamantidis AR (2013) Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nat Neurosci 16:1637–1643CrossRefGoogle Scholar
  23. John J, Wu MF, Boehmer LN, Siegel JM (2004) Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 42:619–634CrossRefGoogle Scholar
  24. Kim TK, Kim JE, Park JY, Lee JE, Choi J, Kim H, Lee EH, Kim SW, Lee JK, Kang HS, Han PL (2015) Antidepressant effects of exercise are produced via suppression of hypocretin/orexin and melanin-concentrating hormone in the basolateral amygdala. Neurobiol Dis 79:59–69CrossRefGoogle Scholar
  25. Kiyashchenko LI, Mileykovskiy BY, Lai YY, Siegel JM (2001) Increased and decreased muscle tone with orexin (hypocretin) microinjections in the locus coeruleus and Pontine Inhibitory Area. J Neurophysiol 85(5):2008–2016CrossRefGoogle Scholar
  26. Konadhode RR, Pelluru D, Shiromani PJ (2015) Neurons containing orexin or melanin concentrating hormone reciprocally regulate wake and sleep. Front Syst Neurosci 8(244):1–9Google Scholar
  27. Lagos P, Torterolo P, Jantos H, Chase MH, Monti JM (2009) Effects on sleep of melanin-concentrating hormone (MCH) microinjections into the dorsal raphe nucleus. Brain Res 1265:103–110CrossRefGoogle Scholar
  28. Lai YY, Kodama T, Siegel JM (2001) Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study. J Neurosci 15:7384–7391CrossRefGoogle Scholar
  29. Lee HS, Eum YJ, Jo SM, Waterhouse BD (2007) Projection patterns from the amygdaloid nuclear complex to subdivisions of the dorsal raphe nucleus in the rat. Brain Res 1143:116–125CrossRefGoogle Scholar
  30. Lee EY, Hwang YG, Lee HS (2017) Hypothalamic neuronal origin of neuropeptide Y (NPY) or cocaine- and amphetamine-regulated transcript (CART) fibers projecting to the tuberomammillary nucleus of the rat. Brain Res 1657:16–28CrossRefGoogle Scholar
  31. Lima FF, Sita LV, Oliveira AR, Costa HC, da Silva JM, Mortara RA, Haemmerle CA, Xavier GF, Canteras NS, Bittencourt JC (2013) Hypothalamic melanin-concentrating hormone projections to the septo-hippocampal complex in the rat. J Chem Neuroanat 47:1–14CrossRefGoogle Scholar
  32. Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip-flop switch for control of REM sleep. Nature 441(7093):589–594CrossRefGoogle Scholar
  33. Lu JW, Fenik VB, Branconi JL, Mann GL, Rukhadze I, Kubin L (2007) Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats. J Physiol 582:553–567CrossRefGoogle Scholar
  34. Luppi PH, Clément O, Sapin E, Gervasoni D, Peyron C, Léger L, Salvert D, Fort P (2011) The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev 15:153–163CrossRefGoogle Scholar
  35. Luppi PH, Clément O, Fort P (2013) Paradoxical (REM) sleep genesis by the brainstem is under hypothalmic control. Curr Opin Neurobiol 23:786–792CrossRefGoogle Scholar
  36. Maquet P, Péters J, Aerts J, Delfiore G, Dequeldre C, Luxen A, Franck G (1996) Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 383:163–166CrossRefGoogle Scholar
  37. McCarley RW (2007) Neurobiology of REM and NREM sleep. Sleep Med 8:302–330CrossRefGoogle Scholar
  38. Mileykovskiy BY, Kiyashchenko L, Kodama T, Lai YY, Siegel JM (2000) Activation of pontine and medullary motor inhibitory regions reduce discharge in neurons located in locus coeruleus and the anatomical equivalent of the midbrain locomotor region. J Neurosci 20:8551–8558CrossRefGoogle Scholar
  39. Monti JM, Lagos P, Jantos H, Torterolo P (2015) Increased REM sleep after intra-locus coeruleus nucleus microinjection of melanin-concentrating hormone (MCH) in the rat. Prog Neuropsychopharmacol Biol Psychiatry 56:185–188CrossRefGoogle Scholar
  40. Monti JM, Torterolo P, Jantos H, Lagos P (2016) Microinjection of the melanin-concentrating hormone into the sublaterodorsal tegmental nucleus inhibits REM sleep in the rat. Neurosci Lett 630:66–69CrossRefGoogle Scholar
  41. Nakamura S, Tsumori T, Yokota S, Oka T, Yasui Y (2009) Amygdaloid axons innervate melanin-concentrating hormone- and orexin-containing neurons in the mouse lateral hypothalamus. Brain Res 1278:66–74CrossRefGoogle Scholar
