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Hierarchical neural architecture underlying thirst regulation

Augustine, Vineet and Gokce, Sertan Kutal and Lee, Sangjun and Wang, Bo and Davidson, Thomas J. and Reimann, Frank and Gribble, Fiona and Deisseroth, Karl and Lois, Carlos and Oka, Yuki (2018) Hierarchical neural architecture underlying thirst regulation. Nature, 555 (7695). pp. 204-209. ISSN 0028-0836. PMCID PMC6086126. doi:10.1038/nature25488.

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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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URLURL TypeDescription ReadCube access CentralArticle
Augustine, Vineet0000-0003-4431-1663
Lee, Sangjun0000-0002-0846-8252
Lois, Carlos0000-0002-7305-2317
Oka, Yuki0000-0003-2686-0677
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.
Group:Tianqiao and Chrissy Chen Institute for Neuroscience
Funding AgencyGrant Number
Searle Scholars ProgramUNSPECIFIED
Edward Mallinckrodt, Jr. FoundationUNSPECIFIED
Okawa FoundationUNSPECIFIED
McKnight FoundationUNSPECIFIED
Klingenstein-Simons FoundationUNSPECIFIED
NIHU01 NS099717
Subject Keywords:Motivation; Neural circuits
Issue or Number:7695
PubMed Central ID:PMC6086126
Record Number:CaltechAUTHORS:20171214-164018661
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:83936
Deposited By: George Porter
Deposited On:09 Jan 2018 20:33
Last Modified:15 Nov 2021 20:15

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