Skip to main content
SpringerLink
Log in

Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation

  • Review
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Orexin-expressing neurons in the lateral hypothalamus with their wide projections throughout the brain are important for the regulation of sleep and wakefulness, ingestive behavior, and the coordination of these behaviors in the environmental context. To further identify downstream effector targets of the orexin system, we examined in detail orexin-A innervation of the caudal raphé nuclei in the medulla, known to harbor sympathetic preganglionic motor neurons involved in thermal, cardiovascular, and gastrointestinal regulation. All three components of the caudal raphé nuclei, raphé pallidus, raphé obscurus, and parapyramidal nucleus, are innervated by orexin-A-immunoreactive fibers. Using confocal microscopy, we demonstrate close anatomical appositions between varicose orexin-A immunoreactive axon profiles and sympathetic premotor neurons identified with either a transneuronal retrograde pseudorabies virus tracer injected into the interscapular brown fat pads, or with in situ hybridization of pro-TRH mRNA. Furthermore, orexin-A injected into the fourth ventricle induced c-Fos expression in the raphé pallidus and parapyramidal nucleus. These findings suggest that orexin neurons in the hypothalamus can modulate brown fat thermogenesis, cardiovascular, and gastrointestinal functions by acting directly on neurons in the caudal raphé nuclei, and support the idea that orexin’s simultaneous stimulation of food intake and sympathetic activity might have evolved as a mechanism to stay alert while foraging.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Appel NM, Wessendorf MW, Elde RP (1987) Thyrotropin-releasing hormone in spinal cord: coexistence with serotonin and with substance P in fibers and terminals apposing identified preganglionic sympathetic neurons. Brain Res 415:137–143

    Google Scholar 

  • Asakawa A, Inui A, Inui T, Katsuura G, Fujino MA, Kasuga M (2002) Orexin reverses cholecystokinin-induced reduction in feeding. Diabetes Obes Metab 4:399–401

    Google Scholar 

  • Bamshad M, Song CK, Bartness TJ (1999) CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am J Physiol 276:R1569–R1578

    CAS  PubMed  Google Scholar 

  • Banfield BW, Kaufman JD, Randall JA, Pickard GE (2003) Development of pseudorabies virus strains expressing red fluorescent proteins: new tools for multisynaptic labeling applications. J Virol 77:10106–10112

    Google Scholar 

  • Blessing WW, Nalivaiko E (2001) Raphe magnus/pallidus neurons regulate tail but not mesenteric arterial blood flow in rats. Neuroscience 105:923–929

    Google Scholar 

  • Blessing WW, Yu YH, Nalivaiko E (1999) Raphe pallidus and parapyramidal neurons regulate ear pinna vascular conductance in the rabbit. Neurosci Lett 270:33–36

    Google Scholar 

  • Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T (1998) Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 402:460–447

    Google Scholar 

  • Cano G, Passerin AM, Schiltz JC, Card JP, Morrison SF, Sved AF (2003) Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure. J Comp Neurol 460:303–326

    Google Scholar 

  • Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451

    Article  CAS  PubMed  Google Scholar 

  • Chiba T, Masuko S (1989) Coexistence of varying combinations of neuropeptides with 5-hydroxytryptamine in neurons of the raphe pallidus et obscurus projecting to the spinal cord. Neurosci Res 7:13–23

    Google Scholar 

  • Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, Beuckmann CT, Chemelli RM, Sakurai T, Yanagisawa M, Saper CB, Scammell TE (2001) Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21:RC168

    Google Scholar 

  • Ciriello J, de Oliveira CV (2003) Cardiac effects of hypocretin-1 in nucleus ambiguus. Am J Physiol Regul Integr Comp Physiol 284:R1611–R1620

    Google Scholar 

  • Ciriello J, Li Z, de Oliveira CV (2003a) Cardioacceleratory responses to hypocretin-1 injections into rostral ventromedial medulla. Brain Res 991:84–95

    Google Scholar 

  • Ciriello J, McMurray JC, Babic T, de Oliveira CV (2003b) Collateral axonal projections from hypothalamic hypocretin neurons to cardiovascular sites in nucleus ambiguus and nucleus tractus solitarius. Brain Res 991:133–141

    Google Scholar 

  • Clegg DJ, Air EL, Woods SC, Seeley RJ (2002) Eating elicited by orexin-a, but not melanin-concentrating hormone, is opioid mediated. Endocrinology 143:2995–3000

    Google Scholar 

  • Curran T, Morgan JI (1995) Fos: an immediate-early transcription factor in neurons. J Neurobiol 26:403–412

    Google Scholar 

  • Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 96:748–753

    Google Scholar 

  • Dube MG, Kalra SP, Kalra PS (1999) Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. Brain Res 842:473–477

    Google Scholar 

  • Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, Tatro JB, Hoffman GE, Ollmann MM, Barsh GS, Sakurai T, Yanagisawa M, Elmquist JK (1998) Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 402:442–459

