Satiation is the process by which eating and drinking reduce appetite. For thirst, oropharyngeal cues have a critical role in driving satiation by reporting to the brain the volume of fluid that has been ingested1,2,3,4,5,6,7,8,9,10,11,12. By contrast, the mechanisms that relay the osmolarity of ingested fluids remain poorly understood. Here we show that the water and salt content of the gastrointestinal tract are precisely measured and then rapidly communicated to the brain to control drinking behaviour in mice. We demonstrate that this osmosensory signal is necessary and sufficient for satiation during normal drinking, involves the vagus nerve and is transmitted to key forebrain neurons that control thirst and vasopressin secretion. Using microendoscopic imaging, we show that individual neurons compute homeostatic need by integrating this gastrointestinal osmosensory information with oropharyngeal and blood-borne signals. These findings reveal how the fluid homeostasis system monitors the osmolarity of ingested fluids to dynamically control drinking behaviour.
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We thank Inscopix and J. Parker for technical assistance, the René Remie Surgical Skills Center for surgical training, and members of the Knight laboratory for comments on the manuscript. C.A.Z. is supported by the NSF Graduate Research Fellowship (DGE-1144247), UCSF Discovery Fellowship, Genentech Foundation Predoctoral Fellowship, and NIH National Research Service Award (F31-HL137383). Z.A.K. is a Howard Hughes Medical Institute Investigator, and this work was supported by the New York Stem Cell Foundation, a Pathway Award from the American Diabetes Association, Rita Allen Foundation, McKnight Foundation, Alfred P. Sloan Foundation, Brain and Behavior Research Foundation, Esther A. and Joseph Klingenstein Foundation, UCSF Program for Breakthrough Biomedical Research, and the UCSF Nutrition Obesity Research Center (DK0908722). This work was also supported by an NIH New Innovator Award (DP2-DK109533), R01-DK106399, and R01-NS094781.
Nature thanks C. Bourque, M. McKinley and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Fig. 1 Gastrointestinal osmolarity influences drinking behaviour and biases salt preference.
a, b, Additional data related to Fig. 1b, c. a, Cumulative water or 300 mM NaCl intake after dehydration (n = 5 mice). b, Example of SFO neuron dynamics during drinking after dehydration. c, Ingestion of hypertonic fluids activates SFO neurons regardless of hydration state. Average SFO activity and drinking behaviour of hydrated mice given ad libitum access to isotonic (300 mM sucrose) or hypertonic (300 mM sucrose + 600 mM mannitol) sugar solutions of similar sweetness (n = 5 mice). d, Increases in gastrointestinal osmolarity bias salt and water preference. Left, preference in a two-bottle test after intragastric treatment with hypertonic (red; n = 8 mice) or isotonic (black; n = 9 mice) NaCl (two-way ANOVA, Holm–Šídák correction). Right, cumulative water (solid lines) and 300 mM NaCl (dashed lines) intakes in the same two-bottle test. e–g, Post-ingestive SFO neuron activity does not reflect the delayed consequences of taste or sensorimotor experience associated with an individual drinking bout. e, Mice initially do not distinguish between bottles that contain water and bottles that contain 300 mM NaCl in a three-bottle test after dehydration (n = 4 mice, linear regression, R2 = 0.3163, P = 0.0233). f, Example of SFO neuron dynamics during drinking from water (black) and 300 mM NaCl (blue, red) bottles after dehydration. g, Left, SFO neuron dynamics during individual water (42 bouts) or NaCl (71 bouts) drinking bouts in trials 1 and 2 of the three-bottle test. Right, average SFO activity after individual drinking bouts (n = 4 mice). In this experiment (e–g), gastrointestinal osmolarity quickly becomes hypertonic as the dehydrated mice alternate between drinking from water and NaCl bottles, such that SFO neuron activity rebounds even after water-drinking bouts; this suggests that the stabilization signal that either quenches or re-activates SFO neurons after ingestion reflects gastrointestinal osmolarity. Error bars represent mean ± s.e.m. Shaded areas in a, c–e, g represent mean ± s.e.m.; shaded areas in b represent individual licks; shaded area in the linear regression (right) in e represents 95% confidence interval for the line of best fit; shaded areas in f represent individual drinking bouts. **P < 0.01, ***P < 0.001.
