Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The neural basis of homeostatic and anticipatory thirst

Key Points

  • Thirst has a key role in the maintenance of body fluid homeostasis by driving water intake to compensate for losses incurred as a result of breathing, sweating and the production of urine

  • Thirst is associated with the activation of neurons in the anterior cingulate cortex and insular cortex; activation of these neurons might be induced via relay midline thalamic neurons

  • Two distinct types of thirst emerge under different circumstances: homeostatic thirst is evoked in response to an existing water deficit, whereas anticipatory thirst occurs before an impending deficit

  • Homeostatic thirst is induced in response to hypernatraemia, hyperosmolality and hypovolaemia, whereas anticipatory thirst occurs in response to food intake or hyperthermia or before sleep

  • Thirst is rapidly inhibited by oropharyngeal afferents in response to water intake; inputs from gastric distension sensors can also provide feedback signals that suppress thirst

Abstract

Water intake is one of the most basic physiological responses and is essential to sustain life. The perception of thirst has a critical role in controlling body fluid homeostasis and if neglected or dysregulated can lead to life-threatening pathologies. Clear evidence suggests that the perception of thirst occurs in higher-order centres, such as the anterior cingulate cortex (ACC) and insular cortex (IC), which receive information from midline thalamic relay nuclei. Multiple brain regions, notably circumventricular organs such as the organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), monitor changes in blood osmolality, solute load and hormone circulation and are thought to orchestrate appropriate responses to maintain extracellular fluid near ideal set points by engaging the medial thalamic–ACC/IC network. Thirst has long been thought of as a negative homeostatic feedback response to increases in blood solute concentration or decreases in blood volume. However, emerging evidence suggests a clear role for thirst as a feedforward adaptive anticipatory response that precedes physiological challenges. These anticipatory responses are promoted by rises in core body temperature, food intake (prandial) and signals from the circadian clock. Feedforward signals are also important mediators of satiety, inhibiting thirst well before the physiological state is restored by fluid ingestion. In this Review, we discuss the importance of thirst for body fluid balance and outline our current understanding of the neural mechanisms that underlie the various types of homeostatic and anticipatory thirst.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Feedback mechanisms to maintain body fluid balance.
Figure 2: Neural pathways that control thirst homeostasis.
Figure 3: Optogenetic manipulation of neuronal activity.
Figure 4: Neural pathways involved in the anticipatory stimulation of thirst during food intake and hyperthermia.
Figure 5: Circadian regulation of thirst.

References

  1. Morgan, R. M., Patterson, M. J. & Nimmo, M. A. Acute effects of dehydration on sweat composition in men during prolonged exercise in the heat. Acta Physiol. Scand. 182, 37–43 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Effros, R. M. et al. Epithelial lining fluid solute concentrations in chronic obstructive lung disease patients and normal subjects. J. Appl. Physiol. 99, 1286–1292 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Griese, M., Noss, J. & Schramel, P. Elemental and ion composition of exhaled air condensate in cystic fibrosis. J. Cyst. Fibros. 2, 136–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Bolt, E. E., Hagens, M., Willems, D. & Onwuteaka-Philipsen, B. D. Primary care patients hastening death by voluntarily stopping eating and drinking. Ann. Family Med. 13, 421–428 (2015).

    Article  Google Scholar 

  5. Arima, H., Azuma, Y., Morishita, Y. & Hagiwara, D. Central diabetes insipidus. Nagoya J. Med. Sci. 78, 349–358 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cuesta, M., Hannon, M. J. & Thompson, C. J. Adipsic diabetes insipidus in adult patients. Pituitary 20, 372–380 (2017).

    Article  PubMed  Google Scholar 

  7. Eisenberg, Y. & Frohman, L. A. Adipsic diabetes insipidus: a review. Endocr. Pract. 22, 76–83 (2016).

    Article  PubMed  Google Scholar 

  8. Manning, S., Shaffie, R. & Arora, S. Case Report: Severe hypernatremia from psychogenic adipsia. F1000Res. 6, 34 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Pereira, M. C., Vieira, M. M., Pereira, J. S. & Salgado, D. Adipsia in a diabetes insipidus patient. Case Rep. Oncol. 8, 385–388 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Koch, C. A. & Fulop, T. Clinical aspects of changes in water and sodium homeostasis in the elderly. Rev. Endocr. Metab. Disord. 18, 49–66 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Fitzsimons, J. T. The physiology of thirst and sodium appetite. Monogr. Physiol. Soc. 35, 1–572 (1979).

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  13. McKinley, M. J. & Johnson, A. K. The physiological regulation of thirst and fluid intake. News Physiol. Sci. 19, 1–6 (2004).

    PubMed  Google Scholar 

  14. Zimmerman, C. A., Leib, D. E. & Knight, Z. A. Neural circuits underlying thirst and fluid homeostasis. Nat. Rev. Neurosci. 18, 459–469 (2017). This paper reviews recent studies dissecting the neural circuits underlying thirst.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bourque, C. W. Central mechanisms of osmosensation and systemic osmoregulation. Nat. Rev. Neurosci. 9, 519–531 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Verbalis, J. G. Disorders of body water homeostasis. Best Pract. Res. Clin. Endocrinol. Metab. 17, 471–503 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Lafontan, M., Visscher, T. L., Farpour-Lambert, N. & Yumuk, V. Opportunities for intervention strategies for weight management: global actions on fluid intake patterns. Obes. Facts 8, 54–76 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Popkin, B. M., D'Anci, K. E. & Rosenberg, I. H. Water, hydration, and health. Nutr. Rev. 68, 439–458 (2010).

    Article  PubMed  Google Scholar 

  19. Orlandi, C., Zimmer, C. A. & Gheorghiade, M. Tolvaptan for the treatment of hyponatremia and congestive heart failure. Future Cardiol. 2, 627–634 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Redondo, N., Gomez-Martinez, S. & Marcos, A. Sensory attributes of soft drinks and their influence on consumers' preferences. Food Function 5, 1686–1694 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Adler, S. M. & Verbalis, J. G. Disorders of body water homeostasis in critical illness. Endocrinol. Metab. Clin. North Am. 35, 873–894 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Brvar, M. et al. Polydipsia as another mechanism of hyponatremia after 'ecstasy' (3,4 methyldioxymethamphetamine) ingestion. Eur. J. Emerg. Med. 11, 302–304 (2004).

    Article  PubMed  Google Scholar 

  23. Kalantar-Zadeh, K., Nguyen, M. K., Chang, R. & Kurtz, I. Fatal hyponatremia in a young woman after ecstasy ingestion. Nat. Clin. Pract. Nephrol. 2, 283–288 (2006).

