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.
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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Strange, K. Cellular volume homeostasis. Adv. Physiol. Educ. 28, 155–159 (2004).
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).
Somero, G. N. Protons, osmolytes, and fitness of internal milieu for protein function. Am. J. Physiol. 251, R197–R213 (1986).
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).
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).
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).
Lang, F. Mechanisms and significance of cell volume regulation. J. Am. Coll. Nutr. 26, 613S–623S (2007).
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).
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).
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).
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).
Saly, V. & Andrew, R. D. CA3 neuron excitation and epileptiform discharge are sensitive to osmolality. J. Neurophysiol. 69, 2200–2208 (1993).
Pasantes-Morales, H. & Tuz, K. Volume changes in neurons: hyperexcitability and neuronal death. Contrib. Nephrol. 152, 221–240 (2006).
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).
Machino, T. & Yoshizawa, T. Brain shrinkage due to acute hypernatremia. Neurology 67, 880 (2006).
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).
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).
Geelen, G. et al. Inhibition of plasma vasopressin after drinking in dehydrated humans. Am. J. Physiol. 247, R968–R971 (1984).
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).
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).
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).
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.
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).
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.
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).
Baylis, P. H. Osmoregulation and control of vasopressin secretion in healthy humans. Am. J. Physiol. 253, R671–R678 (1987).
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.
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).
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).
Emmeluth, C. et al. Natriuresis caused by increased carotid Na+ concentration after renal denervation. Am. J. Physiol. 270, F510–F517 (1996).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
Turlejska, E. & Baker, M. A. Elevated CSF osmolality inhibits thermoregulatory heat loss responses. Am. J. Physiol. 251, R749–R754 (1986).
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).
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).
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).
Robertson, G. L., Shelton, R. L. & Athar, S. The osmoregulation of vasopressin. Kidney Int. 10, 25–37 (1976).
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).
Maresh, C. M. et al. Perceptual responses in the heat after brief intravenous versus oral rehydration. Med. Sci. Sports Exerc. 33, 1039–1045 (2001).
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).
Gilman, A. The relation between blood osmotic pressure, fluid distribution and voluntary water intake. Am. J. Physiol. 120, 323–328 (1937).
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.
Wolf, A. V. Osmometric analysis of thirst in man and dog. Am. J. Physiol., 161 75–86 (1950).
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.
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).
Kuramochi, G. & Kobayashi, I. Regulation of the urine concentration mechanism by the oropharyngeal afferent pathway in man. Am. J. Nephrol. 20, 42–47 (2000).
Dooley, C. P. & Valenzuela, J. E. Duodenal volume and osmoreceptors in the stimulation of human pancreatic secretion. Gastroenterology 86, 23–27 (1984).
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).
Choi-Kwon, S. & Baertschi, A. J. Splanchnic osmosensation and vasopressin: mechanisms and neural pathways. Am. J. Physiol. 261, E18–E25 (1991).
Baertschi, A. J. & Vallet, P. G. Osmosensitivity of the hepatic portal vein area and vasopressin release in rats. J. Physiol. 315, 217–230 (1981).
Adachi, A. Thermosensitive and osmoreceptive afferent fibers in the hepatic branch of the vagus nerve. J. Auton. Nerv. Syst. 10, 269–273 (1984).
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).
Haberich, F. J. Osmoreception in the portal circulation. Fed. Proc. 27, 1137–1141 (1968).
Stricker, E. M. & Hoffmann, M. L. Presystemic signals in the control of thirst, salt appetite, and vasopressin secretion. Physiol. Behav. 91, 404–412 (2007).
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).
Baertschi, A. J. & Pence, R. A. Gut-brain signaling of water absorption inhibits vasopressin in rats. Am. J. Physiol. 268, R236–R247 (1995).
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).
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).
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).
Chwalbinska-Moneta, J. Role of hepatic portal osmoreception in the control of ADH release. Am. J. Physiol. 236, E603–E609 (1979).
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).
Niijima, A. Afferent discharges from osmoreceptors in the liver of the guinea pig. Science 166, 1519–1520 (1969).
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).
Vallet, P. G. & Baertschi, A. J. Spinal afferents for peripheral osmoreceptors in the rat. Brain Res. 239, 271–274 (1982).
Craig, A. D. Interoception: the sense of the physiological condition of the body. Curr. Opin. Neurobiol. 13, 500–505 (2003).
Craig, A. D. A new view of pain as a homeostatic emotion. Trends Neurosci. 26, 303–307 (2003).
Blackshaw, L. A., Brookes, S. J., Grundy, D. & Schemann, M. Sensory transmission in the gastrointestinal tract. Neurogastroenterol. Motil. 19, 1–19 (2007).
Grundy, D. Neuroanatomy of visceral nociception: vagal and splanchnic afferent. Gut 51 (Suppl. 1), i2–i5 (2002).
Grundy, D. Signalling the state of the digestive tract. Auton. Neurosci. 125, 76–80 (2006).
Mei, N. & Garnier, L. Osmosensitive vagal receptors in the small intestine of the cat. J. Auton. Nerv. Syst. 16, 159–170 (1986).
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).
McKinley, M. J. et al. The sensory circumventricular organs of the mammalian brain (Springer, 2003).
Andersson, B. Thirst--and brain control of water balance. Am. Sci. 59, 408–415 (1971).
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).
Buggy, J. & Jonhson, A. K. Preoptic-hypothalamic periventricular lesions: thirst deficits and hypernatremia. Am. J. Physiol. 233, R44–R52 (1977).
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).
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).
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).
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).
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).
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.
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).
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).
