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Central mechanisms of osmosensation and systemic osmoregulation

Nature Reviews Neuroscience volume 9, pages 519–531 (2008)Cite this article

Key Points

  • Mammals defend against large changes in extracellular fluid osmolality by making appropriate changes in salt and water ingestion, and by inducing complementary changes in Na+ and water excretion by the kidney. The former responses are mediated by changes in behaviour; the latter are mediated by changes in hormone release and by autonomic innervation of the kidney.

  • These osmoregulatory responses are controlled by osmoreceptors — specialized neurons that encode the osmotic set-point in their basal rate of action-potential discharge and that can mediate the effects of hypotonicity or hypertonicity through proportional changes in the rate of action-potential firing.

  • Osmosensory transduction in osmoreceptor neurons is a mechanical process during which osmotically induced changes in cell volume lead to inverse changes in the probability of opening of nonselective cation channels that might be members of the transient receptor potential vanilloid family of ion channels.

  • Osmoreceptor neurons are located in a number of areas in the periphery and in the brain. Signals derived from peripheral osmoreceptors reach the brain through the vagus nerve and the spinal cord. Primary cerebral osmoreceptors are located in the organum vasculosum of the lamina terminalis. Signals derived from both sources are integrated in a number of brain areas.

  • Peripheral osmoreceptors signal ingestion-related information that is used to adjust osmoregulatory responses before ingested salt or water has an impact on systemic osmolality. In contrast to these anticipatory effects of peripheral osmoreceptors, central osmoreceptors relay sustained information concerning the online systemic osmotic status of the animal.

  • The information that is encoded by osmoreceptors is integrated in various parts of the brain and is ultimately relayed to neurons in the frontal cortex that command specific behaviours and to specific subsets of neuroendocrine and pre-autonomic neurons in the hypothalamus to modulate renal function.

Abstract

Systemic osmoregulation is a vital process whereby changes in plasma osmolality, detected by osmoreceptors, modulate ingestive behaviour, sympathetic outflow and renal function to stabilize the tonicity and volume of the extracellular fluid. Furthermore, changes in the central processing of osmosensory signals are likely to affect the hydro-mineral balance and other related aspects of homeostasis, including thermoregulation and cardiovascular balance. Surprisingly little is known about how the brain orchestrates these responses. Here, recent advances in our understanding of the molecular, cellular and network mechanisms that mediate the central control of osmotic homeostasis in mammals are reviewed.

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Figure 1: Extracellular fluid osmolality in animals.
Figure 2: Basic mechanisms of osmoregulation.
Figure 3: Osmoregulatory circuits in the mammalian brain and the periphery.
Figure 4: Cerebral osmosensors are excited by hypertonicity.
Figure 5: Osmosensory transduction is a mechanical process.

References

  1. Strange, K. Cellular volume homeostasis. Adv. Physiol. Educ. 28, 155–159 (2004).

    PubMed  Google Scholar 

  2. Steenbergen, C., Hill, M. L. & Jennings, R. B. Volume regulation and plasma membrane injury in aerobic, anaerobic, and ischemic myocardium in vitro. Effects of osmotic cell swelling on plasma membrane integrity. Circ. Res. 57, 864–875 (1985).

    CAS  PubMed  Google Scholar 

  3. Somero, G. N. Protons, osmolytes, and fitness of internal milieu for protein function. Am. J. Physiol. 251, R197–R213 (1986).

    CAS  PubMed  Google Scholar 

  4. McAllen, R., Walker, D. & Taylor, A. The environmental effects of salinity and temperature on the oxygen consumption and total body osmolality of the marine flatworm Procerodes littoralis. J. Exp. Mar. Biol. Ecol. 268, 103–113 (2002).

    Google Scholar 

  5. Dietz, T. H., Byrne, R. A., Lynn, J. W. & Silverman, H. Paracellular solute uptake by the freshwater zebra mussel Dreissena polymorpha. Am. J. Physiol. 269, R300–R307 (1995).

    CAS  PubMed  Google Scholar 

  6. Hosoi, M., Takeuchi, K., Sawada, H. & Toyohara, H. Expression and functional analysis of mussel taurine transporter, as a key molecule in cellular osmoconforming. J. Exp. Biol. 208, 4203–4211 (2005).

    CAS  PubMed  Google Scholar 

  7. Lang, F. Mechanisms and significance of cell volume regulation. J. Am. Coll. Nutr. 26, 613S–623S (2007).

    CAS  PubMed  Google Scholar 

  8. Pierce, S. K., Edwards, S. C., Mazzocchi, P. H., Klingler, L. J. & Warren, M. K. Proline betaine: a unique osmolyte in an extremely euryhaline osmoconformer. Biol. Bull. 167, 495–500 (1984).

    CAS  PubMed  Google Scholar 

  9. Yancey, P. H., Blake, W. R. & Conley, J. Unusual organic osmolytes in deep-sea animals: adaptations to hydrostatic pressure and other perturbants. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 133, 667–676 (2002).

    PubMed  Google Scholar 

  10. Pasantes-Morales, H., Franco, R., Torres-Marquez, M. E., Hernandez-Fonseca, K. & Ortega, A. Amino acid osmolytes in regulatory volume decrease and isovolumetric regulation in brain cells: contribution and mechanisms. Cell. Physiol. Biochem. 10, 361–370 (2000).

    CAS  PubMed  Google Scholar 

  11. Massieu, L., Montiel, T., Robles, G. & Quesada, O. Brain amino acids during hyponatremia in vivo: clinical observations and experimental studies. Neurochem. Res. 29, 73–81 (2004).

    CAS  PubMed  Google Scholar 

  12. Saly, V. & Andrew, R. D. CA3 neuron excitation and epileptiform discharge are sensitive to osmolality. J. Neurophysiol. 69, 2200–2208 (1993).

    CAS  PubMed  Google Scholar 

  13. Pasantes-Morales, H. & Tuz, K. Volume changes in neurons: hyperexcitability and neuronal death. Contrib. Nephrol. 152, 221–240 (2006).

    CAS  PubMed  Google Scholar 

  14. Ayus, J. C., Varon, J. & Arieff, A. I. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann. Intern. Med. 132, 711–714 (2000).

    CAS  PubMed  Google Scholar 

  15. Machino, T. & Yoshizawa, T. Brain shrinkage due to acute hypernatremia. Neurology 67, 880 (2006).

    PubMed  Google Scholar 

  16. Edwards, A. M. et al. Influence of moderate dehydration on soccer performance: physiological responses to 45 min of outdoor match-play and the immediate subsequent performance of sport-specific and mental concentration tests. Br. J. Sports Med. 41, 385–391 (2007).

    PubMed  PubMed Central  Google Scholar 

  17. Saat, M., Sirisinghe, R. G., Singh, R. & Tochihara, Y. Effects of short-term exercise in the heat on thermoregulation, blood parameters, sweat secretion and sweat composition of tropic-dwelling subjects. J. Physiol. Anthropol. Appl. Human Sci. 24, 541–549 (2005).