Extended Data Fig. 2 The gut-to-brain osmosensory signal depends on fluid tonicity but not osmolyte identity.
a, b, Intragastric infusion does not rapidly alter the state of the blood. a, Schematic. b, Plasma osmolality of samples collected during approximately 3–6 min after the start of the 5-min intragastric infusion (n = 9 mice per group, one-way ANOVA, Holm–Šídák correction). c–e, The gut-to-brain osmosensory signal depends on fluid tonicity but not osmolyte identity. c, Top, SFO neuron dynamics of individual mice in response to intragastric infusion of equi-osmotic concentrations of NaCl, which is absorbed into the bloodstream from the gastrointestinal tract, and mannitol, which is not absorbed (n = 4 mice). Bottom, SFO neuron dynamics of a separate cohort of individual mice in response to intragastric infusion of equiosmotic concentrations of NaCl, which does not permeate cell membranes and has high tonicity, and glucose, which does permeate cell membranes and has low tonicity (n = 5 mice). d, Left, average SFO activity during intragastric infusion of NaCl or mannitol. Right, quantification (n = 4 mice, one-way ANOVA, Holm–Šídák correction). e, Left, average SFO activity during intragastric infusion of NaCl or glucose. Right, quantification (n = 5 mice, one-way ANOVA, Holm–Šídák correction). f–h, SFO neurons encode systemic and gastrointestinal osmosensory signals additively rather than hierarchically. f, Schematic. g, Example (left) and average (right; n = 4 mice) of SFO neuron dynamics during 1.5 M NaCl intraperitoneal injection followed by intragastric infusion of water. h, Example (left) and average (right; n = 3 mice) of SFO neuron dynamics during 1.5 M NaCl intragastric infusion followed by intraperitoneal injection of water. Error bars represent mean ± s.e.m. Shaded areas in summary traces (d, e, g, h) represent mean ± s.e.m., and in example traces (g, h) represent intragastric infusion. NS, not significant, *P < 0.05, **P < 0.01.
Extended Data Fig. 3 The gut-to-brain osmosensory signal completely satiates, but only mildly stimulates, thirst.
a, b, Additional data related to Figs. 1e–g and 2a, b. a, Left, average SFO activity during intragastric infusions and subsequent drinking while hydrated. Right, cumulative water intake (n = 4 mice). b, Left, average SFO activity during intragastric infusions and subsequent drinking after dehydration. Right, cumulative water intake (n = 4 mice). c, Correlation between SFO activity change and latency to drinking after 1-ml infusions into hydrated (black; n = 23 experiments from 4 mice, linear regression, R2 = 0.0705, P = 0.2208) or dehydrated (red; n = 12 experiments from 4 mice, linear regression, R2 = 0.1321, P = 0.2456) mice. d, Additional data related to Fig. 2c. Average SFO activity after systemic (intraperitoneal) or intragastric treatment with 150 μl NaCl while hydrated. Shaded areas in a, b, d represent mean ± s.e.m., and in c represent 95% confidence interval for the line of best fit.
a–d, The gut-to-brain osmosensory signal is disrupted by subdiaphragmatic vagotomy. a, Vagal motor neuron somas (located in the brainstem and labelled by intraperitoneal injection of wheat germ agglutinin (WGA-555)) were largely absent following subdiaphragmatic vagotomy (two examples per condition). Scale bar, 1 mm. b, Drinking after dehydration was less suppressed by intragastric infusion of water in vagotomized mice (middle; n = 7 mice) compared to sham mice (left; n = 6 mice). Right, quantification (two-tailed Student’s t-test). c, Drinking was similarly suppressed in both groups by systemic (intraperitoneal) delivery of water (n = 4 sham and 7 vagotomy mice, two-tailed Student’s t-test). d, SFO modulation by water and 500 mM NaCl intragastric infusions, but not by 1.5 M NaCl intraperitoneal injection, was attenuated in vagotomized mice compared to sham mice (n = 8 mice per group, two-tailed Student’s t-tests). e–i, The gut-to-brain osmosensory signal involves Trpv1-positive sensory neurons. e, To specifically ablate Trpv1-positive sensory neurons, we treated mice that contain a BAC transgene expressing GFP and the diphtheria toxin (DTX) receptor from the Trpv1 gene start codon (Trpv1-Gfp-2a-Dtr mice) with DTX. Scale bar, 100 μm. f, Quantification (n = 3 control and 2 DTX mice). NG, nodose ganglion; DRG, dorsal root ganglion. g, Treatment with DTX did not ablate Trpv1-positive neurons in the brain. Scale bar, 1 mm. h, Hydrated mice avoided drinking 300 mM sucrose that contained 100 μM capsaicin (cap.) before—but not after, DTX ablation of Trpv1-positive sensory neurons (n = 5 mice, two-way ANOVA, Holm–Šídák correction). Veh., vehicle. i, SFO modulation by intragastric infusion of water was significantly attenuated after DTX ablation of Trpv1-positive sensory neurons, and modulation by intragastric infusion of 500 mM NaCl was slightly attenuated (n = 7 mice, two-tailed Student’s t-tests). j, The response of SFO neurons to serotonin and other visceral hormones. j, SFO neuron dynamics during injection of two doses of serotonin (left; n = 5 mice) and to a single dose (2 mg kg−1) of amylin, cholecystokinin (CCK), ghrelin or leptin (right; n = 6 mice, one-way ANOVA, Holm–Šídák correction) in hydrated mice. Error bars and shaded areas represent mean ± s.e.m. NS, not significant, *P < 0.05, **P < 0.01.
