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How Does the Brain Sense Osmolality?

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How Does the Brain Sense Osmolality?
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  How Does the Brain Sense Osmolality? Joseph G. Verbalis Professor of Medicine and Physiology, Georgetown University School of Medicine, Washington, DC Body fluid homeostasis is directed atmaintaining the stability of the osmo-lality of body fluids (osmotic ho-meostasis) and the intravascular bloodvolume (volume homeostasis). Os-motic regulation serves to minimizeosmotically induced perturbations incell volume, which has adverse effectson multiple cellular functions. Body fluid osmolality in humans is main-tained between 280 and 295 mOsm/kgH 2 O, representing one of the mosthighly regulated parameters of body physiology. This is accomplishedthrough an integration of thirst, argi-nine vasopressin (AVP) secretion, andrenal responsiveness to AVP. To pre-serve plasma osmolality within suchnarrow tolerances, pituitary AVP se-cretion must vary in response to smallchanges in plasma osmolality, which isachieved through the activation or in-hibition of central osmoreceptor cells.Understanding where and how thebrain senses the osmolality of body flu-ids and transduces this informationinto mechanisms that regulate AVP se-cretion and thirst is the subject of thiscommentary.  WHERE ARE OSMORECEPTORSLOCATED? The pioneering investigations of Verney in the 1940s 1 found infusion of hyperos-motic solutions into blood vessels thatperfusedtheanteriorhypothalamuspro-duced an antidiuresis in dogs, thereby identifying this area as the site of osmo-responsive elements in the brain. Themostparsimoniousexplanationforthesefindings would be that the AVP-secret-ing magnocellular neurons themselvesare the osmoreceptors. Although theseneurons do display osmoreceptive char-acteristics, 2 their location inside theblood–brain barrier does not positionthem to respond quickly to smallchanges in osmolality in the circulation.Subsequent studies strongly implicatedthe circumventricular organ named theorganum vasculosum of the lamina ter-minalis (OVLT), which lacks a blood–brain barrier, as well as areas of the adja-centhypothalamusneartheanteriorwallof the third cerebral ventricle as the siteof the principle brain osmoreceptors.Destructionofthisareaofthebrainabol-ishes both AVP secretion and thirst re-sponses to hyperosmolality in experi-mental animals 3 and in human subjectswith brain damage that infarcts the re-gionaroundtheOVLT,whotypicallyareunable to maintain normal plasma os-molalities even under basal conditions. 4 In contrast to the effects of such lesionsto eliminate both osmotically stimulatedthirst and AVP secretion, diabetes insip-iduscausedbydestructionofthemagno-cellular AVP neurons in the supraoptic(SON) and paraventricular (PVN) nu-clei eliminates dehydration-inducedAVP secretion but not thirst, clearly in-dicating that osmotically stimulatedthirst must be generated proximally tothe AVP-secreting cells themselves (Fig-ure1A).Otherregionshavealsobeenre-ported to contain putative osmorecep-tors, including the hepatic portalcirculation, leading to the suggestionthat osmoreceptors are widely distribut-ed. 5 However, cells in these areas likely act to modulate the activity of the pri-maryOVLTosmoreceptorsbecausethey are not able to maintain osmotically stimulated AVP secretion or thirst afterlesions of the OVLT.Involvement of the OVLT and sur-rounding areas of the anterior hypothal-amusinosmoreceptionisalsosupportedby studies using immunohistochemical Published online ahead of print. Publication dateavailable at www.jasn.org. Correspondence:  Dr. Joseph G. Verbalis, Divisionof Endocrinology and Metabolism, 232 Building D,Georgetown University Medical Center, 3800 Res-ervoir Road NW, Washington, DC 20007. Phone:202-687-2818; Fax: 