    PubMed  Google Scholar 

  18. Geelen, G. et al. Inhibition of plasma vasopressin after drinking in dehydrated humans. Am. J. Physiol. 247, R968–R971 (1984).

    CAS  PubMed  Google Scholar 

  19. Shirreffs, S. M., Merson, S. J., Fraser, S. M. & Archer, D. T. The effects of fluid restriction on hydration status and subjective feelings in man. Br. J. Nutr. 91, 951–958 (2004).

    CAS  PubMed  Google Scholar 

  20. Geelen, G., Greenleaf, J. E. & Keil, L. C. Drinking-induced plasma vasopressin and norepinephrine changes in dehydrated humans. J. Clin. Endocrinol. Metab. 81, 2131–2135 (1996).

    CAS  PubMed  Google Scholar 

  21. Andersen, L. J., Jensen, T. U., Bestle, M. H. & Bie, P. Gastrointestinal osmoreceptors and renal sodium excretion in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R287–R294 (2000).

    CAS  PubMed  Google Scholar 

  22. Dunn, F. L., Brennan, T. J., Nelson, A. E. & Robertson, G. L. The role of blood osmolality and volume in regulating vasopressin secretion in the rat. J. Clin. Invest. 52, 3212–3219 (1973). This study examined the effects of systemic osmotic stimuli combined with changes in vascular volume to provide clear evidence that the osmotic modulation of VP release is enhanced during hypovolaemia and inhibited during hypervolaemia.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. McKinley, M. J., Denton, D. A. & Weisinger, R. S. Sensors for antidiuresis and thirst—osmoreceptors or CSF sodium detectors? Brain Res. 141, 89–103 (1978).

    CAS  PubMed  Google Scholar 

  24. Thrasher, T. N., Brown, C. J., Keil, L. C. & Ramsay, D. J. Thirst and vasopressin release in the dog: an osmoreceptor or sodium receptor mechanism? Am. J. Physiol. 238, R333–R339 (1980). This study examined the effects of intravenous infusions of various solutions on changes in thirst and VP release, together with changes in the composition of the cerebrospinal fluid. The data indicated that cerebral osmoreceptors that mediate thirst and VP release are located on the blood side of the blood–brain barrier.

    CAS  PubMed  Google Scholar 

  25. Zerbe, R. L. & Robertson, G. L. Osmoregulation of thirst and vasopressin secretion in human subjects: effect of various solutes. Am. J. Physiol. 244, E607–E614 (1983).

    CAS  PubMed  Google Scholar 

  26. Baylis, P. H. Osmoregulation and control of vasopressin secretion in healthy humans. Am. J. Physiol. 253, R671–R678 (1987).

    CAS  PubMed  Google Scholar 

  27. Egan, G. et al. Neural correlates of the emergence of consciousness of thirst. Proc. Natl Acad. Sci. USA 100, 15241–15246 (2003). This paper used functional MRI to obtain the first evidence that areas of the lamina terminalis and of the ACC become activated during systemic hyperosmolality in human subjects. The study further showed that an acute bout of water intake suppresses thirst and activity in the ACC before osmolality is restored and while lamina terminalis activity remains elevated.

    CAS  PubMed  Google Scholar 

  28. Thornborough, J. R., Passo, S. S. & Rothballer, A. B. Receptors in cerebral circulation affecting sodium excretion in the cat. Am. J. Physiol. 225, 138–141 (1973).

    CAS  PubMed  Google Scholar 

  29. Blaine, E. H., Denton, D. A., McKinley, M. J. & Weller, S. A central osmosensitive receptor for renal sodium excretion. J. Physiol. 244, 497–509 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Emmeluth, C. et al. Natriuresis caused by increased carotid Na+ concentration after renal denervation. Am. J. Physiol. 270, F510–F517 (1996).

    CAS  PubMed  Google Scholar 

  31. Huang, W., Lee, S. L., Arnason, S. S. & Sjoquist, M. Dehydration natriuresis in male rats is mediated by oxytocin. Am. J. Physiol. 270, R427–R433 (1996).

    CAS  PubMed  Google Scholar 

  32. McKinley, M. J., Lichardus, B., McDougall, J. G. & Weisinger, R. S. Periventricular lesions block natriuresis to hypertonic but not isotonic NaCl loads. Am. J. Physiol. 262, F98–F107 (1992).

    CAS  PubMed  Google Scholar 

  33. Andersen, L. J., Andersen, J. L., Pump, B. & Bie, P. Natriuresis induced by mild hypernatremia in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1754–R1761 (2002). This study provided conclusive evidence that systemic hyperosmolality can provoke natriuresis in humans.

    CAS  PubMed  Google Scholar 

  34. Huang, W., Lee, S. L. & Sjoquist, M. Natriuretic role of endogenous oxytocin in male rats infused with hypertonic NaCl. Am. J. Physiol. 268, R634–R640 (1995).

    CAS  PubMed  Google Scholar 

  35. Rasmussen, M. S., Simonsen, J. A., Sandgaard, N. C., Hoilund-Carlsen, P. F. & Bie, P. Mechanisms of acute natriuresis in normal humans on low sodium diet. J. Physiol. 546, 591–603 (2003).

    CAS  PubMed  Google Scholar 

  36. Brimble, M. J. & Dyball, R. E. Characterization of the responses of oxytocin- and vasopressin-secreting neurones in the supraoptic nucleus to osmotic stimulation. J. Physiol. 271, 253–271 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Weisinger, R. S., Denton, D. A. & McKinley, M. J. Self-administered intravenous infusion of hypertonic solutions and sodium appetite of sheep. Behav. Neurosci. 97, 433–444 (1983).

    CAS  PubMed  Google Scholar 

  38. Blackburn, R. E., Samson, W. K., Fulton, R. J., Stricker, E. M. & Verbalis, J. G. Central oxytocin and ANP receptors mediate osmotic inhibition of salt appetite in rats. Am. J. Physiol. 269, R245–R251 (1995).

    CAS  PubMed  Google Scholar 

  39. Blackburn, R. E., Samson, W. K., Fulton, R. J., Stricker, E. M. & Verbalis, J. G. Central oxytocin inhibition of salt appetite in rats: evidence for differential sensing of plasma sodium and osmolality. Proc. Natl Acad. Sci. USA 90, 10380–10384 (1993).

    CAS  PubMed  Google Scholar 

  40. Baker, M. A. & Dawson, D. D. Inhibition of thermal panting by intracarotid infusion of hypertonic saline in dogs. Am. J. Physiol. 249, R787–R791 (1985).

    CAS  PubMed  Google Scholar 

  41. Turlejska, E. & Baker, M. A. Elevated CSF osmolality inhibits thermoregulatory heat loss responses. Am. J. Physiol. 251, R749–R754 (1986).

    CAS  PubMed  Google Scholar 

  42. Sawka, M. N., Francesconi, R. P., Young, A. J. & Pandolf, K. B. Influence of hydration level and body fluids on exercise performance in the heat. JAMA 252, 1165–1169 (1984).