Bourque, C. W., Oliet, S. H. & Richard, D. Osmoreceptors, osmoreception, and osmoregulation. Front. Neuroendocrinol. 15, 231–274 (1994).
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.
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.
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).
Nakashima, T., Hori, T., Kiyohara, T. & Shibata, M. Osmosensitivity of preoptic thermosensitive neurons in hypothalamic slices in vitro. Pflugers Arch. 405, 112–117 (1985).
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).
Anderson, J. W., Washburn, D. L. & Ferguson, A. V. Intrinsic osmosensitivity of subfornical organ neurons. Neuroscience 100, 539–547 (2000).
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.
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.
Bourque, C. W. Osmoregulation of vasopressin neurons: a synergy of intrinsic and synaptic processes. Prog. Brain Res. 119, 59–76 (1998).
Qiu, D. L. et al. Effect of hypertonic saline on rat hypothalamic paraventricular nucleus magnocellular neurons in vitro. Neurosci. Lett. 355, 117–120 (2004).
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).
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.
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.
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.
Nilius, B., Owsianik, G., Voets, T. & Peters, J. A. Transient receptor potential cation channels in disease. Physiol. Rev. 87, 165–217 (2007).
Clapham, D. E. SnapShot: mammalian TRP channels. Cell 129, 220 (2007).
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.
Oliet, S. H. & Bourque, C. W. Gadolinium uncouples mechanical detection and osmoreceptor potential in supraoptic neurons. Neuron 16, 175–181 (1996).
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).
Kung, C. A possible unifying principle for mechanosensation. Nature 436, 647–654 (2005).
Christensen, A. P. & Corey, D. P. TRP channels in mechanosensation: direct or indirect activation? Nature Rev. Neurosci. 8, 510–521 (2007).
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).
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).
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).
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).
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).
Honore, E. The neuronal background K2P channels: focus on TREK1. Nature Rev. Neurosci. 8, 251–261 (2007).
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).
Walters, J. K. & Hatton, G. I. Supraoptic neuronal activity in rats during five days of water deprivation. Physiol. Behav. 13, 661–667 (1974).
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).
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).
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).
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).
Bicknell, R. J. Optimizing release from peptide hormone secretory nerve terminals. J. Exp. Biol. 139, 51–65 (1988).
Johnson, A. K. The sensory psychobiology of thirst and salt appetite. Med. Sci. Sports Exerc. 39, 1388–1400 (2007).
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).
Daniels, D. & Fluharty, S. J. Salt appetite: a neurohormonal viewpoint. Physiol. Behav. 81, 319–337 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
Craig, A. D. How do you feel? Interoception: the sense of the physiological condition of the body. Nature Rev. Neurosci. 3, 655–666 (2002).
Robinson, B. W. & Mishkin, M. Alimentary responses to forebrain stimulation in monkeys. Exp. Brain Res. 4, 330–366 (1968).
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.
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).
Sorenson, C. A. & Ellison, G. D. Striatal organization of feeding behavior in the decorticate rat. Exp. Neurol. 29, 162–174 (1970).
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).
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).
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).
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).
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).
Michelini, L. C. The NTS and integration of cardiovascular control during exercise in normotensive and hypertensive individuals. Curr. Hypertens. Rep. 9, 214–221 (2007).
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).
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).
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).
Bie, P., Wamberg, S. & Kjolby, M. Volume natriuresis vs. pressure natriuresis. Acta Physiol. Scand. 181, 495–503 (2004).
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).
DiBona, G. F. Sympathetic nervous system and the kidney in hypertension. Curr. Opin. Nephrol. Hypertens. 11, 197–200 (2002).
Verbalis, J. G., Mangione, M. P. & Stricker, E. M. Oxytocin produces natriuresis in rats at physiological plasma concentrations. Endocrinology 128, 1317–1322 (1991).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Shimizu, H. et al. Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. Neuron 54, 59–72 (2007).
Noda, M. The subfornical organ, a specialized sodium channel, and the sensing of sodium levels in the brain. Neuroscientist 12, 80–91 (2006).
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).
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).
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).
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).
Liamis, G. et al. Clinical and laboratory characteristics of hypernatraemia in an internal medicine clinic. Nephrol. Dial. Transplant. 23, 136–143 (2008).
Smellie, W. S. et al. Best practice in primary care pathology: review 8. J. Clin. Pathol. 60, 740–748 (2007).
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).
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).
Webb, A. K., Phillips, M. J. & Hanson, G. C. Iatrogenic nondiabetic hyperosmolar states. J. R. Soc. Med. 72, 578–586 (1979).
Upadhyay, A., Jaber, B. L. & Madias, N. E. Incidence and prevalence of hyponatremia. Am. J. Med. 119, S30–S35 (2006).
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).
Stiefel, D. & Petzold, A. H2O coma. Neurocrit. Care 6, 67–71 (2007).
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).
Arieff, A. I. Management of hyponatraemia. BMJ 307, 305–308 (1993).
Liedtke, W. et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103, 525–535 (2000).
Liedtke, W. & Friedman, J. M. Abnormal osmotic regulation in trpv4−/− mice. Proc. Natl Acad. Sci. USA 100, 13698–13703 (2003).
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).
Muraki, K. et al. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ. Res. 93, 829–838 (2003).
Birder, L. A. et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nature Neurosci. 5, 856–860 (2002).
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.
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).
Sharif Naeini, R., Ciura, S. & Bourque, C. W. [TRPVs: ion channels that make you thirsty!]. Med. Sci. (Paris) 22, 1035–1037 (2006).
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).
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.
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.
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.
An increase in the flow of urine produced by the kidney.
The excretion of Na+ in urine.
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.
A condition in which the plasma has a lower concentration of free Na+ ions than is normal for the species in question.
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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