European Journal of Applied Physiology

, Volume 109, Issue 1, pp 27–33 | Cite as

Multiple thermoregulatory effectors with independent central controls

  • Robin M. McAllen
  • Mutsumi Tanaka
  • Yoichiro Ootsuka
  • Michael J. McKinley
Review Article


This review first considers how mammalian body temperature regulation evolved, and how the brain’s responses to thermoregulatory challenges are likely to be organised differently from the way an engineer would design them. This is because thermoregulatory effector mechanisms would have evolved one at a time, with each being superimposed on pre-existing mechanisms. There may be no functional need for the final ensemble of control loops to be coordinated by neural cross-connections: appropriate thermal thresholds would solve the problem sufficiently. Investigations first into thermoregulatory behaviours and later into unconscious thermoregulatory mechanisms (autonomic and shivering) have led investigators to the realisation that multiple control loops exist in the brain, with each effector system apparently regulated by its own central temperature sensors. This theme is developed with reference to data on four temperature-regulated neural outflows that have been studied on anaesthetized rats under standard conditions in the authors’ laboratory. Direct comparisons were made between the behaviour of sympathetic nerves supplying the tail vasculature, vessels in the proximal hairy skin, interscapular brown adipose tissue (BAT) and fusimotor fibres to hind limb muscle. All four outflows were activated by cooling the skin, and all were silenced by neuronal inhibition in the medullary raphé. Their thermal thresholds were quite different, however, as were their relative responsiveness to core temperature. This was ranked as: tail > back skin > BAT > fusimotor. These and other data indicate that the four thermoeffector outflows are driven by separate neural pathways, each regulated by independent brain temperature sensors.


Rat tail Cutaneous vasomotor BAT Fusimotor Preoptic Thermoregulation 



RMcA and MMcK hold NHMRC Fellowships (566667 and 454369). YO held a fellowship from the High Blood Pressure Research Council of Australia. The work was supported by NHMRC project grants 232305 and 454601, the Robert J Jr and Helen C Kleberg Foundation and the G Harold and Leila Y Mathers Foundation.