    CAS  PubMed  Google Scholar 

  43. Fortney, S. M., Wenger, C. B., Bove, J. R. & Nadel, E. R. Effect of hyperosmolality on control of blood flow and sweating. J. Appl. Physiol. 57, 1688–1695 (1984).

    CAS  PubMed  Google Scholar 

  44. Takamata, A., Yoshida, T., Nishida, N. & Morimoto, T. Relationship of osmotic inhibition in thermoregulatory responses and sweat sodium concentration in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R623–R629 (2001).

    CAS  PubMed  Google Scholar 

  45. Robertson, G. L., Shelton, R. L. & Athar, S. The osmoregulation of vasopressin. Kidney Int. 10, 25–37 (1976).

    CAS  PubMed  Google Scholar 

  46. Claybaugh, J. R., Sato, A. K., Crosswhite, L. K. & Hassell, L. H. Effects of time of day, gender, and menstrual cycle phase on the human response to a water load. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R966–R973 (2000).

    CAS  PubMed  Google Scholar 

  47. Maresh, C. M. et al. Perceptual responses in the heat after brief intravenous versus oral rehydration. Med. Sci. Sports Exerc. 33, 1039–1045 (2001).

    CAS  PubMed  Google Scholar 

  48. Smith, D., Moore, K., Tormey, W., Baylis, P. H. & Thompson, C. J. Downward resetting of the osmotic threshold for thirst in patients with SIADH. Am. J. Physiol. Endocrinol. Metab. 287, E1019–E1023 (2004).

    CAS  PubMed  Google Scholar 

  49. Gilman, A. The relation between blood osmotic pressure, fluid distribution and voluntary water intake. Am. J. Physiol. 120, 323–328 (1937).

    CAS  Google Scholar 

  50. Verney, E. B. The antidiuretic hormone and the factors which determine its release. Proc. R. Soc. Lond. B Biol. Sci. 135, 25–106 (1947). This classical study examined how infusing solutions of various composition into the carotid artery affected diuresis in water-loaded dogs. It concluded that osmoreceptors in the brain are responsible for the osmotic control of VP release.

    CAS  PubMed  Google Scholar 

  51. Wolf, A. V. Osmometric analysis of thirst in man and dog. Am. J. Physiol., 161 75–86 (1950).

    CAS  PubMed  Google Scholar 

  52. McKinley, M. J., Blaine, E. H. & Denton, D. A. Brain osmoreceptors, cerebrospinal fluid electrolyte composition and thirst. Brain Res. 70, 532–537 (1974). In this study, manipulation of ECF osmolality and composition in conscious sheep provided conclusive evidence that thirst is modulated by cerebrospinal fluid osmolality and by the concentration of Na+ in the cerebrospinal fluid.

    CAS  PubMed  Google Scholar 

  53. Jewell, P. A. & Verney, E. B. An experimental attempt to determine the site of the neurohypophysial osmoreceptors in the dog. Philos. Trans. R. Soc. Lond. B 240, 197–324 (1957).

    Google Scholar 

  54. Kuramochi, G. & Kobayashi, I. Regulation of the urine concentration mechanism by the oropharyngeal afferent pathway in man. Am. J. Nephrol. 20, 42–47 (2000).

    CAS  PubMed  Google Scholar 

  55. Dooley, C. P. & Valenzuela, J. E. Duodenal volume and osmoreceptors in the stimulation of human pancreatic secretion. Gastroenterology 86, 23–27 (1984).

    CAS  PubMed  Google Scholar 

  56. Carlson, S. H., Beitz, A. & Osborn, J. W. Intragastric hypertonic saline increases vasopressin and central Fos immunoreactivity in conscious rats. Am. J. Physiol. 272, R750–758 (1997).

    CAS  PubMed  Google Scholar 

  57. Choi-Kwon, S. & Baertschi, A. J. Splanchnic osmosensation and vasopressin: mechanisms and neural pathways. Am. J. Physiol. 261, E18–E25 (1991).

    CAS  PubMed  Google Scholar 

  58. Baertschi, A. J. & Vallet, P. G. Osmosensitivity of the hepatic portal vein area and vasopressin release in rats. J. Physiol. 315, 217–230 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Adachi, A. Thermosensitive and osmoreceptive afferent fibers in the hepatic branch of the vagus nerve. J. Auton. Nerv. Syst. 10, 269–273 (1984).

    CAS  PubMed  Google Scholar 

  60. Adachi, A., Niijima, A. & Jacobs, H. L. An hepatic osmoreceptor mechanism in the rat: electrophysiological and behavioral studies. Am. J. Physiol. 231, 1043–1049 (1976).

    CAS  PubMed  Google Scholar 

  61. Haberich, F. J. Osmoreception in the portal circulation. Fed. Proc. 27, 1137–1141 (1968).

    CAS  PubMed  Google Scholar 

  62. Stricker, E. M. & Hoffmann, M. L. Presystemic signals in the control of thirst, salt appetite, and vasopressin secretion. Physiol. Behav. 91, 404–412 (2007).

    CAS  PubMed  Google Scholar 

  63. Blair-West, J. R., Gibson, A. P., Woods, R. L. & Brook, A. H. Acute reduction of plasma vasopressin levels by rehydration in sheep. Am. J. Physiol. 248, R68–R71 (1985).

    CAS  PubMed  Google Scholar 

  64. Baertschi, A. J. & Pence, R. A. Gut-brain signaling of water absorption inhibits vasopressin in rats. Am. J. Physiol. 268, R236–R247 (1995).

    CAS  PubMed  Google Scholar 

  65. Huang, W., Sved, A. F. & Stricker, E. M. Water ingestion provides an early signal inhibiting osmotically stimulated vasopressin secretion in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R756–R760 (2000).

    CAS  PubMed  Google Scholar 

  66. Bykowski, M. R., Smith, J. C. & Stricker, E. M. Regulation of NaCl solution intake and gastric emptying in adrenalectomized rats. Physiol. Behav. 92, 781–789 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Huang, W., Sved, A. F. & Stricker, E. M. Vasopressin and oxytocin release evoked by NaCl loads are selectively blunted by area postrema lesions. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R732–R740 (2000).

    CAS  PubMed  Google Scholar 

  68. Chwalbinska-Moneta, J. Role of hepatic portal osmoreception in the control of ADH release. Am. J. Physiol. 236, E603–E609 (1979).

    CAS  PubMed  Google Scholar 

  69. Kobashi, M. & Adachi, A. Effect of portal infusion of hypertonic saline on neurons in the dorsal motor nucleus of the vagus in the rat. Brain Res. 632, 174–179 (1993).

    CAS  PubMed  Google Scholar 

  70. Niijima, A. Afferent discharges from osmoreceptors in the liver of the guinea pig. Science 166, 1519–1520 (1969).

    CAS  PubMed  Google Scholar 

  71. Osaka, T., Kobayashi, A. & Inoue, S. Vago-sympathoadrenal reflex in thermogenesis induced by osmotic stimulation of the intestines in the rat. J. Physiol. 540, 665–671 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Vallet, P. G. & Baertschi, A. J. Spinal afferents for peripheral osmoreceptors in the rat. Brain Res. 239, 271–274 (1982).