    Article  PubMed  Google Scholar 

  24. Traub, S. J., Hoffman, R. S. & Nelson, L. S. The “ecstasy” hangover: hyponatremia due to 3,4-methylenedioxymethamphetamine. J. Urban Health 79, 549–555 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sandifer, M. G. Hyponatremia due to psychotropic drugs. J. Clin. Psychiatry 44, 301–303 (1983).

    CAS  PubMed  Google Scholar 

  26. Lu, X. & Wang, X. Hyponatremia induced by antiepileptic drugs in patients with epilepsy. Expert Opin. Drug Safety 16, 77–87 (2017).

    Article  CAS  Google Scholar 

  27. Furth, S. & Oski, F. A. Hyponatremia and water intoxication. Am. J. Dis. Child. 147, 932–933 (1993).

    CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. Patel, J. K. Polydipsia, hyponatremia, and water intoxication among psychiatric patients. Hospital Commun. Psychiatry 45, 1073–1074 (1994).

    CAS  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. 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. 7, 47–50 (2005).

    Article  CAS  Google Scholar 

  32. Kirkman, M. A., Albert, A. F., Ibrahim, A. & Doberenz, D. Hyponatremia and brain injury: historical and contemporary perspectives. Neurocrit. Care 18, 406–416 (2013).

    Article  PubMed  Google Scholar 

  33. De Smet, H. R., Menadue, M. F., Oliver, J. R. & Phillips, P. A. Increased thirst and vasopressin secretion after myocardial infarction in rats. Am. J. Physiol. 285, R1203–R1211 (2003).

    CAS  Google Scholar 

  34. Sonneville, R. et al. Understanding brain dysfunction in sepsis. Ann. Intensive Care 3, 15 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lyons, O. D., Bradley, T. D. & Chan, C. T. Hypervolemia and sleep apnea in kidney disease. Semin. Nephrol. 35, 373–382 (2015).

    Article  PubMed  Google Scholar 

  36. Iwasa, M. & Takei, Y. Pathophysiology and management of hepatic encephalopathy 2014 update: ammonia toxicity and hyponatremia. Hepatol. Res. 45, 1155–1162 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Wier, L. M. et al. HCUP Facts and Figures: Statistics on Hospital-Based Care in the United States, 2009 (Agency for Healthcare and Research and Quality, 2011).

    Google Scholar 

  38. Magder, S. Volume and its relationship to cardiac output and venous return. Crit. Care 20, 271 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moranville, M. P., Mieure, K. D. & Santayana, E. M. Evaluation and management of shock states: hypovolemic, distributive, and cardiogenic shock. J. Pharm. Pract. 24, 44–60 (2011).

    Article  PubMed  Google Scholar 

  40. Senay Jr., L. C. & Christensen, M. L. Changes in blood plasma during progressive dehydration. J. Appl. Physiol. 20, 1136–1140 (1965).

    Article  Google Scholar 

  41. Bedford, J. J. & Leader, J. P. Response of tissues of the rat to anisosmolality in vivo. Am. J. Physiol. 264, R1164–R1179 (1993).

    CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  44. Spigset, O. & Hedenmalm, K. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug Safety 12, 209–225 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Sterns, R. H. Disorders of plasma sodium—causes, consequences, and correction. N. Engl. J. Med. 372, 55–65 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Stricker, E. M. & Sved, A. F. Thirst. Nutr. 16, 821–826 (2000).

    Article  CAS  Google Scholar 

  47. Rullier, S. Soif [French]. Dictionaire des Sciences Medicales 51, 448–490 (1821).

    Google Scholar 

  48. Cannon, W. B. Croonian Lecture: The physiological basis of thirst. Proc. R. Soc. Lond. B Biol. Sci. 90, 283–301 (1918).

    Article  CAS  Google Scholar 

  49. Wettendorff, H. Modifications de sang sous I'influence de la privation d'eau: contribution a l'étude de la soif [French]. Travaux du Laboratoire de Physiologie, Institut de Physiologie, Instituts, Solvay 4, 353–384. (1901).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Denton, D. A., McKinley, M. J., Farrell, M. & Egan, G. F. The role of primordial emotions in the evolutionary origin of consciousness. Conscious. Cogn. 18, 500–514 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Denton, D. et al. Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousness. Proc. Natl Acad. Sci. USA 96, 5304–5309 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Farrell, M. J. et al. Unique, common, and interacting cortical correlates of thirst and pain. Proc. Natl Acad. Sci. USA 103, 2416–2421 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Saker, P. et al. Regional brain responses associated with drinking water during thirst and after its satiation. Proc. Natl Acad. Sci. USA 111, 5379–5384 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Farrell, M. J. et al. Cortical activation and lamina terminalis functional connectivity during thirst and drinking in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R623–R631 (2011). This human fMRI study reveals the brain regions involved in generating thirst.

    Article  CAS  PubMed  Google Scholar 

  59. Egan, G. et al. Neural correlates of the emergence of consciousness of thirst. Proc. Natl Acad. Sci. USA 100, 15241–15246 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Saker, P., Farrell, M. J., Egan, G. F., McKinley, M. J. & Denton, D. A. Overdrinking, swallowing inhibition, and regional brain responses prior to swallowing. Proc. Natl Acad. Sci. USA 113, 12274–12279 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Becker, C. A., Flaisch, T., Renner, B. & Schupp, H. T. From thirst to satiety: the anterior mid-cingulate cortex and right posterior insula indicate dynamic changes in incentive value. Front. Hum. Neurosci. 11, 234 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Duncan, G. E. et al. Metabolic mapping of functional activity in rat brain and pituitary after water deprivation. Neuroendocrinology 49, 489–495 (1989).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  65. 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–R1401 (2008). This anatomical study demonstrates brain regions and circuits involved in generating thirst in rats.

    Article  CAS  PubMed  Google Scholar 

  66. McCormick, D. A. & Bal, T. Sensory gating mechanisms of the thalamus. Curr. Opin. Neurobiol. 4, 550–556 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Andrews, W. H. & Orbach, J. Sodium receptors activating some nerves of perfused rabbit livers. Am. J. Physiol. 227, 1273–1275 (1974).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. Andrews, W. H. & Orbach, J. Effect of osmotic pressure on spontaneous afferent discharge in the nerves of the perfused rabbit liver. Pflugers Arch. 361, 89–94 (1975).

    Article  CAS  PubMed  Google Scholar 

  71. 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 

  72. King, M. S. & Baertschi, A. J. Central neural pathway mediating splanchnic osmosensation. Brain Res. 550, 268–278 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  74. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Andersson, B., Jobin, M. & Olsson, K. A study of thirst and other effects of an increased sodium concentration in the 3rd brain ventricle. Acta Physiol. Scand. 69, 29–36 (1967).