202-444-7797; E-mail: verbalis@georgetown.eduCopyright © 2007 by the American Society of Nephrology  ABSTRACT For nearly 60 years, we have known that the brain plays a pivotal role in regulatingthe osmolality of body fluids. Over this time period, scientists have determined thestructure and function of arginine vasopressin and its receptors, the role of theposterior pituitary as a storage site, and the determinants of vasopressin release.The cellular mechanisms by which the kidney responds to vasopressin are also wellunderstood. One area that remains unclear is the neural mechanisms underlyingosmoreception. New findings have implicated the TRPV family of cation channels asosmo-mechanoreceptors that may mediate the neuronal responses to changes insystemic tonicity. This topic is reviewed here. J Am Soc Nephrol   18: 3056–3059, 2007. doi: 10.1681/ASN.2007070825 SCIENCE IN RENAL MEDICINE  www.jasn.org 3056  ISSN : 1046-6673/1812-3056 J Am Soc Nephrol  18:  3056–3059, 2007  techniques to detect early gene productsin rats, which serve as markers of cell ac-tivation after dehydration. Intense ex-pression of the cFos protein in andaround the OVLT confirms this area isstrongly activated by induced dehydra-tion, and retrograde tracing studies ver-ify that a subset of the activated neuronssend projections to the magnocellularAVP neurons in the hypothalamus. 6 Al-though many of the neural pathwaysconnecting the OVLT and other circum-ventricular organs with the magnocellu-lar AVP-secreting cells in the SON andPVNhavebeenidentified,theneuralcir-cuitsintheforebrainthatstimulatethirstafter osmoreceptor activation are stilllargely unknown. Recent studies usingfunctional magnetic resonance imagingin humans have shown that the anteriorcingulate area of the cortex is reliably ac-tivatedinconjunctionwiththesensationof thirst. 7 Although data from lesionstudiesinbothanimalsandmansupportthe concept of a single group of osmore-ceptive neurons that control both AVPsecretionandthirst,thishasnotbeende-finitively confirmed. Separate but paral-lel pathways for these complementary functions remain possible (Figure 1B)and could account for the lower osmoticthresholdforactivationofAVPsecretioncompared with thirst. 8  WHAT DO BRAINOSMORECEPTORS RESPOND TO? Neither AVP secretion nor thirst isequallysensitivetoallplasmasolutes.So-dium and its anions, which normally contribute   95% of the osmotic pres-sure of plasma, are the most potent sol-utes in terms of their capacity to stimu-late AVP secretion and thirst, althoughsome sugars such as mannitol and su-crose are also equally effective when in-fused intravenously. 8 In contrast, in-creases in plasma osmolality caused by solutessuchasureaorglucosecauselittleor no increase in plasma AVP levels inhumans or animals (Figure 2). 8,9 Thesedifferencesinresponsetovariousplasmasolutes are independent of any recog-nized nonosmotic influence, which indi-cates they are an intrinsic property of theosmoregulatory mechanism itself. Thus,it is clear that osmoreceptor cells in thebrainprimarilyrespondtoplasmatonic-ityratherthantototalplasmaosmolality.The physiological relevance of this find-ing is that osmoreceptors function pri-marilytopreservecellvolume;elevationsof solutes such as urea, unlike elevationsof sodium, do not cause cellular dehy-drationandconsequentlydonotactivatethe mechanisms that defend body fluidhomeostasis by preserving or increasingbody water stores.  WHAT ARE THE CELLULARMECHANISMS UNDERLYINGOSMORECEPTION? “Effective” solutes are those that pene-trate cells slowly, or not at all, thereby creating an osmotic gradient that causesan efflux of water from osmoreceptorcells. The resultant shrinkage of osmo-sensitiveneuronshasbeenfoundtoacti-vate membrane nonselective cationicconductances that generate inward cur-rent; if of sufficient magnitude, the re-sulting depolarization of the osmorecep-tor neuron then produces an actionpotential. 