    CAS  PubMed  Google Scholar 

  73. Craig, A. D. Interoception: the sense of the physiological condition of the body. Curr. Opin. Neurobiol. 13, 500–505 (2003).

    CAS  PubMed  Google Scholar 

  74. Craig, A. D. A new view of pain as a homeostatic emotion. Trends Neurosci. 26, 303–307 (2003).

    CAS  PubMed  Google Scholar 

  75. Blackshaw, L. A., Brookes, S. J., Grundy, D. & Schemann, M. Sensory transmission in the gastrointestinal tract. Neurogastroenterol. Motil. 19, 1–19 (2007).

    CAS  PubMed  Google Scholar 

  76. Grundy, D. Neuroanatomy of visceral nociception: vagal and splanchnic afferent. Gut 51 (Suppl. 1), i2–i5 (2002).

    PubMed  PubMed Central  Google Scholar 

  77. Grundy, D. Signalling the state of the digestive tract. Auton. Neurosci. 125, 76–80 (2006).

    PubMed  Google Scholar 

  78. Mei, N. & Garnier, L. Osmosensitive vagal receptors in the small intestine of the cat. J. Auton. Nerv. Syst. 16, 159–170 (1986).

    CAS  PubMed  Google Scholar 

  79. Bradbury, M. W. & Coxon, R. V. The penetration of urea into the central nervous system at high blood levels. J. Physiol. 163, 423–435 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. McKinley, M. J. et al. The sensory circumventricular organs of the mammalian brain (Springer, 2003).

    Google Scholar 

  81. Andersson, B. Thirst--and brain control of water balance. Am. Sci. 59, 408–415 (1971).

    CAS  PubMed  Google Scholar 

  82. Buggy, J., Hoffman, W. E., Phillips, M. I., Fisher, A. E. & Johnson, A. K. Osmosensitivity of rat third ventricle and interactions with angiotensin. Am. J. Physiol. 236, R75–R82 (1979).

    CAS  PubMed  Google Scholar 

  83. Buggy, J. & Jonhson, A. K. Preoptic-hypothalamic periventricular lesions: thirst deficits and hypernatremia. Am. J. Physiol. 233, R44–R52 (1977).

    CAS  PubMed  Google Scholar 

  84. Thrasher, T. N. & Keil, L. C. Regulation of drinking and vasopressin secretion: role of organum vasculosum laminae terminalis. Am. J. Physiol. 253, R108–R120 (1987).

    CAS  PubMed  Google Scholar 

  85. Thrasher, T. N., Keil, L. C. & Ramsay, D. J. Lesions of the organum vasculosum of the lamina terminalis (OVLT) attenuate osmotically-induced drinking and vasopressin secretion in the dog. Endocrinology 110, 1837–1839 (1982).

    CAS  PubMed  Google Scholar 

  86. Morita, H. et al. Sequence of forebrain activation induced by intraventricular injection of hypertonic NaCl detected by Mn2+ contrasted T1-weighted MRI. Auton. Neurosci. 113, 43–54 (2004).

    CAS  PubMed  Google Scholar 

  87. McKinley, M. J., Denton, D. A., Oldfield, B. J., De Oliveira, L. B. & Mathai, M. L. Water intake and the neural correlates of the consciousness of thirst. Semin. Nephrol. 26, 249–257 (2006).

    PubMed  Google Scholar 

  88. Sayer, R. J., Hubbard, J. I. & Sirett, N. E. Rat organum vasculosum laminae terminalis in vitro: responses to transmitters. Am. J. Physiol. 247, R374–R379 (1984).

    CAS  PubMed  Google Scholar 

  89. Ciura, S. & Bourque, C. W. Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality. J. Neurosci. 26, 9069–9075 (2006). This study provided the first unequivocal evidence that OVLT neurons are intrinsically osmosensitive. It further showed that the sensitivity of OVLT neurons to hypertonicity is abolished in mice that lack expression of the Trpv1 gene and that such mice have impaired thirst responses during acute hypertonicity.

    CAS  PubMed  Google Scholar 

  90. Vivas, L., Chiaraviglio, E. & Carrer, H. F. Rat organum vasculosum laminae terminalis in vitro: responses to changes in sodium concentration. Brain Res. 519, 294–300 (1990).

    CAS  PubMed  Google Scholar 

  91. Oldfield, B. J., Badoer, E., Hards, D. K. & McKinley, M. J. Fos production in retrogradely labelled neurons of the lamina terminalis following intravenous infusion of either hypertonic saline or angiotensin II. Neuroscience 60, 255–262 (1994).

    CAS  PubMed  Google Scholar 

  92. Bourque, C. W., Oliet, S. H. & Richard, D. Osmoreceptors, osmoreception, and osmoregulation. Front. Neuroendocrinol. 15, 231–274 (1994).

    CAS  PubMed  Google Scholar 

  93. Mason, W. T. Supraoptic neurones of rat hypothalamus are osmosensitive. Nature 287, 154–157 (1980). This study used intracellular microelectrode recordings from supraoptic nucleus neurons in rat hypothalamic slices maintained in vitro to provide the first indication that these neurons are intrinsically osmosensitive.

    CAS  PubMed  Google Scholar 

  94. Bourque, C. W. Ionic basis for the intrinsic activation of rat supraoptic neurones by hyperosmotic stimuli. J. Physiol. 417, 263–277 (1989). This paper provided the first evidence that the excitation of supraoptic nucleus neurons by hypertonicity is due to the activation of a non-selective cation conductance.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Sibbald, J. R., Hubbard, J. I. & Sirett, N. E. Responses from osmosensitive neurons of the rat subfornical organ in vitro. Brain Res. 461, 205–214 (1988).

    CAS  PubMed  Google Scholar 

  96. Nakashima, T., Hori, T., Kiyohara, T. & Shibata, M. Osmosensitivity of preoptic thermosensitive neurons in hypothalamic slices in vitro. Pflugers Arch. 405, 112–117 (1985).

    CAS  PubMed  Google Scholar 

  97. Izawa, S., Inoue, K., Adachi, A. & Funahashi, M. Activity of neurons in the nucleus of the solitary tract of rats: effect of osmotic and mechanical stimuli. Neurosci. Lett. 288, 33–36 (2000).

    CAS  PubMed  Google Scholar 

  98. Anderson, J. W., Washburn, D. L. & Ferguson, A. V. Intrinsic osmosensitivity of subfornical organ neurons. Neuroscience 100, 539–547 (2000).