Extended Data Fig. 5 Vasopressin neurons integrate systemic and gastrointestinal osmosensory signals and are stress-responsive.
a, b, Additional data related to Fig. 3a, b. a, Schematic for fibre photometry recording of vasopressin neurons. Scale bar, 1 mm. b, Vasopressin neuron dynamics (average, left; individual mice, right) during vehicle or NaCl intraperitoneal injection (n = 7 mice). c, Vasopressin neurons are stress-responsive. Vasopressin neuron activity during tail suspension (n = 7 mice). d–j, Additional data related to Fig. 3d. d, Schematic. e, Change in vasopressin neuron activity after infusion, while hydrated or dehydrated (n = 4 mice, two-way ANOVA, Holm–Šídák correction). f, Vasopressin neuron activity during intragastric infusions, while hydrated (n = 4 mice). g, Vasopressin neuron dynamics of individual mice (left) and distribution of ΔF/F0 values before and after intragastric infusion with 500 mM NaCl (right). h, Vasopressin neuron dynamics during intragastric infusions after dehydration (n = 4 mice). i, Vasopressin neuron activity of individual mice (left) and distribution of ΔF/F0 values before and after intragastric infusion with water (right). j, Gastrointestinal osmolarity modulates both the median of ΔF/F0 (left; used here as a proxy for tonic activity) and the standard deviation (σ) of ΔF/F0 (right; used here as a proxy for bursting activity) of vasopressin neurons (n = 4 mice, two-tailed Student’s t-tests). Error bars represent mean ± s.e.m. Shaded areas in b, c, f, h represent mean ± s.e.m., and in g, i represent ‘before’ and ‘after’ infusion periods. *P < 0.05, **P < 0.01, ***P < 0.001. The mouse brain in this figure has been reproduced with permission from ref. 35, Copyright © 2012.
a, Additional data related to Fig. 4b. a, The Nxph4-2a-cre recombination pattern (bottom; crossed to a GFP reporter line) recapitulates the endogenous Nxph4 mRNA expression pattern (top; Allen Institute for Brain Science ISH #73521000) in the organum vasculosum of the lamina terminalis (OVLT), MnPO, SFO and paraventricular hypothalamus (PVH). b, MnPONxph4 neurons are activated by dehydration. Nxph4-2a-cre recombination (green; crossed to a GFP reporter line) and the immediate early gene product FOS (red; induced by 3 M NaCl intraperitoneal injection) co-localize in the MnPO during dehydration. Scale bar, 100 μm. c, d, MnPONxph4 neurons drive thirst. c, Schematic for optogenetic activation of MnPONxph4 neurons. Scale bar, 1 mm. d, Left, water intake in response to photostimulation. Right, quantification (n = 4 mice, two-tailed Student’s t-test). Error bars and shaded areas represent mean ± s.e.m. *P < 0.05. The mouse brains in this figure have been reproduced with permission from ref. 35, Copyright © 2012.
Extended Data Fig. 7 In vivo imaging of individual glutamatergic MnPO neurons during thirst, drinking and gastrointestinal manipulation.
a, Additional data related to Fig. 4d, e. a, Workflow for k-means clustering of individual MnPONxph4 neurons based on their activity during intraperitoneal injection of vehicle or 3 M NaCl, and water drinking. b–d, Additional data related to Fig. 4f–h. b, Schematic. c, Dynamics of individual neurons during intragastric infusion of water while hydrated. d, Dynamics of individual neurons tracked during intragastric infusion of water after dehydration (left) and 3 M NaCl intraperitoneal injection (right). Neurons inhibited ≥ 1σ after intragastric infusion of water were classified as ‘gastrointestinal-tuned’ (red; 26%) and the remaining neurons were classified as ‘gastrointestinal-untuned’ (black; 74%) for the time-course plotted in Fig. 4h.
