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Published March 8, 2018 | Accepted Version + Supplemental Material
Journal Article Open

Hierarchical neural architecture underlying thirst regulation

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.

Additional Information

© 2018 Macmillan Publishers Limited, part of Springer Nature. Received: 03 August 2017; Accepted: 03 January 2018; Published online: 28 February 2018. Code availability: Custom MATLAB code used in this study is available from the corresponding author upon reasonable request. Data availability: Data are available from the corresponding author upon reasonable request. 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 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.

Attached Files

Accepted Version - nihms-980434.pdf

Supplemental Material - nature25488-s1.pdf

Supplemental Material - nature25488-s2.pdf

Supplemental Material - nature25488-s3.xlsx

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Additional details

Created:
August 21, 2023
Modified:
October 18, 2023