    CAS  PubMed  Google Scholar 

  99. Oliet, S. H. & Bourque, C. W. Properties of supraoptic magnocellular neurones isolated from the adult rat. J. Physiol. 455, 291–306 (1992). In this study, recordings were obtained from acutely isolated supraoptic nucleus neurons that were devoid of physical contact with other neurons or glia. The data provided unequivocal evidence that supraoptic nucleus neurons have an intrinsic ability to detect hypo-osmotic stimuli with hyperpolarization and hyperosmotic stimuli with depolarization.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Oliet, S. H. & Bourque, C. W. Mechanosensitive channels transduce osmosensitivity in supraoptic neurons. Nature 364, 341–343 (1993). In this study, recordings from acutely isolated cells showed that the osmosensitivity of supraoptic neurons is due to the expression of mechanically gated cation channels that are inhibited by stretch during increases in cell volume and stimulated during cell shrinking.

    CAS  PubMed  Google Scholar 

  101. Bourque, C. W. Osmoregulation of vasopressin neurons: a synergy of intrinsic and synaptic processes. Prog. Brain Res. 119, 59–76 (1998).

    CAS  PubMed  Google Scholar 

  102. Qiu, D. L. et al. Effect of hypertonic saline on rat hypothalamic paraventricular nucleus magnocellular neurons in vitro. Neurosci. Lett. 355, 117–120 (2004).

    CAS  PubMed  Google Scholar 

  103. Oliet, S. H. & Bourque, C. W. Steady-state osmotic modulation of cationic conductance in neurons of rat supraoptic nucleus. Am. J. Physiol. 265, R1475–R1479 (1993).

    CAS  PubMed  Google Scholar 

  104. Zhang, Z. & Bourque, C. W. Osmometry in osmosensory neurons. Nature Neurosci. 6, 1021–1022 (2003). In this study, measurements of cell volume and capacitance were used to show that neurons in the supraoptic nucleus have a significant membrane reserve and that the surface area of the cells does not change during osmotically induced changes in cell volume. Moreover, changes in cell volume were shown to vary as an inverse function of osmolality and to be sustained for periods as long as 60 minutes.

    CAS  PubMed  Google Scholar 

  105. Zhang, Z., Kindrat, A. N., Sharif Naeini, R. & Bourque, C. W. Actin filaments mediate mechanical gating during osmosensory transduction in rat supraoptic nucleus neurons. J. Neurosci. 27, 4008–4013 (2007). In this study, whole-cell recordings from acutely isolated supraoptic neurons were used to examine the effects of volume changes induced by osmotic stimuli and changes in pipette pressure under conditions in which actin polymerization was enhanced or reduced. The data confirmed that osmosensory transduction is a mechanical process and that the sensitivity of the transduction process varies in proportion with the density of subcortical actin.

    CAS  PubMed  Google Scholar 

  106. Colbert, H. A., Smith, T. L. & Bargmann, C. I. OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in Caenorhabditis elegans. J. Neurosci. 17, 8259–8269 (1997). This paper provided the first genetic and molecular evidence that OSM-9, an ortholog of the TRPV family of cation channels, is involved in an osmotically directed behaviour and might serve as a transduction element for osmosensation.

    CAS  PubMed  Google Scholar 

  107. Nilius, B., Owsianik, G., Voets, T. & Peters, J. A. Transient receptor potential cation channels in disease. Physiol. Rev. 87, 165–217 (2007).

    CAS  PubMed  Google Scholar 

  108. Clapham, D. E. SnapShot: mammalian TRP channels. Cell 129, 220 (2007).

    PubMed  Google Scholar 

  109. Sharif Naeini, R., Witty, M. F., Seguela, P. & Bourque, C. W. An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nature Neurosci. 9, 93–98 (2006). This paper provided the first demonstration that osmosensory transduction and VP release induced by hyperosmolality are impaired in mice that lack expression of the Trpv1 gene. The mice were shown to suffer from chronic ECF hyperosmolality despite having unrestricted access to food and water.

    PubMed  Google Scholar 

  110. Oliet, S. H. & Bourque, C. W. Gadolinium uncouples mechanical detection and osmoreceptor potential in supraoptic neurons. Neuron 16, 175–181 (1996).

    CAS  PubMed  Google Scholar 

  111. Zhang, Z. & Bourque, C. W. Calcium permeability and flux through osmosensory transduction channels of isolated rat supraoptic nucleus neurons. Eur. J. Neurosci. 23, 1491–1500 (2006).

    PubMed  Google Scholar 

  112. Kung, C. A possible unifying principle for mechanosensation. Nature 436, 647–654 (2005).

    CAS  PubMed  Google Scholar 

  113. Christensen, A. P. & Corey, D. P. TRP channels in mechanosensation: direct or indirect activation? Nature Rev. Neurosci. 8, 510–521 (2007).

    CAS  Google Scholar 

  114. Deleuze, C., Duvoid, A. & Hussy, N. Properties and glial origin of osmotic-dependent release of taurine from the rat supraoptic nucleus. J. Physiol. 507, 463–471 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Hussy, N., Deleuze, C., Pantaloni, A., Desarmenien, M. G. & Moos, F. Agonist action of taurine on glycine receptors in rat supraoptic magnocellular neurones: possible role in osmoregulation. J. Physiol. 502, 609–621 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Deleuze, C., Alonso, G., Lefevre, I. A., Duvoid-Guillou, A. & Hussy, N. Extrasynaptic localization of glycine receptors in the rat supraoptic nucleus: further evidence for their involvement in glia-to-neuron communication. Neuroscience 133, 175–183 (2005).

    CAS  PubMed  Google Scholar 

  117. Bres, V. et al. Pharmacological characterization of volume-sensitive, taurine permeable anion channels in rat supraoptic glial cells. Br. J. Pharmacol. 130, 1976–1982 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Han, J., Gnatenco, C., Sladek, C. D. & Kim, D. Background and tandem-pore potassium channels in magnocellular neurosecretory cells of the rat supraoptic nucleus. J. Physiol. 546, 625–639 (2003).

    CAS  PubMed  Google Scholar 

  119. Honore, E. The neuronal background K2P channels: focus on TREK1. Nature Rev. Neurosci. 8, 251–261 (2007).

    CAS  Google Scholar 

  120. Liu, X. H., Zhang, W. & Fisher, T. E. A novel osmosensitive voltage gated cation current in rat supraoptic neurones. J. Physiol. 568, 61–68 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Walters, J. K. & Hatton, G. I. Supraoptic neuronal activity in rats during five days of water deprivation. Physiol. Behav. 13, 661–667 (1974).

    CAS  PubMed  Google Scholar 

  122. Roper, P., Callaway, J. & Armstrong, W. Burst initiation and termination in phasic vasopressin cells of the rat supraoptic nucleus: a combined mathematical, electrical, and calcium fluorescence study. J. Neurosci. 24, 4818–4831 (2004).

    CAS  PubMed  Google Scholar 

  123. Roper, P., Callaway, J., Shevchenko, T., Teruyama, R. & Armstrong, W. AHP's, HAP's and DAP's: how potassium currents regulate the excitability of rat supraoptic neurones. J. Comput. Neurosci. 15, 367–389 (2003).

    PubMed  Google Scholar 

  124. Wakerley, J. B., Poulain, D. A. & Brown, D. Comparison of firing patterns in oxytocin- and vasopressin-releasing neurones during progressive dehydration. Brain Res. 148, 425–440 (1978).