    Article  CAS  PubMed  Google Scholar 

  77. McKinley, M. J., Blaine, E. H. & Denton, D. A. Brain osmoreceptors, cerebrospinal fluid electrolyte composition and thirst. Brain Res. 70, 532–537 (1974).

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Olsson, K. Further evidence for the importance of CSF Na+ concentration in central control of fluid balance. Acta Physiol. Scand. 88, 183–188 (1973).

    Article  CAS  PubMed  Google Scholar 

  80. Olsson, K. Attenuation of dehydrative thirst by lowering of the CSF [Na+]. Acta Physiol. Scand. 94, 536–538 (1975).

    Article  CAS  PubMed  Google Scholar 

  81. Weisinger, R. S., Considine, P., Denton, D. A. & McKinley, M. J. Rapid effect of change in cerebrospinal fluid sodium concentration on salt appetite. Nature 280, 490–491 (1979).

    Article  CAS  PubMed  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. Voisin, D. L. & Bourque, C. W. Integration of sodium and osmosensory signals in vasopressin neurons. Trends Neurosci. 25, 199–205 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Noda, M. & Hiyama, T. Y. Sodium sensing in the brain. Pflugers Arch. 467, 465–474 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Voisin, D. L., Chakfe, Y. & Bourque, C. W. Coincident detection of CSF Na+ and osmotic pressure in osmoregulatory neurons of the supraoptic nucleus. Neuron 24, 453–460 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Miller, R. L. & Loewy, A. D. ENaC γ-expressing astrocytes in the circumventricular organs, white matter, and ventral medullary surface: sites for Na+ regulation by glial cells. J. Chem. Neuroanat. 53, 72–80 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Miller, R. L., Wang, M. H., Gray, P. A., Salkoff, L. B. & Loewy, A. D. ENaC-expressing neurons in the sensory circumventricular organs become c-Fos activated following systemic sodium changes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R1141–R1152 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ruiz, C., Gutknecht, S., Delay, E. & Kinnamon, S. Detection of NaCl and KCl in TRPV1 knockout mice. Chemical Senses 31, 813–820 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Teruyama, R., Sakuraba, M., Wilson, L. L., Wandrey, N. E. & Armstrong, W. E. Epithelial Na+ sodium channels in magnocellular cells of the rat supraoptic and paraventricular nuclei. Am. J. Physiol. Endocrinol. Metab. 302, E273–E285 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hiyama, T. Y. et al. Autoimmunity to the sodium-level sensor in the brain causes essential hypernatremia. Neuron 66, 508–522 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Hiyama, T. Y., Watanabe, E., Okado, H. & Noda, M. The subfornical organ is the primary locus of sodium-level sensing by Nax sodium channels for the control of salt-intake behavior. J. Neurosci. 24, 9276–9281 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hiyama, T. Y. et al. Na(x) channel involved in CNS sodium-level sensing. Nat. Neurosci. 5, 511–512 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Matsumoto, M. et al. Channel properties of Nax expressed in neurons. PLoS ONE 10, e0126109 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Goldin, A. L. Resurgence of sodium channel research. Annu. Rev. Physiol. 63, 871–894 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Bourque, C. W., Voisin, D. L. & Chakfe, Y. Stretch-inactivated cation channels: cellular targets for modulation of osmosensitivity in supraoptic neurons. Progress Brain Res. 139, 85–94 (2002).

    Article  CAS  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  99. Desson, S. E. & Ferguson, A. V. Interleukin 1beta modulates rat subfornical organ neurons as a result of activation of a non-selective cationic conductance. J. Physiol. 550, 113–122 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Amin, M. S. et al. Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1787–R1797 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Watanabe, E. et al. Nav2/NaG channel is involved in control of salt-intake behavior in the CNS. J. Neurosci. 20, 7743–7751 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Coble, J. P., Grobe, J. L., Johnson, A. K. & Sigmund, C. D. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R238–R249 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Mimee, A., Smith, P. M. & Ferguson, A. V. Circumventricular organs: targets for integration of circulating fluid and energy balance signals? Physiol. Behav. 121, 96–102 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Zimmerman, C. A. et al. Thirst neurons anticipate the homeostatic consequences of eating and drinking. Nature 537, 680–684 (2016). This study demonstrates that thirst-promoting SFO neurons are required for prandial thirst.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Miselis, R. R., Shapiro, R. E. & Hand, P. J. Subfornical organ efferents to neural systems for control of body water. Science 205, 1022–1025 (1979).

    Article  CAS  PubMed  Google Scholar 

  106. Nissen, R., Bourque, C. W. & Renaud, L. P. Membrane properties of organum vasculosum lamina terminalis neurons recorded in vitro. Am. J. Physiol. 264, R811–R815 (1993).

    CAS  PubMed  Google Scholar 

  107. Kinsman, B. J., Simmonds, S. S., Browning, K. N. & Stocker, S. D. Organum vasculosum of the lamina terminalis detects NaCl to elevate sympathetic nerve activity and blood pressure. Hypertension 69, 163–170 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Grob, M., Drolet, G. & Mouginot, D. Specific Na+ sensors are functionally expressed in a neuronal population of the median preoptic nucleus of the rat. J. Neurosci. 24, 3974–3984 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tremblay, C. et al. Neuronal sodium leak channel is responsible for the detection of sodium in the rat median preoptic nucleus. J. Neurophysiol. 105, 650–660 (2011).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  112. Camacho, A. & Phillips, M. I. Horseradish peroxidase study in rat of the neural connections of the organum vasculosum of the lamina terminalis. Neurosci. Lett. 25, 201–204 (1981).

    Article  CAS  PubMed  Google Scholar 

  113. Oka, Y., Ye, M. & Zuker, C. S. Thirst driving and suppressing signals encoded by distinct neural populations in the brain. Nature 520, 349–352 (2015). This study demonstrates that SFO neurons containing nitric oxide synthase (NOS) promote thirst.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gizowski, C., Zaelzer, C. & Bourque, C. W. Clock-driven vasopressin neurotransmission mediates anticipatory thirst prior to sleep. Nature 537, 685–688 (2016). This study demonstrates that thirst prior to sleep is driven by the circadian clock.

    Article  CAS  PubMed  Google Scholar 

  115. McKinley, M. J. et al. The median preoptic nucleus: front and centre for the regulation of body fluid, sodium, temperature, sleep and cardiovascular homeostasis. Acta Physiol. 214, 8–32 (2015).

    Article  CAS  Google Scholar 

  116. Saper, C. B. & Levisohn, D. Afferent connections of the median preoptic nucleus in the rat: anatomical evidence for a cardiovascular integrative mechanism in the anteroventral third ventricular (AV3V) region. Brain Res. 288, 21–31 (1983).