Extended Data Fig. 8 Glutamatergic MnPO neurons relay the gastrointestinal osmosensory signal to vasopressin neurons.
a–d, Glutamatergic MnPO neurons are necessary for relaying gastrointestinal osmosensory information to SON vasopressin neurons. a, Schematic for simultaneous fibre photometry recording of vasopressin neurons and chemogenetic inhibition of glutamatergic MnPO neurons. Scale bar, 100 μm. b, Injection of CNO inhibited water intake after dehydration (n = 5 mice). c, Example of vasopressin neuron dynamics during intraperitoneal injection of CNO or vehicle (left) and subsequent intragastric infusion of 1.5 M NaCl by oral gavage (right). Inset, water intake after dehydration for the example mouse. d, Quantification of vasopressin neuron response to intraperitoneal injection (left) and NaCl intragastric infusion (right) (n = 5 mice, two-tailed Student’s t-tests). e–h, Glutamatergic MnPO neurons are not necessary for relaying gastrointestinal osmosensory information to SFO thirst neurons. e, Schematic for simultaneous fibre photometry recording of SFO neurons and chemogenetic inhibition of glutamatergic MnPO neurons. Scale bar, 100 μm. f, Injection of CNO inhibited water intake after dehydration (n = 5 mice). g, Example of SFO neuron dynamics during intragastric infusion of 1.5 M NaCl by oral gavage, after intraperitoneal injection CNO or vehicle. Inset, water intake after dehydration for the example mouse. h, Quantification of SFO neuron response to intraperitoneal injection (left) and intragastric infusion of NaCl (right) (n = 5 mice, two-tailed Student’s t-tests). i, CNO inhibits drinking in mice that express the Gi-coupled human M4D designer receptor (hM4D(Gi)) in glutamatergic MnPO neurons but not in control mice that lack hM4D(Gi). i, Injection of CNO significantly inhibited water intake after dehydration in MnPOCamk2a::hM4D(Gi) + SON mice with photometry implants (n = 5 mice; quantified from b) and MnPONos1::hM4D(Gi) + SFO mice with photometry implants (n = 5 mice; quantified from f) but not in control mice (n = 6 mice, two-way ANOVA, Holm–Šídák correction). Error bars and shaded areas represent mean ± s.e.m. n.s., not significant; *P < 0.05, **P < 0.01. The mouse brains in this figure have been reproduced with permission from ref. 35, Copyright © 2012.
Extended Data Fig. 9 In vivo imaging of individual GABAergic MnPO neurons during thirst, drinking and gastrointestinal manipulation.
a, Individual GABAergic MnPO neurons do not encode systemic osmolarity in their baseline activity. Left, dynamics of individual neurons during intraperitoneal injection of 3 M NaCl while hydrated. Right, comparison to thirst-activated MnPONxph4 neurons (cluster 1 from Fig. 4e). b, c, Dynamics of ingestion-tuned GABAergic MnPO neurons during hypertonic NaCl drinking. b, Left, dynamics of individual neurons during 300 mM NaCl drinking after dehydration (left). Right, proportion of ingestion-activated (red, modulated ≥ 1σ during first min of drinking), ingestion-inhibited (blue, modulated ≤ −1σ) and untuned (black) neurons during water (top; n = 77 neurons from Fig. 5c, d) or 300 mM NaCl (bottom; n = 95 neurons) drinking. c, Average responses of ingestion-activated, ingestion-inhibited and untuned neurons during 300 mM NaCl drinking (n = 95 neurons). Note that ingestion of NaCl persists for much longer than ingestion of water after dehydration (see Fig. 5d, Extended Data Fig. 1a), which may explain differences in the dynamics of ingestion-tuned GABAergic MnPO neurons when mice drink these fluids. d, e, Additional data related to Fig. 5e–g. d, Schematic. e, Dynamics of individual neurons during intragastric infusion of 500 mM NaCl while hydrated.
Anatomically and temporally distinct peripheral sensory signals encode information about the current hydration state of the body (blood) as well as the volume (oropharynx) and osmolarity (gastrointestinal tract) of recently ingested fluids. These signals converge on the thirst circuit of the brain to generate an integrated central representation of fluid balance at the level of individual neurons, which use this information to dynamically control drinking behaviour and vasopressin secretion in real time. Illustration from iStock/artsholic.
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Zimmerman, C.A., Huey, E.L., Ahn, J.S. et al. A gut-to-brain signal of fluid osmolarity controls thirst satiation. Nature 568, 98–102 (2019). https://doi.org/10.1038/s41586-019-1066-x
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