Central Mechanisms of Osmosensation and Systemic Osmoregulation
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REVIEWS Central mechanisms of osmosensation and systemic osmoregulation Charles W. Bourque Abstract | Systemic osmoregulation is a vital process whereby changes in plasma osmolality, detected by osmoreceptors, modulate ingestive behaviour, sympathetic outflow and renal function to stabilize the tonicity and volume of the extracellular fluid. Furthermore, changes in the central processing of osmosensory signals are likely to affect the hydro-mineral balance and other related aspects of homeostasis, including thermoregulation and cardiovascular balance. Surprisingly little is known about how the brain orchestrates these responses. Here, recent advances in our understanding of the molecular, cellular and network mechanisms that mediate the central control of osmotic homeostasis in mammals are reviewed. osmolality Osmolality Changes in extracellular fluid (ECF) cause changes in ECF osmolality can cause severe neurological A quantitative measure of the water to flow across cell membranes to equilibrate the symptoms in these species owing to the effects of altered total solute concentration in osmolality of the cytoplasm with that of the ECF1. By electrolyte concentrations on neuronal excitability12,13 and a solution expressed in moles altering cell volume and intracellular ionic strength, the physical trauma that can be caused by such condi- per kilogram of solution. large changes in ECF osmolality can affect the physical tions14,15 (BOX 1). In this Review I address the mechanisms Osmolality is not the same 2 as osmolarity, which is the integrity of cells and tissues and the biological activity by which mammals defend against large changes in ECF number of moles of total of life-sustaining macromolecules3. This is a threat that osmolality. Following a brief overview of the processes solutes per litre of solution. most animals face as they interact with their habitat. that are involved in systemic osmoregulation as a whole, Some aquatic animals, termed osmoconformers, seem- I focus on the location and function of the osmoreceptors Osmolyte Any dissolved substance that ingly make little effort to resist osmotic forces and adopt that mediate osmosensation and on the neural pathways contributes to the osmolality ECF osmolality values that are comparable to those of through which relevant homeostatic responses can be of a solution. their external environment4,5. Osmoconformers tolerate modulated by these unique sensory elements. such conditions because they have evolved molecular Hypertonic conditions and biochemical mechanisms that optimize cell volume Systemic osmoregulation in mammals Conditions in which the ECF 1,6,7 contains a higher concentration regulation and minimize increases in ionic strength by Although mammals strive to maintain a constant ECF of membrane-impermeant synthesizing osmolytes under hypertonic conditions8–11. By osmolality, values measured in an individual can fluctu- solutes than is observed at rest contrast, animals termed osmoregulators have evolved ate around the set-point owing to intermittent changes in in that particular species. mechanisms that maintain ECF osmolality near a stable the rates of water intake and water loss (through evapo- value. These animals engage physiological responses ration or diuresis) and to variations in the rates of Na+ that actively oppose osmotic perturbations and serve intake and excretion (natriuresis). In humans, for exam- to restore ECF osmolality towards a seemingly fixed ple, 40 minutes of strenuous exercise in the heat16,17 or osmotic ‘set-point’. Although it is not known whether 24 hours of water deprivation18,19 causes plasma osmolal- Centre for Research in this value represents a true singular physical entity or ity to rise by more than 10 mosmol kg–1. In a dehydrated Neuroscience, Research whether it is a balance point between different feedback individual, drinking the equivalent of two large glasses Institute of the McGill University Health Centre, systems that participate in the control of body fluid of water (~850 ml) lowers osmolality by approximately –1 20 Room L7-216, Montreal balance, the term set-point is retained to designate the 6 mosmol kg within 30 minutes . Analogously, inges- General Hospital, 1650 value that is observed at rest. As a class, the mammals tion of 13 g of salt increases plasma osmolality by approx- Cedar Avenue, Montreal, stand out because they maintain a common ECF osmotic imately 5 mosmol kg–1 within 30 minutes21. Although Quebec, H3G 1A4, Canada. set-point (near 300 mosmol kg–1) (FIG. 1; Supplementary osmotic perturbations larger than these can be deleteri- e-mail: [email protected] information S1 (table)). This is important because, as ous to health, changes