    Article  CAS  PubMed  Google Scholar 

  117. Lind, R. W., Van Hoesen, G. W. & Johnson, A. K. An HRP study of the connections of the subfornical organ of the rat. J. Comp. Neurol. 210, 265–277 (1982).

    Article  CAS  PubMed  Google Scholar 

  118. Nation, H. L., Nicoleau, M., Kinsman, B. J., Browning, K. N. & Stocker, S. D. DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite. J. Neurophysiol. 115, 3123–3129 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Abbott, S. B., Machado, N. L., Geerling, J. C. & Saper, C. B. Reciprocal control of drinking behavior by median preoptic neurons in mice. J. Neurosci. 36, 8228–8237 (2016). This study demonstrates that optogenetic activation of glutamatergic MnPO/OVLT neurons drives thirst.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Allen, W. E. et al. Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357, 1149–1155 (2017). This study demonstrates that MnPO neurons encode the negative valence associated with thirst.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  123. Stricker, E. M. Osmoregulation and volume regulation in rats: inhibition of hypovolemic thirst by water. Am. J. Physiol. 217, 98–105 (1969).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  125. Kucharczyk, J., Assaf, S. Y. & Mogenson, G. J. Differential effects of brain lesions on thirst induced by the administration of angiotensin-II to the preoptic region, subfornical organ and anterior third ventricle. Brain Res. 108, 327–337 (1976).

    Article  CAS  PubMed  Google Scholar 

  126. Thrasher, T. N., Simpson, J. B. & Ramsay, D. J. Lesions of the subfornical organ block angiotensin-induced drinking in the dog. Neuroendocrinology 35, 68–72 (1982).

    Article  CAS  PubMed  Google Scholar 

  127. Johnson, A. K. & Buggy, J. Periventricular preoptic-hypothalamus is vital for thirst and normal water economy. Am. J. Physiol. 234, R122–R129 (1978).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  129. 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).

    Article  CAS  PubMed  Google Scholar 

  130. Mangiapane, M. L., Thrasher, T. N., Keil, L. C., Simpson, J. B. & Ganong, W. F. Deficits in drinking and vasopressin secretion after lesions of the nucleus medianus. Neuroendocrinology 37, 73–77 (1983).

    Article  CAS  PubMed  Google Scholar 

  131. Johnson, A. K., Cunningham, J. T. & Thunhorst, R. L. Integrative role of the lamina terminalis in the regulation of cardiovascular and body fluid homeostasis. Clin. Exp. Pharmacol. Physiol. 23, 183–191 (1996).

    Article  CAS  PubMed  Google Scholar 

  132. McKinley, M. J. et al. Efferent neural pathways of the lamina terminalis subserving osmoregulation. Progress Brain Res. 91, 395–402 (1992).

    Article  CAS  Google Scholar 

  133. 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).

    Article  PubMed  Google Scholar 

  134. Ciura, S., Liedtke, W. & Bourque, C. W. Hypertonicity sensing in organum vasculosum lamina terminalis neurons: a mechanical process involving TRPV1 but not TRPV4. J. Neurosci. 31, 14669–14676 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zaelzer, C. et al. ΔN-TRPV1: a molecular co-detector of body temperature and osmotic stress. Cell Rep. 13, 23–30 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Sharif-Naeini, R., Ciura, S., Zhang, Z. & Bourque, C. W. Contribution of TRPV channels to osmosensory transduction, thirst, and vasopressin release. Kidney Int. 73, 811–815 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Sudbury, J. R., Ciura, S., Sharif-Naeini, R. & Bourque, C. W. Osmotic and thermal control of magnocellular neurosecretory neurons — role of an N-terminal variant of trpv1. Eur. J. Neurosci. 32, 2022–2030 (2010).

    Article  PubMed  Google Scholar 

  138. Kinsman, B. et al. Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R1092–R1100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 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).

    Article  CAS  PubMed  Google Scholar 

  140. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Choe, K. Y., Olson, J. E. & Bourque, C. W. Taurine release by astrocytes modulates osmosensitive glycine receptor tone and excitability in the adult supraoptic nucleus. J. Neurosci. 32, 12518–12527 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Choe, K. Y., Trudel, E. & Bourque, C. W. Effects of salt loading on the regulation of rat hypothalamic magnocellular neurosecretory cells by ionotropic GABA and glycine receptors. J Neuroendocrinol 28 (2016).

  143. Hussy, N., Deleuze, C., Desarmenien, M. G. & Moos, F. C. Osmotic regulation of neuronal activity: a new role for taurine and glial cells in a hypothalamic neuroendocrine structure. Prog. Neurobiol. 62, 113–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Prager-Khoutorsky, M. & Bourque, C. W. Anatomical organization of the rat organum vasculosum laminae terminalis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R324–R337 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Hochstenbach, S. L. & Ciriello, J. Effect of lesions of forebrain circumventricular organs on c-fos expression in the central nervous system to plasma hypernatremia. Brain Res. 713, 17–28 (1996).

    Article  CAS  PubMed  Google Scholar 

  146. Lechner, S. G. et al. The molecular and cellular identity of peripheral osmoreceptors. Neuron 69, 332–344 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Russell, P. J., Abdelaal, A. E. & Mogenson, G. J. Graded levels of hemorrhage, thirst and angiotensin II in the rat. Physiol. Behav. 15, 117–119 (1975).

    Article  CAS  PubMed  Google Scholar 

  148. Fitzsimons, J. T. Drinking by rats depleted of body fluid without increase in osmotic pressure. J. Physiol. 159, 297–309 (1961).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Joris, L., Dab, I. & Quinton, P. M. Elemental composition of human airway surface fluid in healthy and diseased airways. Am. Rev. Respir. Dis. 148, 1633–1637 (1993).

    Article  CAS  PubMed  Google Scholar 

  150. Zardetto-Smith, A. M., Thunhorst, R. L., Cicha, M. Z. & Johnson, A. K. Afferent signaling and forebrain mechanisms in the behavioral control of extracellular fluid volume. Ann. NY Acad. Sci. 689, 161–176 (1993).