  42. Nishino S, Mignot E (2011) Narcolepsy and cataplexy. Handb Clin Neurol 99:783–814CrossRefGoogle Scholar
  43. Niu JG, Yokota S, Tsumori T, Oka T, Yasui Y (2012) Projections from the anterior basomedial and anterior cortical amygdaloid nuclei to melanin-concentrating hormone-containing neurons in the lateral hypothalamus of the rat. Brain Res 1479:31–43CrossRefGoogle Scholar
  44. Rao Y, Lu M, Ge F, Marsh DJ, Qian S, Wang AH, Picciotto MR, Gao XB (2008) Regulation of synaptic efficacy in hypocretin/orexin-containing neurons by melanin concentrating hormone in the lateral hypothalamus. J Neurosci 26:9101–9110CrossRefGoogle Scholar
  45. Saito Y, Cheng M, Leslie FM, Civelli O (2001) Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain. J Comp Neurol 435:26–40CrossRefGoogle Scholar
  46. Sakai K, Crochet S, Onoe H (2001) Pontine structures and mechanisms involved in the generation of paradoxical (REM) sleep. Arch Ital Biol 139:93–107PubMedGoogle Scholar
  47. Sapin E, Lapray D, Berod A, Goutagny R, Leger L, Ravassard P, Clément O, Hanriot L, Fort P, Luppi PH (2009) Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS One 4:e4272CrossRefGoogle Scholar
  48. Schwartz MD, Kilduff TS (2015) The neurobiology of sleep and wakefulness. Psychiatr Clin North Am 38:615–644CrossRefGoogle Scholar
  49. Takahashi K, Koyama Y, Kayama Y, Yamamoto M (2002) Effects of orexin on the laterodorsal tegmental neurones. Psychiatry Clin Neurosci 56:335–336CrossRefGoogle Scholar
  50. Tan C, Sano H, Iwaasa H, Pan J, Sailer AW, Hreniuk DL et al (2002) Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. Genomics 79:785–792CrossRefGoogle Scholar
  51. Torterolo P, Lagos P, Monti JM (2011) Melanin-concentrating hormone: a new sleep factor? Front Neurol 2(14):1–12Google Scholar
  52. van den Pol AN, Acuna-Goycolea C, Clark KR, Ghosh PK (2004) Physiological properties of hypothalamic MCh neurons identified with selective expression of reporter gene after recombinant virus infection. Neuron 42:635–652CrossRefGoogle Scholar
  53. Van Dort CJ, Zachs DP, Kenny JD, Zheng S, Goldblum RR, Gelwan NA et al (2015) Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc Natl Acad Sci USA 112:584–589CrossRefGoogle Scholar
  54. Verret L, Goutagny R, Fort P, Cagnon L, Salvert D, Léger L, Boissard R, Salin P, Peyron C, Luppi PH (2003) BioMed Central Neurosci 4:1–10Google Scholar
  55. Wallace DM, Magnuson DJ, Gray TS (1992) Organization of amygdaloid projections to brainstem dopaminergic, noradrenergic, and adrenergic cell groups in the rat. Brain Res Bull 28:447–454CrossRefGoogle Scholar
  56. Wang HL, Morales M (2009) Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat. Eur J Neurosci 29:340–358CrossRefGoogle Scholar
  57. Weng FI, Williams RH, Hawryluk JM, Lu J, Scammell TE, Saper CB, Arrigoni E (2014) Carbachol excites sublaterodorsal nucleus neurons projecting to the spinal cord. J Physiol 592:1601–1617CrossRefGoogle Scholar
  58. Wu MF, Gulyani SA, Yau E, Mignot E, Phan B, Siegel JM (1999) Locus coeruleus neurons: cessation of activity during cataplexy. Neuroscience 91:1389–1399CrossRefGoogle Scholar
  59. Wu MF, John J, Bochmer LN, Yau D, Nguyen GB, Siegel JM (2004) Activity of dorsal raphe cells across the sleep-waking cycle and during cataplexy in narcoleptic dogs. J Physiol 554:202–215CrossRefGoogle Scholar
  60. Yoon YS, Lee HS (2013) Projections from melanin-concentrating hormone (MCH) neurons to the dorsal raphe or the nuclear core of the locus coeruleus in the rat. Brain Res 1490:72–82CrossRefGoogle Scholar
  61. Zhang J, Xi M, Fung SJ, Sampogna S, Chase MH (2012) Projections from the central nucleus of the amygdala to the nucleus pontis oralis in the rat: an anterograde labelling study. Neurosci Lett 525:157–162CrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Anatomy, School of MedicineKonkuk UniversitySeoulRepublic of Korea

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