10 Conversely,“ineffective”sol-utes that penetrate cells readily create noosmotic gradient and thus have little tono effect on the cell volume of the osmo-receptors.Electrophysiologicalstudiesof neurons in the OVLT show they display changes in action potential firing ratethat vary in proportion to the tonicity of extracellular fluid, supporting the likeli-hood that these cells represent osmosen-sory neurons. 5 Osmotically evokedchanges in the firing rate of the OVLTneurons in turn synaptically regulate theelectrical activity of downstream effectorneurons,importantlyincludingthemag-nocellular AVP neurons in the SON andPVN, through graded changes in releaseof the excitatory neurotransmitter gluta-mate. This mechanism agrees well with AB Na+Na+ THIRSTAVPTHIRST   Primaryosmo-receptorsPrimarythirstosmo-receptorPrimaryAVPosmo- receptor AVP Na+Na+Na+Na+Na+Na+ Figure 1.  Brain osmoreceptor pathways.The primary brain osmoreceptors lie out-side the blood–brain barrier in the OVLT.Different neural projections connect theprimary osmoreceptors to brain areas re-sponsible for AVP secretion and thirst.Whether the same (A) or different subsets(B) of osmoreceptors project to both areasis presently unknown. Although osmore-ceptors can both stimulate as well as in-hibit AVP secretion and thirst in responseto systemic hyper-and hypotonicity, re-spectively, it is also not known whether there are separate subsets of excitatoryand inhibitory osmoreceptor cells, or whether this is a property of single osmo-receptive cells. 0285 295 Plasma Osmolality(mOsm/kg H 2 O)   sodium chloridemannitolureaglucose    P   l  a  s  m  a   V  a  s  o  p  r  e  s  s   i  n   (  p  g   /  m   L   ) 305 31512345678910 Figure2.  Solute specificity of brain osmo-receptors. The lines represent the relation-ship of plasma AVP to plasma osmolality inhealthy adults during intravenous infusionof hypertonic solutions of different solutes.Note that effective solutes,  i.e. , those com-partmentalized to the extracellular fluid(NaCl and mannitol), are much more effec-tive at eliciting AVP secretion than the non-effective solutes, urea and glucose, thatdistribute across cell membranes into theintracellular fluid as well (adapted fromZerbe and Robertson GL. 8 ) SCIENCE IN RENAL MEDICINE www.jasn.org J Am Soc Nephrol  18:  3056–3059, 2007 How Does the Brain Sense Osmolality?  3057  theobservedrelationshipbetweentheef-fect of specific solutes such as sodium,mannitol, and glucose on AVP secretion(Figure 2).The presumption that the cell vol-ume of the osmoreceptor cells repre-sents the primary signaling event by which osmoreceptors detect changes inthe tonicity of the extracellular fluidraises some interesting dilemmas.First, most cells in the body regulatetheir volume to prevent or minimizethe detrimental effects of cell swellingor shrinkage on cellular functions.However, if osmoreceptors displayedvolume-regulatory increases or de-creases in response to changes in extra-cellular tonicity, this would not allow for an absolute plasma osmolality around which body fluid homeostasisis maintained; that is, chronic hyperos-molality would not elicit sustainedstimulitoAVPsecretionandthirst.Re-sults using OVLT neurons in short-term dispersed cultures indeed suggestthat these cells do not volume-regulate,consistent with their putative functionas the primary brain osmoreceptors. 11 Whether this is also true after longerperiodsofsustainedchangesintonicity has not been studied. Second, in re-sponse to chronic changes in tonicity,the magnocellular AVP neurons un-dergo effects opposite of those ex-pected. These neurons enlarge in re-sponse to chronic hypertonicity  12 andshrink in response to chronic hypoto-nicity. 