    Article  CAS  PubMed  Google Scholar 

  151. Fitzsimons, J. T. Angiotensin, thirst, and sodium appetite. Physiol Rev. 78, 583–686 (1998).

    Article  CAS  PubMed  Google Scholar 

  152. Stocker, S. D., Stricker, E. M. & Sved, A. F. Arterial baroreceptors mediate the inhibitory effect of acute increases in arterial blood pressure on thirst. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1718–R1729 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. Stocker, S. D., Stricker, E. M. & Sved, A. F. Acute hypertension inhibits thirst stimulated by ANG II, hyperosmolality, or hypovolemia in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R214–R224 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Stricker, E. M. & Sved, A. F. Controls of vasopressin secretion and thirst: similarities and dissimilarities in signals. Physiol. Behav. 77, 731–736 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Dampney, R. A., Polson, J. W., Potts, P. D., Hirooka, Y. & Horiuchi, J. Functional organization of brain pathways subserving the baroreceptor reflex: studies in conscious animals using immediate early gene expression. Cell. Mol. Neurobiol. 23, 597–616 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Thunhorst, R. L., Xu, Z., Cicha, M. Z., Zardetto-Smith, A. M. & Johnson, A. K. Fos expression in rat brain during depletion-induced thirst and salt appetite. Am. J. Physiol. 274, R1807–R1814 (1998).

    CAS  PubMed  Google Scholar 

  157. Badoer, E., McKinley, M. J., Oldfield, B. J. & McAllen, R. M. Distribution of hypothalamic, medullary and lamina terminalis neurons expressing Fos after hemorrhage in conscious rats. Brain Res. 582, 323–328 (1992).

    Article  CAS  PubMed  Google Scholar 

  158. Potts, P. D., Ludbrook, J., Gillman-Gaspari, T. A., Horiuchi, J. & Dampney, R. A. Activation of brain neurons following central hypervolaemia and hypovolaemia: contribution of baroreceptor and non-baroreceptor inputs. Neuroscience 95, 499–511 (2000).

    Article  CAS  PubMed  Google Scholar 

  159. Godino, A., Giusti-Paiva, A., Antunes-Rodrigues, J. & Vivas, L. Neurochemical brain groups activated after an isotonic blood volume expansion in rats. Neuroscience 133, 493–505 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Howe, B. M., Bruno, S. B., Higgs, K. A., Stigers, R. L. & Cunningham, J. T. FosB expression in the central nervous system following isotonic volume expansion in unanesthetized rats. Exp. Neurol. 187, 190–198 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Randolph, R. R., Li, Q., Curtis, K. S., Sullivan, M. J. & Cunningham, J. T. Fos expression following isotonic volume expansion of the unanesthetized male rat. Am. J. Physiol. 274, R1345–R1352 (1998).

    CAS  PubMed  Google Scholar 

  162. Gizowski, C. & Bourque, C. W. Neurons that drive and quench thirst. Science 357, 1092–1093 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Simpson, J. B. & Routtenberg, A. Subfornical organ: a dipsogenic site of action of angiotensin II. Science 201, 379–381 (1978).

    Article  CAS  PubMed  Google Scholar 

  164. Simpson, J. B. & Routtenberg, A. Subfornical organ: site of drinking elicitation by angiotensin II. Science 181, 1172–1175 (1973).

    Article  CAS  PubMed  Google Scholar 

  165. 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).

    Article  CAS  PubMed  Google Scholar 

  166. Kuwahara, K. & Nakao, K. Regulation and significance of atrial and brain natriuretic peptides as cardiac hormones. Endocr. J. 57, 555–565 (2010).

    Article  CAS  PubMed  Google Scholar 

  167. Ehrlich, K. J. & Fitts, D. A. Atrial natriuretic peptide in the subfornical organ reduces drinking induced by angiotensin or in response to water deprivation. Behav. Neurosci. 104, 365–372 (1990).

    Article  CAS  PubMed  Google Scholar 

  168. Stanhewicz, A. E. & Kenney, W. L. Determinants of water and sodium intake and output. Nutr. Rev. 73 (Suppl. 2), 73–82 (2015).

    Article  PubMed  Google Scholar 

  169. Stricker, E. M. & Stricker, M. L. Pre-systemic controls of fluid intake and vasopressin secretion. Physiol. Behav. 103, 86–88 (2011).

    Article  CAS  PubMed  Google Scholar 

  170. Fitzsimons, T. J. & Le Magnen, J. Eating as a regulatory control of drinking in the rat. J. Comp. Physiol. Psychol. 67, 273–283 (1969).

    Article  CAS  PubMed  Google Scholar 

  171. Mandelblat-Cerf, Y. et al. Bidirectional anticipation of future osmotic challenges by vasopressin neurons. Neuron 93, 57–65 (2017).

    Article  CAS  PubMed  Google Scholar 

  172. Hatton, G. I. & Almli, C. R. Plasma osmotic pressure and volume changes as determinants of drinking thresholds. Physiol. Behav. 4, 207–214 (1969).

    Article  Google Scholar 

  173. Gamble, J. L., Putnam, M. C. & McKhann, C. F. The optimal water requirement in renal functions: 1. Measurements of water drinking by rats according to increments of urea and of several salts in the food. Am. J. Physiol. 88, 571–580 (1929).

    Article  CAS  Google Scholar 

  174. Kraly, F. S., Kim, Y. M., Dunham, L. M. & Tribuzio, R. A. Drinking after intragastric NaCl without increase in systemic plasma osmolality in rats. Am. J. Physiol. 269, R1085–R1092 (1995).

    CAS  PubMed  Google Scholar 

  175. Stricker, E. M., Huang, W. & Sved, A. F. Early osmoregulatory signals in the control of water intake and neurohypophyseal hormone secretion. Physiol. Behav. 76, 415–421 (2002).

    Article  CAS  PubMed  Google Scholar 

  176. Manesh, R., Hoffmann, M. L. & Stricker, E. M. Water ingestion by rats fed a high-salt diet may be mediated, in part, by visceral osmoreceptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R1742–R1749 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Krause, E. G., de Kloet, A. D. & Sakai, R. R. Post-ingestive signals and satiation of water and sodium intake of male rats. Physiol. Behav. 99, 657–662 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Kobashi, M. & Adachi, A. Projection of nucleus tractus solitarius units influenced by hepatoportal afferent signal to parabrachial nucleus. J. Autonom. Nerv. System 16, 153–158 (1986).

    Article  CAS  Google Scholar 

  179. Kobashi, M. & Adachi, A. Convergence of hepatic osmoreceptive inputs on sodium-responsive units within the nucleus of the solitary tract of the rat. J. Neurophysiol. 54, 212–219 (1985).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  181. Morita, H. et al. Fos induction in rat brain neurons after stimulation of the hepatoportal Na-sensitive mechanism. Am. J. Physiol. 272, R913–923 (1997).

    CAS  PubMed  Google Scholar 

  182. Starbuck, E. M. & Fitts, D. A. Influence of the subfornical organ on meal-associated drinking in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R669–R677 (2001).

    Article  CAS  PubMed  Google Scholar 

  183. Gu, G. B. & Ju, G. The parabrachio-subfornical organ projection in the rat. Brain Res. Bull. 38, 41–47 (1995).

    Article  CAS  PubMed  Google Scholar 

  184. Han, Z. S., Gu, G. B., Sun, C. Q. & Ju, G. Convergence of somatosensory and baroreceptive inputs onto parabrachio-subfornical organ neurons in the rat: an electrophysiological study. Brain Res. 566, 239–247 (1991).