    CAS  PubMed  Google Scholar 

  125. Fisher, T. E. & Bourque, C. W. The function of Ca2+ channel subtypes in exocytotic secretion: new perspectives from synaptic and non-synaptic release. Prog. Biophys. Mol. Biol. 77, 269–303 (2001).

    CAS  PubMed  Google Scholar 

  126. Bicknell, R. J. Optimizing release from peptide hormone secretory nerve terminals. J. Exp. Biol. 139, 51–65 (1988).

    CAS  PubMed  Google Scholar 

  127. Johnson, A. K. The sensory psychobiology of thirst and salt appetite. Med. Sci. Sports Exerc. 39, 1388–1400 (2007).

    PubMed  Google Scholar 

  128. Grob, M., Trottier, J. F. & Mouginot, D. Heterogeneous co-localization of AT 1A receptor and Fos protein in forebrain neuronal populations responding to acute hydromineral deficit. Brain Res. 996, 81–88 (2004).

    CAS  PubMed  Google Scholar 

  129. Daniels, D. & Fluharty, S. J. Salt appetite: a neurohormonal viewpoint. Physiol. Behav. 81, 319–337 (2004).

    CAS  PubMed  Google Scholar 

  130. Antunes-Rodrigues, J., de Castro, M., Elias, L. L., Valenca, M. M. & McCann, S. M. Neuroendocrine control of body fluid metabolism. Physiol. Rev. 84, 169–208 (2004).

    CAS  PubMed  Google Scholar 

  131. Brimble, M. J., Dyball, R. E. & Forsling, M. L. Oxytocin release following osmotic activation of oxytocin neurones in the paraventricular and supraoptic nuclei. J. Physiol. 278, 69–78 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Oldfield, B. J., Hards, D. K. & McKinley, M. J. Neurons in the median preoptic nucleus of the rat with collateral branches to the subfornical organ and supraoptic nucleus. Brain Res. 586, 86–90 (1992).

    CAS  PubMed  Google Scholar 

  133. Armstrong, W. E., Tian, M. & Wong, H. Electron microscopic analysis of synaptic inputs from the median preoptic nucleus and adjacent regions to the supraoptic nucleus in the rat. J. Comp. Neurol. 373, 228–239 (1996).

    CAS  PubMed  Google Scholar 

  134. Yang, C. R., Senatorov, V. V. & Renaud, L. P. Organum vasculosum lamina terminalis-evoked postsynaptic responses in rat supraoptic neurones in vitro. J. Physiol. 477, 59–74 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. McKellar, S. & Loewy, A. D. Organization of some brain stem afferents to the paraventricular nucleus of the hypothalamus in the rat. Brain Res. 217, 351–357 (1981).

    CAS  PubMed  Google Scholar 

  136. Jhamandas, J. H., Harris, K. H. & Krukoff, T. L. Parabrachial nucleus projection towards the hypothalamic supraoptic nucleus: electrophysiological and anatomical observations in the rat. J. Comp. Neurol. 308, 42–50 (1991).

    CAS  PubMed  Google Scholar 

  137. Aradachi, H., Honda, K., Negoro, H. & Kubota, T. Median preoptic neurones projecting to the supraoptic nucleus are sensitive to haemodynamic changes as well as to rise in plasma osmolality in rats. J. Neuroendocrinol. 8, 35–43 (1996).

    CAS  PubMed  Google Scholar 

  138. Honda, K., Negoro, H., Higuchi, T. & Tadokoro, Y. The role of the anteroventral 3rd ventricle area in the osmotic control of paraventricular neurosecretory cells. Exp. Brain Res. 76, 497–502 (1989).

    CAS  PubMed  Google Scholar 

  139. Richard, D. & Bourque, C. W. Synaptic control of rat supraoptic neurones during osmotic stimulation of the organum vasculosum lamina terminalis in vitro. J. Physiol. 489, 567–577 (1995). This study applied local osmotic stimuli to the OVLT during intracellular recordings from supraoptic nucleus neurons in superfused explants of rat hypothalamus. The data showed that osmosensory signals encoded by OVLT neurons are distributed to supraoptic neurons through action-potential-dependent excitatory postsynaptic potentials mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Thrasher, T. N., Nistal-Herrera, J. F., Keil, L. C. & Ramsay, D. J. Satiety and inhibition of vasopressin secretion after drinking in dehydrated dogs. Am. J. Physiol. 240, E394–E401 (1981).

    CAS  PubMed  Google Scholar 

  141. Farrell, M. J. et al. Effect of aging on regional cerebral blood flow responses associated with osmotic thirst and its satiation by water drinking: a PET study. Proc. Natl Acad. Sci. USA 105, 382–387 (2008).

    CAS  PubMed  Google Scholar 

  142. Craig, A. D. How do you feel? Interoception: the sense of the physiological condition of the body. Nature Rev. Neurosci. 3, 655–666 (2002).

    CAS  Google Scholar 

  143. Robinson, B. W. & Mishkin, M. Alimentary responses to forebrain stimulation in monkeys. Exp. Brain Res. 4, 330–366 (1968).

    CAS  PubMed  Google Scholar 

  144. Hollis, J. H., McKinley, M. J., D'Souza, M., Kampe, J. & Oldfield, B. J. The trajectory of sensory pathways from the lamina terminalis to the insular and cingulate cortex; a neuroanatomical framework for the generation of thirst. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1390–R401 (2008). This study combined an array of anatomical techniques, including retrograde and trans-synaptic labelling, together with Fos immunocytochemistry, to provide the first comprehensive description of the central pathway that relays osmosensory information encoded by OVLT neurons to cortical areas that are involved in the genesis of thirst. A large array of neurons in midline thalamic nuclei were shown to serve as intermediate relay elements between the OVLT and relevant cortical areas.

    CAS  PubMed  Google Scholar 

  145. Pastuskovas, C. V., Cassell, M. D., Johnson, A. K. & Thunhorst, R. L. Increased cellular activity in rat insular cortex after water and salt ingestion induced by fluid depletion. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1119–R1125 (2003).

    CAS  PubMed  Google Scholar 

  146. Sorenson, C. A. & Ellison, G. D. Striatal organization of feeding behavior in the decorticate rat. Exp. Neurol. 29, 162–174 (1970).

    CAS  PubMed  Google Scholar 

  147. Sewards, T. V. & Sewards, M. A. Representations of motivational drives in mesial cortex, medial thalamus, hypothalamus and midbrain. Brain Res. Bull. 61, 25–49 (2003).

    PubMed  Google Scholar 

  148. de Oliveira, L. B., Callera, J. C., De Luca, L. A. Jr, Colombari, D. S. & Menani, J. V. GABAergic mechanisms of the lateral parabrachial nucleus on sodium appetite. Brain Res. Bull. 73, 238–247 (2007).

    CAS  PubMed  Google Scholar 

  149. Heidi Kimura, E. et al. Sodium intake by hyperosmotic rats treated with a GABAA receptor agonist into the lateral parabrachial nucleus. Brain Res. 1190, 86–93 (2008).