13 This is postulated to be a resultof changes in cell synthetic machinery;upregulation of the many proteins re-quired for increased AVP synthesisduring chronic hypertonicity causescell hypertrophy, and downregulationof these proteins during chronic hypo-tonicity produces the opposite effects.Thus, the true determinant of osmore-ceptor activity must be the degree of stretch of the osmoreceptor cell mem-brane, with subsequent effects onstretch-activated or stretch-inactivatedchannels, rather than the absolute sizeof the neurons. 10 In this sense, osmore-ceptors function as mechanoreceptorsthat detect the degree of membranestretch at the cellular level, similar tothe function of baroreceptors at thevascular level.The cellular osmosensing mechanismutilized by the OVLT cells is an intrinsicdepolarizing receptor potential, whichthese cells generate through a moleculartransduction complex. Recent resultssuggest this likely includes members of the transient receptor potential vanilloid(TRPV) family of cation channel pro-teins. These channels are generally acti-vatedbycellmembranestretchtocauseanonselective conductance of cations,with a preference for Ca 2  . Multiplestudies have characterized various mem-bersoftheTRPVfamilyascellularmech-anoreceptors in different tissues. 14 Both  in vitro  and  in vivo  studies of theTRPV family of cation channel proteinsprovides evidence supporting roles forTRPV1, TRPV2, and TRPV4 proteins inthe transduction of osmotic stimuli inmammals. 15 AnN-terminal trpv1 variantis expressed in OVLT cells, and  trpv1 -null mice have defects in osmotically stimulated AVP secretion and thirst. 5 Heterologous expression of the  trpv2 gene in Chinese hamster ovary (CHO)cells causes an activation of Ca 2  influx in response to hypotonicity, a responsethat can be mimicked by cell membranestretch. 15 trpv4 -Transfected cells re-spond similarly to hypotonicity and me-chanical stretch, and they display defi-cient volume-regulatory decreases inresponsetohypoosmolality. 16 But invivo studies have yielded inconsistent find-ings.  trpv4 -Null mice have a potentiatedAVP response to a combined hypertonicandhypovolemicstimulusinonestudy  17 but blunted responses of both AVP se-cretion and thirst to a selective hyper-tonic stimulus in another. 18 These find-ings are not necessarily contradictory because both AVP secretion and thirstare likely under bimodal control; that is,they are stimulated by hypertonicity andinhibited by hypotonicity. 19 In supportofthispossibility,treatmentwithdesmo-pressin leads to hyponatremia in  trpv4 -null mice but not wild-type controls, in-dicatingafailureofosmoticinhibitionof drinking. 18 Thus, different channelsand/or different sets of osmoreceptorcells may mediate opposite responses tocell membrane stretch, although osmo-sensitive inhibitory neurons have not yetbeen identified in the OVLT. 5 The combined studies to date there-fore strongly support the characteriza-tion of TRPV1, TRPV2, and TRPV4 asosmomechano-TRPs. 15 However, de-spite the very promising nature of thesefindings, several dilemmas are evidentwithregardtotheirinvolvementinbrainosmoreception. First, it is striking thatanimalswithgenedeletionsofindividualmembers of the TRPV family manifestblunted AVP secretion and thirst buthave a normal basal plasma osmolality.Theseresultsstandinmarkedcontrasttoanimals with lesions that destroy theOVLT and surrounding hypothalamus,in which osmotically stimulated AVP se-cretion and thirst are virtually abolished,leading to chronically elevated plasmaosmolality.Thisraisesthelikelihoodthatdifferent ion channels, or possibly com-binations of subunits from differentchannels, mediate osmoresponsivity inthe brain and compensate for the ab-senceofindividualionchannels.Second,itissurprisingthatalloftheTRPVchan-nels appear to be activated by membranestretch, including the cell swelling in-duced by extracellular hypotonicity,whereas  in vitro  studies of putativeOVLT osmoreceptors have indicatedthat the mechanism responsible for hy-perosmolar activation of these cells is ac-tivation of a stretch-inactivated cationicconductance that responds to cellshrinkage. 