    Article  CAS  PubMed  Google Scholar 

  185. McKinley, M. J. et al. The sensory circumventricular organs of the mammalian brain. Adv. Anat. Embryol. Cell Biol. 172, III–XII (2003).

    CAS  PubMed  Google Scholar 

  186. Sladek, C. D. & Johnson, A. K. Integration of thermal and osmotic regulation of water homeostasis: the role of TRPV channels. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R669–R678 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Bel'skaya, L. V., Kosenok, V. K. & Sarf, E. A. Chronophysiological features of the normal mineral composition of human saliva. Arch. Oral Biol. 82, 286–292 (2017).

    Article  CAS  PubMed  Google Scholar 

  188. Lund, J. P., Barker, J. H., Dellow, P. G. & Stevenson, J. A. Water intake of normal and desalivate rats on exposure to environmental heat. Can. J. Physiol. Pharmacol. 47, 849–852 (1969).

    Article  CAS  PubMed  Google Scholar 

  189. Grace, J. E. & Stevenson, J. A. Thermogenic drinking in the rat. Am. J. Physiol. 220, 1009–1015 (1971).

    Article  CAS  PubMed  Google Scholar 

  190. Box, B. M., Montis, F., Yeomans, C. & Stevenson, J. A. Thermogenic drinking in cold-acclimated rats. Am. J. Physiol. 225, 162–165 (1973).

    Article  CAS  PubMed  Google Scholar 

  191. Barney, C. C. & Folkerts, M. M. Thermal dehydration-induced thirst in rats: role of body temperature. Am. J. Physiol. 269, R557–R564 (1995).

    CAS  PubMed  Google Scholar 

  192. Morrison, S. F. & Nakamura, K. Central neural pathways for thermoregulation. Front. Biosci. 16, 74–104 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  193. Palkar, R., Lippoldt, E. K. & McKemy, D. D. The molecular and cellular basis of thermosensation in mammals. Curr. Opin. Neurobiol. 34, 14–19 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Schepers, R. J. & Ringkamp, M. Thermoreceptors and thermosensitive afferents. Neurosci. Biobehav. Rev. 34, 177–184 (2010).

    Article  CAS  PubMed  Google Scholar 

  195. Craig, A. D., Bushnell, M. C., Zhang, E. T. & Blomqvist, A. A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773 (1994).

    Article  CAS  PubMed  Google Scholar 

  196. Nakamura, K. & Morrison, S. F. A thermosensory pathway that controls body temperature. Nat. Neurosci. 11, 62–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  197. Jessen, C., Feistkorn, G. & Nagel, A. Temperature sensitivity of skeletal muscle in the conscious goat. J. Appl. Physiol. 54, 880–886 (1983).

    Article  CAS  PubMed  Google Scholar 

  198. Fajardo, O., Meseguer, V., Belmonte, C. & Viana, F. TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. J. Neurosci. 28, 7863–7875 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Riedel, W. Warm receptors in the dorsal abdominal wall of the rabbit. Pflugers Arch. 361, 205–206 (1976).

    Article  CAS  PubMed  Google Scholar 

  200. Rawson, R. O. & Quick, K. P. Localization of intra-abdominal thermoreceptors in the ewe. J. Physiol. 222, 665–667 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Adelson, D. W., Wei, J. Y. & Kruger, L. Warm-sensitive afferent splanchnic C-fiber units in vitro. J. Neurophysiol. 77, 2989–3002 (1997).

    Article  CAS  PubMed  Google Scholar 

  202. Wit, A. & Wang, S. C. Temperature-sensitive neurons in preoptic-anterior hypothalamic region: effects of increasing ambient temperature. Am. J. Physiol. 215, 1151–1159 (1968).

    Article  CAS  PubMed  Google Scholar 

  203. Takamata, A., Mack, G. W., Stachenfeld, N. S. & Nadel, E. R. Body temperature modification of osmotically induced vasopressin secretion and thirst in humans. Am. J. Physiol. 269, R874–880 (1995).

    CAS  PubMed  Google Scholar 

  204. Boulant, J. A. Cellular mechanisms of temperature sensitivity in hypothalamic neurons. Progress Brain Res. 115, 3–8 (1998).

    Article  CAS  Google Scholar 

  205. Fealey, R. D. Interoception and autonomic nervous system reflexes thermoregulation. Handb. Clin. Neurol. 117, 79–88 (2013).

    Article  PubMed  Google Scholar 

  206. Morrison, S. F. Central control of body temperature. F1000Res. 5, 880 (2016).

    Article  CAS  Google Scholar 

  207. Boulant, J. A. Hypothalamic mechanisms in thermoregulation. Fed. Proc. 40, 2843–2850 (1981).

    CAS  PubMed  Google Scholar 

  208. Barbour, H. G. Die wirkung unmittelbarer erwarmung und abkuhlung der warmezentra auf die korpertemperatur [German]. Arch. Exp. Path. Pharmak. 70, 1–15 (1912).

    Article  Google Scholar 

  209. Hammouda, M. The central and the reflex mechanism of panting. J. Physiol. 77, 319–336 (1933).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Magoun, H. W., Harrison, F., Brobeck J. R., Ranson, S. W. & Paolini, P. Activation of heat loss mechanisms by local heating of the brain. J. Neurophysiol. 87, 885–905 (1986).

    Google Scholar 

  211. Jacobson, F. H. & Squires, R. D. Thermoregulatory responses of the cat to preoptic and environmental temperatures. Am. J. Physiol. 218, 1575–1582 (1970).

    Article  CAS  PubMed  Google Scholar 

  212. Szczepanska-Sadowska, E. Plasma ADH increase and thirst suppression elicited by preoptic heating in the dog. Am. J. Physiol. 226, 155–161 (1974).

    Article  CAS  PubMed  Google Scholar 

  213. Morrison, S. F., Nakamura, K. & Madden, C. J. Central control of thermogenesis in mammals. Exp. Physiol. 93, 773–797 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Tan, C. L. et al. Warm-sensitive neurons that control body temperature. Cell 167, 47–59.e15 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Nakamura, K. & Morrison, S. F. A thermosensory pathway mediating heat-defense responses. Proc. Natl Acad. Sci. USA 107, 8848–8853 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Andersson, B. & Larsson, B. Influence of local temperature changes in the preoptic area and rostral hypothalamus on the regulation of food and water intake. Acta Physiol. Scand. 52, 75–89 (1961).