in the 1–3% range play an integral doi:10.1038/nrn2400 it is encased in a rigid cranium, the mammalian brain part in the control of body-fluid homeostasis. In fact, Published online 29 May 2008 can be damaged by shrinking or swelling. Indeed, large differences between the ECF osmolality and the desired natUre reVieWS | NEUROSCIENCE VOLUME 9 | JULY 2008 | 519 REVIEWS Shark Homeostatic responses to hypo-osmolality. ECF hypo- Desert frog (aestivating) 22 Desert beetle osmolality suppresses basal VP secretion in rats and Drosophila 45,46 Lizard humans . Because renal water reabsorption is partly Dolphin stimulated by VP levels at rest45, this inhibition of VP Chicken Cat release effectively stimulates diuresis (FIG. 2). Intravenous Trout Whale infusion of hypo-osmotic solutions reduces thirst in dehy- Seal drated humans47. Moreover, the threshold for osmotically Fresh water Mouse Ocean Manatee modulated thirst in water-replete individuals seems to lie Marmot 48 Camel a few milliosmoles below the osmotic set-point . Thus, Dog Sheep ECF hypo-osmolality can also promote homeostasis by Monkey inhibiting any desire to drink that might prevail under Goat Pig basal conditions (FIG. 2). As mentioned above, natriuresis Rat 31,34 Human is stimulated by systemic release of oxytocin in rats . Horse Rabbit Interestingly, the basal electrical activity of hypothalamic Cow oxytocin-releasing neurosecretory neurons is inhibited Catfish 36 Lamprey by hypo-osmolality . It is therefore possible that a reduc- River eel Flatworm tion in basal circulating oxytocin levels might reduce Turtle natriuresis under these conditions (FIG. 2). Analogously, Snail Tadpole Clam a decrease in central oxytocin release might enhance salt appetite during ECF hypotonicity (FIG. 2). Whether 0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 ECF hypo-osmolality specifically inhibits natriuresis or Extracellular fluid osmolality (mosmol kg–1) stimulates salt appetite has yet to be determined. Figure 1 | Extracellular fluid osmolality in animals. The plot shows values of Nature Reviews | Neuroscience extracellular fluid (ECF) osmolality observed in various animals. The values, organized in Osmoreceptors in the brain and the periphery ascending order along the y-axis, were taken from published studies (Supplementary The fact that there is feedback control of osmoregulatory information S1). Although different types of organisms (empty circles) can display values that span the full range of environmental osmolalities, mammals (filled circles) display responses implies the existence of a sensory mechanism 49–52 osmotic set-points that cluster around 300 mosmol kg–1. Aestivating frogs spend the that can detect osmotic perturbations. Early studies summer in a state of dormancy. provided clear evidence that “cellular dehydration” (that is, cell shrinking) was required for thirst and VP release to be stimulated during ECF hyperosmolality: these set-point induce proportional homeostatic responses responses could be induced by infusions of concentrated according to the principle of negative feedback (FIG. 2). solutions containing membrane-impermeable solutes, Functionally speaking, therefore, it would seem that which extract water from cells, but not by infusions of sensory osmoreceptors actively generate a basal signal solutes that readily equilibrate across the cell membrane at the desired set-point and have the ability to modulate (such as urea). Verney coined the term osmoreceptor to this signal in a manner that encodes both the polarity designate the specialized sensory elements. He further and the magnitude of a change in osmolality. showed that these were present in the brain50,53 and pos- tulated that they might comprise “tiny osmometers” and Homeostatic responses to hyperosmolality. Studies in “stretch receptors” that would allow osmotic stimuli to mammals22–24, including in humans25–27, have estab- be “transmuted into electrical” signals50. Osmoreceptors lished that ECF hyperosmolality stimulates the sensa- are therefore defined functionally as neurons that are tion of thirst, to promote water intake, and the release endowed with an intrinsic ability to detect changes in of vasopressin (VP, also known as antidiuretic hor- ECF osmolality. As such, it is reasonable to posit that mone), to enhance water reabsorption in the kidney. the osmotic set-point is encoded by the resting electri- Hyperosmolality resulting from infusions of either cal activity of these cells, and that the magnitude and NaCl or non-NaCl hypertonic solutions into the carotid polarity of ambient osmotic perturbations is signalled artery also increases the rate of natriuresis from the to downstream neurons by proportional changes in the kidney in various mammals28–32, including man33. In action-potential firing rate (or firing pattern). Although