    Google Scholar 

  150. Contreras, R. J. & Stetson, P. W. Changes in salt intake lesions of the area postrema and the nucleus of the solitary tract in rats. Brain Res. 211, 355–366 (1981).

    CAS  PubMed  Google Scholar 

  151. Edwards, G. L., Beltz, T. G., Power, J. D. & Johnson, A. K. Rapid-onset “need-free” sodium appetite after lesions of the dorsomedial medulla. Am. J. Physiol. 264, R1242–R1247 (1993).

    CAS  PubMed  Google Scholar 

  152. Michelini, L. C. The NTS and integration of cardiovascular control during exercise in normotensive and hypertensive individuals. Curr. Hypertens. Rep. 9, 214–221 (2007).

    PubMed  Google Scholar 

  153. Toney, G. M., Chen, Q. H., Cato, M. J. & Stocker, S. D. Central osmotic regulation of sympathetic nerve activity. Acta Physiol. Scand. 177, 43–55 (2003).

    CAS  PubMed  Google Scholar 

  154. Kantzides, A. & Badoer, E. Fos, RVLM-projecting neurons, and spinally projecting neurons in the PVN following hypertonic saline infusion. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R945–R953 (2003).

    CAS  PubMed  Google Scholar 

  155. de Araujo, I. E., Kringelbach, M. L., Rolls, E. T. & McGlone, F. Human cortical responses to water in the mouth, and the effects of thirst. J. Neurophysiol. 90, 1865–1876 (2003).

    PubMed  Google Scholar 

  156. Bie, P., Wamberg, S. & Kjolby, M. Volume natriuresis vs. pressure natriuresis. Acta Physiol. Scand. 181, 495–503 (2004).

    CAS  PubMed  Google Scholar 

  157. DiBona, G. F. Physiology in perspective: The Wisdom of the Body. Neural control of the kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R633–R641 (2005).

    CAS  PubMed  Google Scholar 

  158. DiBona, G. F. Sympathetic nervous system and the kidney in hypertension. Curr. Opin. Nephrol. Hypertens. 11, 197–200 (2002).

    PubMed  Google Scholar 

  159. Verbalis, J. G., Mangione, M. P. & Stricker, E. M. Oxytocin produces natriuresis in rats at physiological plasma concentrations. Endocrinology 128, 1317–1322 (1991).

    CAS  PubMed  Google Scholar 

  160. Farquhar, W. B., Wenner, M. M., Delaney, E. P., Prettyman, A. V. & Stillabower, M. E. Sympathetic neural responses to increased osmolality in humans. Am. J. Physiol. Heart Circ. Physiol. 291, H2181–H2186 (2006).

    CAS  PubMed  Google Scholar 

  161. Scrogin, K. E., Grygielko, E. T. & Brooks, V. L. Osmolality: a physiological long-term regulator of lumbar sympathetic nerve activity and arterial pressure. Am. J. Physiol. 276, R1579–R1586 (1999).

    CAS  PubMed  Google Scholar 

  162. Scrogin, K. E., McKeogh, D. F. & Brooks, V. L. Is osmolality a long-term regulator of renal sympathetic nerve activity in conscious water-deprived rats? Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R560–R568 (2002).

    CAS  PubMed  Google Scholar 

  163. Weiss, M. L., Claassen, D. E., Hirai, T. & Kenney, M. J. Nonuniform sympathetic nerve responses to intravenous hypertonic saline infusion. J. Auton. Nerv. Syst. 57, 109–115 (1996).

    CAS  PubMed  Google Scholar 

  164. Badoer, E., Ng, C. W. & De Matteo, R. Glutamatergic input in the PVN is important in renal nerve response to elevations in osmolality. Am. J. Physiol. Renal Physiol. 285, F640–F650 (2003).

    CAS  PubMed  Google Scholar 

  165. Bealer, S. L., Delle, M., Skarphedinsson, J. O., Carlsson, S. & Thoren, P. Differential responses in adrenal and renal nerves to CNS osmotic stimulation. Brain Res. Bull. 39, 205–209 (1996).

    CAS  Google Scholar 

  166. Shi, P., Stocker, S. D. & Toney, G. M. Organum vasculosum laminae terminalis contributes to increased sympathetic nerve activity induced by central hyperosmolality. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R2279–R2289 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. May, C. N., McAllen, R. M. & McKinley, M. J. Renal nerve inhibition by central NaCl and ANG II is abolished by lesions of the lamina terminalis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1827–R1833 (2000).

    CAS  PubMed  Google Scholar 

  168. Stocker, S. D., Cunningham, J. T. & Toney, G. M. Water deprivation increases Fos immunoreactivity in PVN autonomic neurons with projections to the spinal cord and rostral ventrolateral medulla. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R1172–R1183 (2004).

    CAS  PubMed  Google Scholar 

  169. Stocker, S. D., Keith, K. J. & Toney, G. M. Acute inhibition of the hypothalamic paraventricular nucleus decreases renal sympathetic nerve activity and arterial blood pressure in water-deprived rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R719–R725 (2004).

    CAS  Google Scholar 

  170. Sly, D. J., Colvill, L., McKinley, M. J. & Oldfield, B. J. Identification of neural projections from the forebrain to the kidney, using the virus pseudorabies. J. Auton. Nerv. Syst. 77, 73–82 (1999).

    PubMed  Google Scholar 

  171. Sly, D. J., McKinley, M. J. & Oldfield, B. J. Activation of kidney-directed neurons in the lamina terminalis by alterations in body fluid balance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1637–R1646 (2001).

    CAS  PubMed  Google Scholar 

  172. Arnauld, E., Dufy, B. & Vincent, J. D. Hypothalamic supraoptic neurones: rates and patterns of action potential firing during water deprivation in the unanaesthetized monkey. Brain Res. 100, 315–325 (1975).

    CAS  PubMed  Google Scholar 

  173. Shimizu, H. et al. Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. Neuron 54, 59–72 (2007).

    CAS  PubMed  Google Scholar 

  174. Noda, M. The subfornical organ, a specialized sodium channel, and the sensing of sodium levels in the brain. Neuroscientist 12, 80–91 (2006).

    CAS  PubMed  Google Scholar 

  175. Hindmarch, C., Yao, S., Beighton, G., Paton, J. & Murphy, D. A comprehensive description of the transcriptome of the hypothalamoneurohypophyseal system in euhydrated and dehydrated rats. Proc. Natl Acad. Sci. USA 103, 1609–1614 (2006).

    CAS  PubMed  Google Scholar 

  176. Decavel, C. & Curras, M. C. Increased expression of the N-methyl-D-aspartate receptor subunit, NR1, in immunohistochemically identified magnocellular hypothalamic neurons during dehydration. Neuroscience 78, 191–202 (1997).

    CAS  PubMed  Google Scholar 

  177. Tanaka, M. et al. Molecular and functional remodeling of electrogenic membrane of hypothalamic neurons in response to changes in their input. Proc. Natl Acad. Sci. USA 96, 1088–1093 (1999).