10 These and other questionsremain to be answered before we fully understand brain osmoreceptors andhow they function. UNRESOLVED QUESTIONS Although the details of exactly how andwhere various members of the TRPVfamily of cation channel proteins partic-ipate in osmoregulation in different spe-cies remains to be ascertained by addi-tional studies, a strong case can be madefortheirinvolvementinthetransductionof osmotic stimuli in the neural cells inthe OVLT and surrounding hypothala-mus that regulate osmotic homeostasis,which appears to be highly conserved SCIENCE IN RENAL MEDICINE  www.jasn.org 3058  Journal of the American Society of Nephrology J Am Soc Nephrol  18:  3056–3059, 2007  throughout evolution. 15 Future studieswill be necessary to address still unan-swered questions, including the exactstructure of the molecular transductioncomplex that regulates the opening of cationic channel(s) in response tochanges in tonicity; whether differentheteromultimeric combinations of TRPV1, TRPV2, and TRPV4 and possi-bly other cationic channels, mediate dif-ferentialresponsestochangesintonicity;whether separate excitatory and inhibi-tory osmoreceptors control AVP secre-tionandthirst;andthepotentialinvolve-mentoftheTRPVfamilyofionchannelsin the responses of different tissues tochanges in tonicity, particularly the kid-ney and the vasculature. But with prom-ising candidate cells and gene productsnow clearly identified, answers to thesequestions should be forthcoming. DISCLOSURES None. REFERENCES 1. Verney EB: The antidiuretic hormone andthe factors which determine its release.  Proc R Soc London (Ser B)   136: 25–106, 19472. Mason WT, Hatton GI, Kato M, Bicknell RJ:Signaltransductionintheneurohypophysealcompartments.  Prog Brain Res   92: 267–276,19923. Johnson AK, Thunhorst RL: The neuroendo-crinology of thirst and salt appetite: Visceralsensory signals and mechanisms of centralintegration.  Front Neuroendocrinol   18: 292–353, 19974. Baylis PH, Thompson CJ: Osmoregulation of vasopressin secretion and thirst in healthand disease.  Clin Endocrinol (Oxf)   29: 549–576, 19885. Bourque CW, Ciura S, Trudel E, Stachniak TJ,Sharif-Naeini R: Neurophysiological character-ization of mammalian osmosensitive neu-rones.  Exp Physiol   92: 499–505, 20076. 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Oliet SH, Bourque CW: Mechanosensitivechannels transduce osmosensitivity in su-praoptic neurons.  Nature  364: 341–343,199312. Armstrong WE, Gregory WA, Hatton GI: Nu-cleolar proliferation and cell size changes inrat supraoptic neurons following osmoticand volemic challenges.  Brain Res Bull   2:7–14, 197713. Zhang B, Glasgow E, Murase T, Verbalis JG,Gainer H: Chronic hypoosmolality induces aselective decrease in magnocellular neuronesoma and nuclear size in the rat hypotha-lamic supraoptic nucleus.  J Neuroendocri-nol   13: 29–36, 200114. Liedtke W, Kim C: Functionality of the TRPVsubfamily of TRP ion channels: addmechano-TRP and osmo-TRP to the lexicon! Cell Mol Life Sci   62: 2985–3001, 200515. Liedtke W: Role of TRPV ion channels insensory transduction of osmotic stimuli inmammals.  Exp Physiol   92: 507–512, 200716. Becker D, Blase C, Bereiter-Hahn J, Jen-drach M: TRPV4 exhibits a functional role incell-volume regulation.  J Cell Sci   118: 2435–2440, 200517. Mizuno A, Matsumoto N, Imai M, Suzuki M:Impaired osmotic sensation in mice lackingTRPV4.  Am J Physiol Cell Physiol   285: C96–C101, 200318. Liedtke W, Friedman JM: Abnormal osmoticregulation in trpv4  /  mice.  Proc Natl Acad Sci U S A  100: 13698–13703, 200319. Verbalis JG: Osmotic inhibition of neurohy-pophysial secretion.  Ann N Y Acad Sci   689:146–160, 1993 SCIENCE IN RENAL MEDICINE www.jasn.org J Am Soc Nephrol  18:  3056–3059, 2007 How Does the Brain Sense Osmolality?  3059
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