  1. Almeida MC, Steiner AA, Branco LG, Romanovsky AA (2006) Neural substrate of cold-seeking behavior in endotoxin shock. PLoS One 1:e1CrossRefPubMedGoogle Scholar
  2. Blessing WW, Yu YH, Nalivaiko E (1999) Raphe pallidus and parapyramidal neurons regulate ear pinna vascular conductance in the rabbit. Neurosci Lett 270(1):33–36CrossRefPubMedGoogle Scholar
  3. Cabanac M (2006) Adjustable set point: to honor Harold T. Hammel. J Appl Physiol 100(4):1338–1346CrossRefPubMedGoogle Scholar
  4. Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84(1):277–359CrossRefPubMedGoogle Scholar
  5. Chen XM, Hosono T, Yoda T, Fukuda Y, Kanosue K (1998) Efferent projection from the preoptic area for the control of non-shivering thermogenesis in rats. J Physiol 512(Pt 3):883–892CrossRefPubMedGoogle Scholar
  6. Collins DR, Korsak A, Gilbey MP (2002) Cutaneous sympathetic motor rhythms during a fever-like response induced by prostaglandin E(1). Neuroscience 110(2):351–360CrossRefPubMedGoogle Scholar
  7. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517CrossRefPubMedGoogle Scholar
  8. Dickenson AH (1977) Specific responses of rat raphe neurones to skin temperature. J Physiol 273(1):277–293PubMedGoogle Scholar
  9. Gilbert TM, Blatteis CM (1977) Hypothalamic thermoregulatory pathways in the rat. J Appl Physiol 43(5):770–777PubMedGoogle Scholar
  10. Gould S (1983) The panda’s thumb: more reflections on natural history. Penguin Books, HarmondsworthGoogle Scholar
  11. Johnson CD, Gilbey MP (1998) Focally recorded single sympathetic postganglionic neuronal activity supplying rat lateral tail vein. J Physiol 508(Pt 2):575–585CrossRefPubMedGoogle Scholar
  12. Johnson JM, Proppe DW (1996) Cardiovascular adjustments to heat stress. In: Fregley M, Blatteis C (eds) Handbook of physiology: section 4, environmental physiology. American Physiological Society, Washington, DCGoogle Scholar
  13. Kanosue K, Zhang YH, Yanase-Fujiwara M, Hosono T (1994a) Hypothalamic network for thermoregulatory shivering. Am J Physiol 267(1 Pt 2):R275–R282PubMedGoogle Scholar
  14. Kanosue K, Yanase-Fujiwara M, Hosono T (1994b) Hypothalamic network for thermoregulatory vasomotor control. Am J Physiol 267(1 Pt 2):R283–R288PubMedGoogle Scholar
  15. Korsak A, Gilbey MP (2004) Rostral ventromedial medulla and the control of cutaneous vasoconstrictor activity following i.c.v. prostaglandin E(1). Neuroscience 124(3):709–717CrossRefPubMedGoogle Scholar
  16. Madden CJ, Morrison SF (2003) Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis. Neuroscience 122(1):5–15CrossRefPubMedGoogle Scholar
  17. Madden CJ, Morrison SF (2008) Brown adipose tissue sympathetic nerve activity is potentiated by activation of 5-hydroxytryptamine (5-HT)1A/5-HT7 receptors in the rat spinal cord. Neuropharmacology 54(3):487–496CrossRefPubMedGoogle Scholar
  18. Marina N, Taheri M, Gilbey MP (2006) Generation of a physiological sympathetic motor rhythm in the rat following spinal application of 5-HT. J Physiol 571(Pt 2):441–450PubMedGoogle Scholar
  19. Meigal AY, Oksa J, Gerasimova LI, Hohtola E, Lupandin YV, Rintamaki H (2003) Force control of isometric elbow flexion with visual feedback in cold with and without shivering. Aviat Space Environ Med 74(8):816–821PubMedGoogle Scholar
  20. Morgareidge KR, White FN (1969) Cutaneous vascular changes during heating and cooling in the Galapagos marine iguana. Nature 223(5206):587–591CrossRefPubMedGoogle Scholar
  21. Morrison SF (1999) RVLM and raphe differentially regulate sympathetic outflows to splanchnic and brown adipose tissue. Am J Physiol 276(4 Pt 2):R962–R973PubMedGoogle Scholar
  22. Morrison SF (2003) Raphe pallidus neurons mediate prostaglandin E2-evoked increases in brown adipose tissue thermogenesis. Neuroscience 121(1):17–24CrossRefPubMedGoogle Scholar
  23. 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(2 Pt 2):R290–R297PubMedGoogle Scholar
  24. Nagashima K, Nakai S, Tanaka M, Kanosue K (2000) Neuronal circuitries involved in thermoregulation. Auton Neurosci 85(1–3):18–25CrossRefPubMedGoogle Scholar
  25. Nakamura K, Morrison SF (2007) Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue. Am J Physiol Regul Integr Comp Physiol 292(1):R127–R136PubMedGoogle Scholar
  26. Nakamura K, Morrison SF (2008a) A thermosensory pathway that controls body temperature. Nat Neurosci 11(1):62–71CrossRefPubMedGoogle Scholar
  27. Nakamura K, Morrison SF (2008b) Preoptic mechanism for cold-defensive responses to skin cooling. J Physiol 586(10):2611–2620CrossRefPubMedGoogle Scholar
  28. Nakamura K, Matsumura K, Kaneko T, Kobayashi S, Katoh H, Negishi M (2002) The rostral raphe pallidus nucleus mediates pyrogenic transmission from the preoptic area. J Neurosci 22(11):4600–4610PubMedGoogle Scholar
  29. Nakamura K, Matsumura K, Hubschle T, Nakamura Y, Hioki H, Fujiyama F et al (2004) Identification of sympathetic premotor neurons in medullary raphe regions mediating fever and other thermoregulatory functions. J Neurosci 24(23):5370–5380CrossRefPubMedGoogle Scholar
  30. Nautiyal KM, Dailey M, Brito N, Brito MN, Harris RB, Bartness TJ et al (2008) Energetic responses to cold temperatures in rats lacking forebrain–caudal brain stem connections. Am J Physiol Regul Integr Comp Physiol 295(3):R789–R798PubMedGoogle Scholar
  31. Ootsuka Y, McAllen RM (2005) Interactive drives from two brain stem premotor nuclei are essential to support rat tail sympathetic activity. Am J Physiol Regul Integr Comp Physiol 289(4):R1107–R1115PubMedGoogle Scholar
  32. Ootsuka Y, McAllen RM (2006) Comparison between two rat sympathetic pathways activated in cold defense. Am J Physiol Regul Integr Comp Physiol 291(3):R589–R595PubMedGoogle Scholar