    Article  CAS  PubMed  Google Scholar 

  217. Trudel, E. & Bourque, C. W. Circadian modulation of osmoregulated firing in rat supraoptic nucleus neurones. J. Neuroendocrinol. 24, 577–586 (2012).

    Article  CAS  PubMed  Google Scholar 

  218. Moon, D. G. et al. Antidiuretic hormone in elderly male patients with severe nocturia: a circadian study. BJU Int. 94, 571–575 (2004).

    Article  CAS  PubMed  Google Scholar 

  219. Miller, M. Nocturnal polyuria in older people: pathophysiology and clinical implications. J. Am. Geriatr. Soc. 48, 1321–1329 (2000).

    Article  CAS  PubMed  Google Scholar 

  220. Tokonami, N. et al. Local renal circadian clocks control fluid-electrolyte homeostasis and BP. J. Am. Soc. Nephrol. 25, 1430–1439 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Firsov, D., Tokonami, N. & Bonny, O. Role of the renal circadian timing system in maintaining water and electrolytes homeostasis. Mol. Cell. Endocrinol. 349, 51–55 (2012).

    Article  CAS  PubMed  Google Scholar 

  222. Asplund, R. Nocturia, nocturnal polyuria, and sleep quality in the elderly. J. Psychosom. Res. 56, 517–525 (2004).

    Article  CAS  PubMed  Google Scholar 

  223. Windle, R. J., Forsling, M. L. & Guzek, J. W. Daily rhythms in the hormone content of the neurohypophysial system and release of oxytocin and vasopressin in the male rat: effect of constant light. J. Endocrinol. 133, 283–290 (1992).

    Article  CAS  PubMed  Google Scholar 

  224. Trudel, E. & Bourque, C. W. Central clock excites vasopressin neurons by waking osmosensory afferents during late sleep. Nat. Neurosci. 13, 467–474 (2010).

    Article  CAS  PubMed  Google Scholar 

  225. Spiteri, N. J. Circadian patterning of feeding, drinking and activity during diurnal food access in rats. Physiol. Behav. 28, 139–147 (1982).

    Article  CAS  PubMed  Google Scholar 

  226. Satinoff, E. & Prosser, R. A. Suprachiasmatic nuclear lesions eliminate circadian rhythms of drinking and activity, but not of body temperature, in male rats. J. Biol. Rhythms 3, 1–22 (1988).

    Article  CAS  PubMed  Google Scholar 

  227. Johnson, R. F., Beltz, T. G., Thunhorst, R. L. & Johnson, A. K. Investigations on the physiological controls of water and saline intake in C57BL/6 mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R394–R403 (2003).

    Article  CAS  PubMed  Google Scholar 

  228. Lee, J. E. et al. Endogenous peptide discovery of the rat circadian clock: a focused study of the suprachiasmatic nucleus by ultrahigh performance tandem mass spectrometry. Mol. Cell. Proteom. 9, 285–297 (2010).

    CAS  Google Scholar 

  229. Abrahamson, E. E. & Moore, R. Y. Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res. 916, 172–191 (2001).

    Article  CAS  PubMed  Google Scholar 

  230. Kalsbeek, A. & Buijs, R. M. Output pathways of the mammalian suprachiasmatic nucleus: coding circadian time by transmitter selection and specific targeting. Cell Tissue Res. 309, 109–118 (2002).

    Article  CAS  PubMed  Google Scholar 

  231. Moore, R. Y., Speh, J. C. & Leak, R. K. Suprachiasmatic nucleus organization. Cell Tissue Res. 309, 89–98 (2002).

    Article  CAS  PubMed  Google Scholar 

  232. Appelgren, B., Eriksson, S. & Jonasson, H. Oro-gastro-intestinal inhibition of hypernatremia-induced drinking in the goat. Acta Physiol. Scand. 115, 273–280 (1982).

    Article  CAS  PubMed  Google Scholar 

  233. Wood, R. J., Rolls, E. T. & Rolls, B. J. Physiological mechanisms for thirst in the nonhuman primate. Am. J. Physiol. 242, R423–R428 (1982).

    CAS  PubMed  Google Scholar 

  234. Krashes, M. J. Physiology: Forecast for water balance. Nature 537, 626–627 (2016).

    Article  CAS  PubMed  Google Scholar 

  235. Zocchi, D., Wennemuth, G. & Oka, Y. The cellular mechanism for water detection in the mammalian taste system. Nat. Neurosci. 20, 927–933 (2017).

    Article  CAS  PubMed  Google Scholar 

  236. Blass, E. M., Jobaris, R. & Hall, W. G. Oropharyngeal control of drinking in rats. J. Comp. Physiol. Psychol. 90, 909–916 (1976).

    Article  CAS  PubMed  Google Scholar 

  237. Maddison, S., Wood, R. J., Rolls, E. T., Rolls, B. J. & Gibbs, J. Drinking in the rhesus monkey: peripheral factors. J. Comp. Physiol. Psychol. 94, 365–374 (1980).

    Article  CAS  PubMed  Google Scholar 

  238. Davis, J. D., Smith, G. P. & McCann, D. P. The control of water and sodium chloride intake by postingestional and orosensory stimulation in water-deprived rats. Physiol. Behav. 75, 7–14 (2002).

    Article  CAS  PubMed  Google Scholar 

  239. Paintal, A. S. Impulses in vagal afferent fibres from stretch receptors in the stomach and their role in the peripheral mechanism of hunger. Nature 172, 1194–1195 (1953).

    Article  CAS  PubMed  Google Scholar 

  240. Malbert, C. H. & Leitner, L. M. Mechanoreceptors sensitive to flow at the gastroduodenal junction of the cat. Am. J. Physiol. 265, G310–G313 (1993).

    CAS  PubMed  Google Scholar 

  241. Paintal, A. S. A study of gastric stretch receptors; their role in the peripheral mechanism of satiation of hunger and thirst. J. Physiol. 126, 255–270 (1954).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Raybould, H. E., Gayton, R. J. & Dockray, G. J. CNS effects of circulating CCK8: involvement of brainstem neurones responding to gastric distension. Brain Res. 342, 187–190 (1985).

    Article  CAS  PubMed  Google Scholar 

  243. Olson, B. R. et al. c-Fos expression in rat brain and brainstem nuclei in response to treatments that alter food intake and gastric motility. Mol. Cell. Neurosci. 4, 93–106 (1993).

    Article  CAS  PubMed  Google Scholar 

  244. Hyde, T. M. & Miselis, R. R. Area postrema and adjacent nucleus of the solitary tract in water and sodium balance. Am. J. Physiol. 247, R173–R182 (1984).

    CAS  PubMed  Google Scholar 

  245. Curtis, K. S., Verbalis, J. G. & Stricker, E. M. Area postrema lesions in rats appear to disrupt rapid feedback inhibition of fluid intake. Brain Res. 726, 31–38 (1996).