    Google Scholar 

  • Espana RA, Plahn S, Berridge CW (2002) Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin. Brain Res 943:224–236

    Google Scholar 

  • Fung SJ, Yamuy J, Sampogna S, Morales FR, Chase MH (2001) Hypocretin (orexin) input to trigeminal and hypoglossal motoneurons in the cat: a double-labeling immunohistochemical study. Brain Res 903:257–262

    Google Scholar 

  • Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345–354

    Google Scholar 

  • Harrison TA, Chen CT, Dun NJ, Chang JK (1999) Hypothalamic orexin A-immunoreactive neurons project to the rat dorsal medulla. Neurosci Lett 273:17–20

    Google Scholar 

  • Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M, Arch JR (1999) Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides 20:1099–1105

    Google Scholar 

  • Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96:45–51

    Google Scholar 

  • Haynes AC, Chapman H, Taylor C, Moore GB, Cawthorne MA, Tadayyon M, Clapham JC, Arch JR (2002) Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice. Regul Pept 104:153–159

    Google Scholar 

  • Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103:777–797

    Google Scholar 

  • Hoffman GE, Smith MS, Verbalis JG (1993) c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems. Front Neuroendocrinol 14:173–213

    Google Scholar 

  • Hwang LL, Chen CT, Dun NJ (2001) Mechanisms of orexin-induced depolarizations in rat dorsal motor nucleus of vagus neurones in vitro. J Physiol 537:511–520

    Google Scholar 

  • Ishii Y, Blundell JE, Halford JC, Upton N, Porter R, Johns A, Rodgers RJ (2004) Differential effects of the selective orexin-1 receptor antagonist SB-334867 and lithium chloride on the behavioural satiety sequence in rats. Physiol Behav 81:129–140

    Google Scholar 

  • Krowicki ZK, Burmeister MA, Berthoud HR, Scullion RT, Fuchs K, Hornby PJ (2002) Orexins in rat dorsal motor nucleus of the vagus potently stimulate gastric motor function. Am J Physiol Gastrointest Liver Physiol 283:G465–G472

    Google Scholar 

  • Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25

    Google Scholar 

  • Martinez V, Barrachina MD, Ohning G, Tache Y (2002) Cephalic phase of acid secretion involves activation of medullary TRH receptor subtype 1 in rats. Am J Physiol Gastrointest Liver Physiol 283:G1310–G1319

    Google Scholar 

  • Monda M, Viggiano A, Fuccio F, De Luca V (2004) Clozapine blocks sympathetic and thermogenic reactions induced by orexin A in rat. Physiol Res 53:507–513

    Google Scholar 

  • Morrison SF (2003) Raphe pallidus neurons mediate prostaglandin E2-evoked increases in brown adipose tissue thermogenesis. Neuroscience 121:17–24

    Google Scholar 

  • Morrison SF (2004) Activation of 5-HT1A receptors in raphe pallidus inhibits leptin-evoked increases in brown adipose tissue thermogenesis. Am J Physiol Regul Integr Comp Physiol 286:R832–R837

    Google Scholar 

  • Morrison SF, Sved AF, Passerin AM (1999) GABA-mediated inhibition of raphe pallidus neurons regulates sympathetic outflow to brown adipose tissue. Am J Physiol 276:R290–R297

    Google Scholar 

  • Nakamura K, Matsumura K, Hubschle T, Nakamura Y, Hioki H, Fujiyama F, Boldogkoi Z, Konig M, Thiel HJ, Gerstberger R, Kobayashi S, Kaneko T (2004) Identification of sympathetic premotor neurons in medullary raphe regions mediating fever and other thermoregulatory functions. J Neurosci 24:5370–5380

    Google Scholar 

  • Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260

    Google Scholar 

  • Palkovits M, Mezey E, Eskay RL, Brownstein MJ (1986) Innervation of the nucleus of the solitary tract and the dorsal vagal nucleus by thyrotropin-releasing hormone-containing raphe neurons. Brain Res 373:246–251

    Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, North Ryde, NSW, Australia

    Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015

    CAS  PubMed  Google Scholar 

  • van den Pol AN (1999) Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 19:3171–3182

    Google Scholar 

  • Poulat P, Marlier L, Rajaofetra N, Privat A (1992) 5-Hydroxytryptamine, substance P and thyrotropin-releasing hormone synapses in the intermediolateral cell column of the rat thoracic spinal cord. Neurosci Lett 136:19–22

    Google Scholar 

  • Rinaman L, Miselis RR, Kreider MS (1989) Ultrastructural localization of thyrotropin-releasing hormone immunoreactivity in the dorsal vagal complex in rat. Neurosci Lett 104:7–12