    CAS  PubMed  Google Scholar 

  178. Zhang, W., Star, B., Rajapaksha, W. R. & Fisher, T. E. Dehydration increases L-type Ca2+ current in rat supraoptic neurons. J. Physiol. 580, 181–193 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Liamis, G. et al. Clinical and laboratory characteristics of hypernatraemia in an internal medicine clinic. Nephrol. Dial. Transplant. 23, 136–143 (2008).

    PubMed  Google Scholar 

  180. Smellie, W. S. et al. Best practice in primary care pathology: review 8. J. Clin. Pathol. 60, 740–748 (2007).

    CAS  PubMed  Google Scholar 

  181. Ofran, Y., Lavi, D., Opher, D., Weiss, T. A. & Elinav, E. Fatal voluntary salt intake resulting in the highest ever documented sodium plasma level in adults (255 mmol L−1): a disorder linked to female gender and psychiatric disorders. J. Intern. Med. 256, 525–528 (2004).

    CAS  PubMed  Google Scholar 

  182. Turk, E. E., Schulz, F., Koops, E., Gehl, A. & Tsokos, M. Fatal hypernatremia after using salt as an emetic—report of three autopsy cases. Leg. Med. (Tokyo) 7, 47–50 (2005).

    Google Scholar 

  183. Webb, A. K., Phillips, M. J. & Hanson, G. C. Iatrogenic nondiabetic hyperosmolar states. J. R. Soc. Med. 72, 578–586 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Upadhyay, A., Jaber, B. L. & Madias, N. E. Incidence and prevalence of hyponatremia. Am. J. Med. 119, S30–S35 (2006).

    CAS  PubMed  Google Scholar 

  185. Sjoblom, E., Hojer, J., Ludwigs, U. & Pirskanen, R. Fatal hyponatraemic brain oedema due to common gastroenteritis with accidental water intoxication. Intensive Care Med. 23, 348–350 (1997).

    CAS  PubMed  Google Scholar 

  186. Stiefel, D. & Petzold, A. H2O coma. Neurocrit. Care 6, 67–71 (2007).

    PubMed  Google Scholar 

  187. Kushnir, M., Schattner, A., Ezri, T. & Konichezky, S. Schizophrenia and fatal self-induced water intoxication with appropriately-diluted urine. Am. J. Med. Sci. 300, 385–387 (1990).

    CAS  PubMed  Google Scholar 

  188. Arieff, A. I. Management of hyponatraemia. BMJ 307, 305–308 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Liedtke, W. et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103, 525–535 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Liedtke, W. & Friedman, J. M. Abnormal osmotic regulation in trpv4−/− mice. Proc. Natl Acad. Sci. USA 100, 13698–13703 (2003).

    CAS  PubMed  Google Scholar 

  191. Wainwright, A., Rutter, A. R., Seabrook, G. R., Reilly, K. & Oliver, K. R. Discrete expression of TRPV2 within the hypothalamo-neurohypophysial system: implications for regulatory activity within the hypothalamic-pituitary-adrenal axis. J. Comp. Neurol. 474, 24–42 (2004).

    PubMed  Google Scholar 

  192. Muraki, K. et al. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ. Res. 93, 829–838 (2003).

    CAS  PubMed  Google Scholar 

  193. Birder, L. A. et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nature Neurosci. 5, 856–860 (2002).

    CAS  PubMed  Google Scholar 

  194. Liedtke, W., Tobin, D. M., Bargmann, C. I. & Friedman, J. M. Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 100 (Suppl. 2), 14531–14536 (2003). In this study, the mammalian TRPV4 gene was introduced into mutant worms that lacked a functional osm-9 gene. The data showed that TRPV4 can rescue the hypertonicity-avoidance phenotype of the mutant, indicating that TRPV4 might be part of the osmosensory transducer. This study is important because it shows that a channel that was identified as being hypotonicity-activated when expressed heterologously can become hypertonicity-activated when expressed in situ.

    CAS  PubMed  Google Scholar 

  195. Taylor, A. C., McCarthy, J. J. & Stocker, S. D. Mice lacking the transient receptor vanilloid potential 1 (TRPV1) channel display normal thirst responses and central Fos activation to hypernatremia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1285–R1293 (2008).

    CAS  PubMed  Google Scholar 

  196. Sharif Naeini, R., Ciura, S. & Bourque, C. W. [TRPVs: ion channels that make you thirsty!]. Med. Sci. (Paris) 22, 1035–1037 (2006).

    Google Scholar 

  197. Denton, D. et al. Correlation of regional cerebral blood flow and change of plasma sodium concentration during genesis and satiation of thirst. Proc. Natl Acad. Sci. USA 96, 2532–2537 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Work in the author's laboratory is supported by operating grants MOP-9939 and MOP-82818 from the Canadian Institutes of Health Research and by a James McGill Research Chair. The Research Institute of the McGill University Health Centre receives support from the Fonds de la Recherche en Santé du Québec.

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    Charles W. Bourque

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Extracellular fluid (ECF) osmolalities in various animals (PDF 133 kb)

Supplementary information S2 (box)

CNS areas involved in osmoregulation (PDF 143 kb)

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Glossary

Osmolality

A quantitative measure of the total solute concentration in a solution expressed in moles per kilogram of solution. Osmolality is not the same as osmolarity, which is the number of moles of total solutes per litre of solution.

Osmolyte

Any dissolved substance that contributes to the osmolality of a solution.

Hypertonic conditions

Conditions in which the ECF contains a higher concentration of membrane-impermeant solutes than is observed at rest in that particular species.

Diuresis

An increase in the flow of urine produced by the kidney.

Natriuresis

The excretion of Na+ in urine.

Hypernatraemia

A condition in which a solution has a higher concentration of free Na+ than is normal for the species in question.

Patch-clamp pipette

A glass pipette with a tip diameter of approximately 1 μm. To make patch-clamp recordings, it is filled with a medium that approximates the composition of the cytoplasm. It is held by a plastic holder that makes a contact between this fluid and a silver electrode attached to an amplifier. A flexible tube connected to the same holder is used to alter the hydrostatic pressure inside the pipette and the cell to which it is connected.

Organic osmolyte

An organic molecule that is synthesized by a cell to increase the effective osmolality of the intracellular compartment and thus resist the shrinking that would otherwise be caused by extracellular hypertonicity.

Hyponatraemia

A condition in which the plasma has a lower concentration of free Na+ ions than is normal for the species in question.

Neurohypophysis

The posterior pituitary gland, also known as the pars nervosa of the pituitary.

Dilutional hyponatraemia

A condition in which the plasma becomes hyponatraemic as a result of excessive water intake, as opposed to as a result of sodium loss.

Hypovolaemic hyponatraemia

A condition in which the plasma becomes hyponatraemic in combination with a significant reduction in total blood volume.

Superfused explant

A small explant of adult brain tissue that is kept functional by the superfusion of an oxygenated artificial cerebrospinal fluid.

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Bourque, C. Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci 9, 519–531 (2008). https://doi.org/10.1038/nrn2400

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