  33. Ootsuka Y, Blessing WW, McAllen RM (2004) Inhibition of rostral medullary raphe neurons prevents cold-induced activity in sympathetic nerves to rat tail and rabbit ear arteries. Neurosci Lett 357(1):58–62CrossRefPubMedGoogle Scholar
  34. Osaka T (2004) Cold-induced thermogenesis mediated by GABA in the preoptic area of anesthetized rats. Am J Physiol Regul Integr Comp Physiol 287(2):R306–R313PubMedGoogle Scholar
  35. Owens NC, Ootsuka Y, Kanosue K, McAllen RM (2002) Thermoregulatory control of sympathetic fibres supplying the rat’s tail. J Physiol 543(Pt 3):849–858CrossRefPubMedGoogle Scholar
  36. Partridge LD (1982) The good enough calculi of evolving control systems: evolution is not engineering. Am J Physiol 242(3):R173–R177PubMedGoogle Scholar
  37. Perkins JF Jr (1945) The role of proprioceptors in shivering. Am J Physiol 145(2):264–271Google Scholar
  38. Rathner JA, McAllen RM (1999) Differential control of sympathetic drive to the rat tail artery and kidney by medullary premotor cell groups. Brain Res 834(1–2):196–199CrossRefPubMedGoogle Scholar
  39. Rathner JA, Owens NC, McAllen RM (2001) Cold-activated raphe-spinal neurons in rats. J Physiol 535(Pt 3):841–854CrossRefPubMedGoogle Scholar
  40. Rathner JA, Madden CJ, Morrison SF (2008) Central pathway for spontaneous and prostaglandin E2-evoked cutaneous vasoconstriction. Am J Physiol Regul Integr Comp Physiol 295(1):R343–R354PubMedGoogle Scholar
  41. Roberts WW (1988) Differential thermosensor control of thermoregulatory grooming, locomotion, and relaxed postural extension. Ann NY Acad Sci 525:363–374CrossRefPubMedGoogle Scholar
  42. Romanovsky AA (2007) Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am J Physiol Regul Integr Comp Physiol 292(1):R37–R46PubMedGoogle Scholar
  43. Romanovsky AA, Shido O, Sakurada S, Sugimoto N, Nagasaka T (1996) Endotoxin shock: thermoregulatory mechanisms. Am J Physiol 270(4 Pt 2):R693–R703PubMedGoogle Scholar
  44. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J et al (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58(7):1526–1531CrossRefPubMedGoogle Scholar
  45. Satinoff E, Rutstein J (1970) Behavioral thermoregulation in rats with anterior hypothalamic lesions. J Comp Physiol Psychol 71(1):77–82CrossRefPubMedGoogle Scholar
  46. Seebacher F, Franklin CE (2005) Physiological mechanisms of thermoregulation in reptiles: a review. J Comp Physiol B 175(8):533–541CrossRefPubMedGoogle Scholar
  47. Smith JE, Gilbey MP (2000) Coherent rhythmic discharges in sympathetic nerves supplying thermoregulatory circulations in the rat. J Physiol 523(Pt 2):449–457CrossRefPubMedGoogle Scholar
  48. Tache Y, Yang H, Kaneko H (1995) Caudal raphe-dorsal vagal complex peptidergic projections: role in gastric vagal control. Peptides 16(3):431–435CrossRefPubMedGoogle Scholar
  49. Tanaka M, McAllen RM (2005) A subsidiary fever center in the medullary raphe? Am J Physiol Regul Integr Comp Physiol 289(6):R1592–R1598PubMedGoogle Scholar
  50. Tanaka M, Nagashima K, McAllen RM, Kanosue K (2002) Role of the medullary raphe in thermoregulatory vasomotor control in rats. J Physiol 540(Pt 2):657–664CrossRefPubMedGoogle Scholar
  51. Tanaka M, Owens NC, Nagashima K, Kanosue K, McAllen RM (2006) Reflex activation of rat fusimotor neurons by body surface cooling, and its dependence on the medullary raphe. J Physiol 572(Pt 2):569–583CrossRefPubMedGoogle Scholar
  52. Tanaka M, Ootsuka Y, McKinley MJ, McAllen RM (2007) Independent vasomotor control of rat tail and proximal hairy skin. J Physiol 582(Pt 1):421–433CrossRefPubMedGoogle Scholar
  53. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND et al (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360(15):1500–1508CrossRefPubMedGoogle Scholar
  54. Von Euler C, Soderberg U (1957) The influence of hypothalamic thermoceptive structures on the electroencephalogram and gamma motor activity. Electroencephalogr Clin Neurophysiol 9(3):391–408CrossRefGoogle Scholar
  55. Vybiral S, Szekely M, Jansky L, Cerny L (1987) Thermoregulation of the rabbit during the late phase of endotoxin fever. Pflugers Arch 410(1–2):220–222CrossRefPubMedGoogle Scholar
  56. 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(3):773–779CrossRefPubMedGoogle Scholar
  57. Zaretsky DV, Zaretskaia MV, DiMicco JA (2003a) Stimulation and blockade of GABA(A) receptors in the raphe pallidus: effects on body temperature, heart rate, and blood pressure in conscious rats. Am J Physiol Regul Integr Comp Physiol 285(1):R110–R116PubMedGoogle Scholar
  58. Zaretsky DV, Zaretskaia MV, Samuels BC, Cluxton LK, DiMicco JA (2003b) Microinjection of muscimol into raphe pallidus suppresses tachycardia associated with air stress in conscious rats. J Physiol 546(Pt 1):243–250CrossRefPubMedGoogle Scholar
  59. Zhang YH, Yanase-Fujiwara M, Hosono T, Kanosue K (1995) Warm and cold signals from the preoptic area: which contribute more to the control of shivering in rats? J Physiol 485(Pt 1):195–202PubMedGoogle Scholar
  60. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B et al (2009) The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 23(9):3113–3120CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Robin M. McAllen
    • 1
    • 2
  • Mutsumi Tanaka
    • 1
  • Yoichiro Ootsuka
    • 1
    • 3
  • Michael J. McKinley
    • 1
    • 4
  1. 1.Howard Florey InstituteUniversity of MelbourneMelbourneAustralia
  2. 2.Department of Anatomy and Cell BiologyUniversity of MelbourneMelbourneAustralia
  3. 3.School of MedicineFlinders UniversityAdelaideAustralia
  4. 4.Department of PhysiologyUniversity of MelbourneMelbourneAustralia

Personalised recommendations