    Article  CAS  PubMed  Google Scholar 

  246. Curtis, K. S. & Stricker, E. M. Enhanced fluid intake by rats after capsaicin treatment. Am. J. Physiol. 272, R704–R709 (1997).

    CAS  PubMed  Google Scholar 

  247. Hajat, S., Vardoulakis, S., Heaviside, C. & Eggen, B. Climate change effects on human health: projections of temperature-related mortality for the UK during the 2020s, 2050s and 2080s. J. Epidemiol. Commun. Health 68, 641–648 (2014).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' work is supported by a Foundation Grant from the Canadian Institutes of Health Research (CIHR, FDN 143337), an operating grant from the Heart and Stroke Foundation of Canada (G-16-00014197), a James McGill Chair to C.W.B., and a Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award to C.G. The Research Institute of the McGill University Health Centre receives generous funding from the Fonds de Recherche Québec Santé.

Author information

Authors and Affiliations

Authors

Contributions

Both authors researched the data for the article, discussed its content and contributed to writing and editing the manuscript before submission.

Corresponding author

Correspondence to Charles W. Bourque.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Adipsia

Lack of thirst even under conditions that normally stimulate thirst, such as dehydration.

Vasomotor tone

The degree of tension in the smooth muscles that surround blood vessels.

Tonicity

A measure of a solution's potential to attract or repel water across a semipermeable membrane and thus generate osmotic pressure. Solutions with a higher total concentration of solutes will attract water and vice versa.

Anterior cingulate cortex

ACC. The anterior part of the cingulate cortex, which is a midline structure that lies dorsal to the corpus callosum. The ACC has a role in regulating body homeostasis and higher-order functions such as reward anticipation and decision making.

Affective motivation

Motivation to complete a task driven by a particular emotion.

Primordial emotions

Instinctive processes that drive behaviour to maintain optimal body homeostasis (for example, thirst, hunger and pain).

Insular cortex

(IC). The portion of the cerebral cortex within the lateral sulcus. It is believed to have roles in consciousness, emotions and regulating body homeostasis.

Interoceptive sensory modalities

Sensory signals related to the internal state of the body and viscera (for example, stomach distension, temperature and acidity).

Cortex

The outermost portion of the brain, thought to mediate consciousness, memory, attention, awareness, language and thought.

Prefrontal regions

The anterior portions of the brain.

Autoradiographic metabolic trapping

A method of visualizing glucose utilization in the brain. It is used as a surrogate to indicate that neurons have been electrically activated.

Immediate early gene c-Fos

A gene that is transcribed and translated transiently and rapidly in response to increased cellular calcium. Expression of an immediate early gene often indicates that neurons have been electrically activated.

Somatosensory information

Signals that encode information relating to sensory modalities such as hearing, touch and vision.

Action potentials

All-or-none electrical impulses generated at the soma of a neuron. An action potential is rapidly conducted to the axon terminal, where it can activate voltage-gated calcium channels and stimulate transmitter release onto a distinct target neuron.

Membrane potential

The electrical potential of a cell.

Organum vasculosum lamina terminalis

(OVLT). A midline brain structure located in the ventral part of the lamina terminalis and contained within the preoptic area of the hypothalamus.

Subfornical organ

(SFO). A midline brain structure that is located at the dorsal aspect of the lamina terminalis and attached to the hippocampal commissure.

Circumventricular organs

Regions of the brain that lack a blood–brain barrier, such as the organum vasculosum lamina terminalis, subfornical organ and area postrema. Neurons in these regions are directly exposed to circulating substances in the blood.

Depolarized

A term used to designate that the membrane potential of a cell has become relatively more positive. In neurons, depolarization commonly causes an increase in electrical excitability.

Median preoptic nucleus

(MnPO). A midline region of the hypothalamus that is part of the lamina terminalis and lies directly above the organum vasculosum lamina terminalis. The MnPO is thought to be an integrative nucleus involved in regulating blood pressure, fluid balance and body temperature.

Optogenetic

A technique that uses light to activate a rhodopsin channel for the purpose of causing depolarization or hyperpolarization. The rhodopsin expression is directed by genetic approaches that enable the control of specific subsets of neurons.

Chemogenetic

A technique that uses a modified G-protein receptor that is specifically activated by a unique and otherwise biologically inactive drug. Because receptor expression can be targeted to specific cells, the drug can be used to control the activity of specific subsets of neurons.

Third ventricle

One of four interconnected cavities in the brain that are filled with cerebrospinal fluid. It is a midline ventricle surrounded by the hypothalamus and thalamus.

Fibre photometry

A technique used to detect changes in fluorescence in vivo by use of an implanted fibre-optic microprobe. When targeted to neurons expressing a calcium-sensitive fluorophore, the technique can be used as a surrogate indicator of neuronal activity.

Supraoptic nucleus

(SON). A nucleus within the hypothalamus that contains magnocellular neurosecretory cells. These cells project to the posterior pituitary (neurohypophysis) and release vasopressin and oxytocin into the circulating peripheral blood.

Vagotomy

A procedure that involves removing part of the vagus nerve.

Homeotherms

Organisms that maintain their core body temperature at a stable temperature.

Euhydrated

Having a normal level of body water at rest. This condition implies an absence of absolute or relative excess hydration or dehydration.

Neurohypophysis

The posterior part of the pituitary gland that contains axon terminals originating from magnocellular neurosecretory neurons in the supraoptic nucleus and paraventricular nucleus.

Magnocellular neurosecretory neurons

Neuroendocrine neurons that synthesize either vasopressin or oxytocin within the supraoptic nucleus and paraventricular nucleus.

Active period

The last 2 h of the wake period. Animals ingest significantly more water at this time compared to the basal period.

Basal period

The 2 h period preceding the active period. During the basal period, animals ingest small volumes of water.

Whole-cell currents

Electrical currents generated by the entire cell membrane and recorded by patch clamp electrophysiology.

Negative valence

Aversive or unpleasant emotion associated with an event or condition.

Oropharyngeal afferents

Nerve fibres carrying sensory signals that originate from different tissues in the mouth or pharynx.

Trigeminal nerve

The fifth cranial nerve; it is a sensory and motor nerve that transmits information responsible for much of orofacial sensation and mediates motor functions associated with biting and chewing.

Area postrema

(AP). A midline circumventricular organ in the brain stem that is involved in the detection of circulating substances, the relay of autonomic signals and the control of emesis.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gizowski, C., Bourque, C. The neural basis of homeostatic and anticipatory thirst. Nat Rev Nephrol 14, 11–25 (2018). https://doi.org/10.1038/nrneph.2017.149

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2017.149

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing