Article | Published:

Hierarchical neural architecture underlying thirst regulation

Nature volume 555, pages 204209 (08 March 2018) | Download Citation

Abstract

Neural circuits for appetites are regulated by both homeostatic perturbations and ingestive behaviour. However, the circuit organization that integrates these internal and external stimuli is unclear. Here we show in mice that excitatory neural populations in the lamina terminalis form a hierarchical circuit architecture to regulate thirst. Among them, nitric oxide synthase-expressing neurons in the median preoptic nucleus (MnPO) are essential for the integration of signals from the thirst-driving neurons of the subfornical organ (SFO). Conversely, a distinct inhibitory circuit, involving MnPO GABAergic neurons that express glucagon-like peptide 1 receptor (GLP1R), is activated immediately upon drinking and monosynaptically inhibits SFO thirst neurons. These responses are induced by the ingestion of fluids but not solids, and are time-locked to the onset and offset of drinking. Furthermore, loss-of-function manipulations of GLP1R-expressing MnPO neurons lead to a polydipsic, overdrinking phenotype. These neurons therefore facilitate rapid satiety of thirst by monitoring real-time fluid ingestion. Our study reveals dynamic thirst circuits that integrate the homeostatic-instinctive requirement for fluids and the consequent drinking behaviour to maintain internal water balance.

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Acknowledgements

We thank B. Ho, A. Qin and M. Liu for technical assistance, D. J. Anderson for sharing Ai110 mice, members of the Oka laboratory, and J. R. Cho for comments. We also thank N. Shah for Casp3 viruses, N. F. Dalleska, and the Beckman Institute at Caltech for technical assistance. This work was supported by Startup funds from the President and Provost of California Institute of Technology and the Biology and Biological Engineering Division of California Institute of Technology. Y.O. is also supported by the Searle Scholars Program, the Mallinckrodt Foundation, the Okawa Foundation, the McKnight Foundation and the Klingenstein-Simons Foundation, and National Institutes of Health U01 (U01 NS099717).

Author information

Author notes

    • Sertan Kutal Gokce
    •  & Sangjun Lee

    These authors contributed equally to this work.

Affiliations

  1. Computation and Neural Systems, California Institute of Technology, Pasadena, California, USA

    • Vineet Augustine
    •  & Yuki Oka
  2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA

    • Vineet Augustine
    • , Sertan Kutal Gokce
    • , Sangjun Lee
    • , Bo Wang
    • , Carlos Lois
    •  & Yuki Oka
  3. Department of Physiology and Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California, USA

    • Thomas J. Davidson
  4. Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK

    • Frank Reimann
    •  & Fiona Gribble
  5. Howard Hughes Medical Institute, Stanford University, Stanford, California, USA

    • Karl Deisseroth
  6. Department of Bioengineering, Stanford University, Stanford, California, USA

    • Karl Deisseroth

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Contributions

V.A. and Y.O. conceived the research program and designed experiments. V.A., with assistance from S.K.G., S.L. and Y.O., carried out the experiments and analysed data. B.W. and C.L. performed all slice patch-clamp recordings. T.J.D. and K.D. provided technical advice on setting up fibre photometry. F.R. and F.G. generated and provided Glp1r-cre mice. V.A. and S.K.G. together with Y.O. wrote the paper. Y.O. supervised the entire work.

Competing interests

F.G. is a consultant for Kallyope. Y.O. has disclosed these methods and findings to the Caltech Office of Technology Transfer, with provisional patent number CIT-7938-P. The other authors declare no competing financial interests.

Corresponding author

Correspondence to Yuki Oka.

Reviewer Information Nature thanks M. McKinley and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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DOI

https://doi.org/10.1038/nature25488

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