Article

Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake

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Abstract

Brain regions that regulate fluid satiation are not well characterized, yet are essential for understanding fluid homeostasis. We found that oxytocin-receptor-expressing neurons in the parabrachial nucleus of mice (OxtrPBN neurons) are key regulators of fluid satiation. Chemogenetic activation of OxtrPBN neurons robustly suppressed noncaloric fluid intake, but did not decrease food intake after fasting or salt intake following salt depletion; inactivation increased saline intake after dehydration and hypertonic saline injection. Under physiological conditions, OxtrPBN neurons were activated by fluid satiation and hypertonic saline injection. OxtrPBN neurons were directly innervated by oxytocin neurons in the paraventricular hypothalamus (OxtPVH neurons), which mildly attenuated fluid intake. Activation of neurons in the nucleus of the solitary tract substantially suppressed fluid intake and activated OxtrPBN neurons. Our results suggest that OxtrPBN neurons act as a key node in the fluid satiation neurocircuitry, which acts to decrease water and/or saline intake to prevent or attenuate hypervolemia and hypernatremia.

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Acknowledgements

We thank B. Roth and K. Deisseroth for AAV plasmid constructs. M. Chiang assisted with animal husbandry. S. Tsang and K. Kafer helped to generate the OxtrCre mice. We thank J. Chen for help with surgery for CalcaCre/+ experiments and C. Roman for help with surgery for CckCre/+ experiments. M. McKinley, B. Jarvie, C. Roman and members of the Palmiter lab provided helpful discussion and feedback. P.J.R. was supported by an Australian American Fellowship and a National Health and Medical Council of Australia CJ Martin Fellowship. C.A.C. was supported by a fellowship from Hope Funds for Cancer Research. R.D.P. was supported by a US National Institutes of Health grant (R01-DA24908). Inscopix provided the calcium-imaging equipment and supplies via their DECODE grant program.

Author information

Affiliations

  1. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA

    • Philip J. Ryan
    • , Silvano I. Ross
    • , Carlos A. Campos
    • , Victor A. Derkach
    •  & Richard D. Palmiter
  2. Department of Biochemistry, University of Washington, Seattle, Washington, USA

    • Philip J. Ryan
    • , Silvano I. Ross
    • , Carlos A. Campos
    • , Victor A. Derkach
    •  & Richard D. Palmiter
  3. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia

    • Philip J. Ryan

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Contributions

P.J.R. and R.D.P. conceived and designed the study. P.J.R. performed and analyzed the experiments. S.I.R and P.J.R. performed the immunohistochemistry and counting of cells. V.A.D. performed electrophysiological experiments. C.A.C. performed GCaMP6 studies. R.D.P. generated OxtrCre mice and provided equipment and reagents. P.J.R. wrote the manuscript with input from R.D.P and other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Philip J. Ryan or Richard D. Palmiter.

Integrated supplementary information

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–10 and Supplementary Tables 1 and 2

  2. Life Sciences Reporting Summary

  3. Supplementary Video 1

    Calcium fluorescence in OxtrPBN neurons during rehydration (2× speed). Upper panel: video of mouse behavior during water rehydration following 24-h dehydration; lower panel: corresponding calcium fluorescence activity in OxtrPBN neurons demonstrating low activity during dehydration and initial presentation of water, followed by increasing activity during drinking bouts, with decreasing activity between bouts (n = 94 neurons from 3 mice)

  4. Supplementary Video 2

    Calcium fluorescence in OxtrPBN neurons during a prolonged drinking bout (2× speed). Upper panel: video of mouse behavior during drinking bout; lower panel: corresponding calcium fluorescence activity in OxtrPBN neurons demonstrating activity during drinking bout

  5. Supplementary Video 3

    Calcium fluorescence in hM3Dq-injected OxtrPBN neurons following intraperitoneal CNO (10× speed).Calcium fluorescence in OxtrPBN neurons following injection of CNO ip, demonstrating increasing activity over ~15 min, which lasted at least 2 h (n = 83 neurons from 2 mice)