    Google Scholar 

  • Ripley B, Overeem S, Fujiki N, Nevsimalova S, Uchino M, Yesavage J, Di Monte D, Dohi K, Melberg A, Lammers GJ, Nishida Y, Roelandse FW, Hungs M, Mignot E, Nishino S (2001) CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 57:2253–2258

    CAS  PubMed  Google Scholar 

  • Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Blundell JE (2000) Dose-response effects of orexin-A on food intake and the behavioural satiety sequence in rats. Regul Pept 96:71–84

    Google Scholar 

  • Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE (2001) SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. Eur J Neurosci 13:1444–1452

    Google Scholar 

  • Rodgers RJ, Ishii Y, Halford JC, Blundell JE (2002) Orexins and appetite regulation. Neuropeptides 36:303–325

    Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    Google Scholar 

  • Sasek CA, Wessendorf MW, Helke CJ (1990) Evidence for co-existence of thyrotropin-releasing hormone, substance P and serotonin in ventral medullary neurons that project to the intermediolateral cell column in the rat. Neuroscience 35:105–119

    Google Scholar 

  • Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H (1999) Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277:R1780–R1785

    Google Scholar 

  • Sunter D, Morgan I, Edwards CM, Dakin CL, Murphy KG, Gardiner J, Taheri S, Rayes E, Bloom SR (2001) Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res 907:27–34

    Google Scholar 

  • Tache Y, Yang H, Kaneko H (1995) Caudal raphe-dorsal vagal complex peptidergic projections: role in gastric vagal control. Peptides 16:431–435

    Google Scholar 

  • Taylor MM, Samson WK (2003) The other side of the orexins: endocrine and metabolic actions. Am J Physiol Endocrinol Metab 284:E13–E17

    Google Scholar 

  • Thorpe AJ, Mullett MA, Wang C, Kotz CM (2003) Peptides that regulate food intake: regional, metabolic, and circadian specificity of lateral hypothalamic orexin A feeding stimulation. Am J Physiol Regul Integr Comp Physiol 284:R1409–R1417

    Google Scholar 

  • Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001) To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24:429–458

    Google Scholar 

  • Yamada H, Okumura T, Motomura W, Kobayashi Y, Kohgo Y (2000) Inhibition of food intake by central injection of anti-orexin antibody in fasted rats. Biochem Biophys Res Commun 267:527–531

    Google Scholar 

  • Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K (1999) Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 849:248–252

    Google Scholar 

  • Yang H, Ohning G, Tache Y (1993) TRH in dorsal vagal complex mediates acid response to excitation of raphe pallidus neurons in rats. Am J Physiol 265:G880–G886

    Google Scholar 

  • Yang H, Yuan PQ, Wang L, Tache Y (2000) Activation of the parapyramidal region in the ventral medulla stimulates gastric acid secretion through vagal pathways in rats. Neuroscience 95:773–779

    Google Scholar 

  • Yang H, Tache Y, Ohning G, Go VL (2002) Activation of raphe pallidus neurons increases insulin through medullary thyrotropin-releasing hormone (TRH)-vagal pathways. Pancreas 25:301–307

    Google Scholar 

  • Yang B, Samson WK, Ferguson AV (2003) Excitatory effects of orexin-A on nucleus tractus solitarius neurons are mediated by phospholipase C and protein kinase C. J Neurosci 23:6215–6222

    Google Scholar 

  • Yoshida K, Nakamura K, Matsumura K, Kanosue K, Konig M, Thiel HJ, Boldogkoi Z, Toth I, Roth J, Gerstberger R, Hubschle T (2003) Neurons of the rat preoptic area and the raphe pallidus nucleus innervating the brown adipose tissue express the prostaglandin E receptor subtype EP3. Eur J Neurosci 18:1848–1860

    Google Scholar 

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

    Google Scholar 

  • Zhang J, Luo P (2002) Orexin B immunoreactive fibers and terminals innervate the sensory and motor neurons of jaw-elevator muscles in the rat. Synapse 44:106–110

    Google Scholar 

  • Zheng H, Patterson LM, Berthoud H-R (2005) Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food in take, and autonomic function. J Comp Neural (in press)

Download references

Acknowledgements

The authors would like to thank Irina Stoyanova, Michele Corkern, and Amy Whittington for their excellent technical help. This research was partially supported by The Community Foundation of Southwestern Michigan and the National Institute of Diabetes and Digestive and Kidney Diseases, Grant DK 47348.

Author information

Authors and Affiliations

  1. Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Hans-Rudolf Berthoud, Laurel M. Patterson, Gregory M. Sutton, Christopher Morrison & Huiyuan Zheng

Authors
  1. Hans-Rudolf Berthoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurel M. Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gregory M. Sutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huiyuan Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans-Rudolf Berthoud.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berthoud, HR., Patterson, L.M., Sutton, G.M. et al. Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation. Histochem Cell Biol 123, 147–156 (2005). https://doi.org/10.1007/s00418-005-0761-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-005-0761-x

Keywords

Search

Navigation