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The cellular basis of distinct thirst modalities

Pool, Allan-Hermann and Wang, Tongtong and Stafford, David A. and Chance, Rebecca K. and Lee, Sangjun and Ngai, John and Oka, Yuki (2020) The cellular basis of distinct thirst modalities. Nature, 588 (7836). pp. 112-117. ISSN 0028-0836. PMCID PMC7718410. doi:10.1038/s41586-020-2821-8.

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[img] Image (JPEG) (Extended Data Fig. 1: Thirst-state-dependent drinking behaviour and genetic labelling of active neurons) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 2: Profiling of cell and neuron types in the SFO and the OVLT) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 3: Expression of putative osmoregulatory channels or hormone receptors and cellular comparison between the SFO and the OVLT) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 4: Stimulus-to-cell-type mapping in the SFO and the OVLT) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 5: Canonical correlation analysis based alignment of transcriptomic neuron types under different physiological conditions) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 6: Multi-colour in situ hybridization for anatomical validation of transcriptomic cell types) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 7: Genetic targeting of osmotic and hypovolaemic thirst-activated cell populations in the SFO and the OVLT) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 8: Characterization of Rxfp1-Cre and Pdyn-Cre activation-derived consumption phenotypes) - Supplemental Material
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[img] Video (MPEG) (Video 1. Optogenetic stimulation of SFO^(Rxfp1) neurons. Optogenetic activation of Rxfp1 neurons in SFO induced robust pure water consumption (left) but the same animals avoided hyperosmotic saline (0.5M NaCl, right)) - Supplemental Material
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[img] Video (MPEG) (Video 2. Optogenetic stimulation of SFO^(Pdyn) neurons. Optogenetic stimulation of Pdyn neurons in SFO triggered consumption of both water (left) and hyperosmotic salt solution (0.5M NaCl, right)) - Supplemental Material
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Fluid intake is an essential innate behaviour that is mainly caused by two distinct types of thirst. Increased blood osmolality induces osmotic thirst that drives animals to consume pure water. Conversely, the loss of body fluid induces hypovolaemic thirst, in which animals seek both water and minerals (salts) to recover blood volume. Circumventricular organs in the lamina terminalis are critical sites for sensing both types of thirst-inducing stimulus. However, how different thirst modalities are encoded in the brain remains unknown. Here we employed stimulus-to-cell-type mapping using single-cell RNA sequencing to identify the cellular substrates that underlie distinct types of thirst. These studies revealed diverse types of excitatory and inhibitory neuron in each circumventricular organ structure. We show that unique combinations of these neuron types are activated under osmotic and hypovolaemic stresses. These results elucidate the cellular logic that underlies distinct thirst modalities. Furthermore, optogenetic gain of function in thirst-modality-specific cell types recapitulated water-specific and non-specific fluid appetite caused by the two distinct dipsogenic stimuli. Together, these results show that thirst is a multimodal physiological state, and that different thirst states are mediated by specific neuron types in the mammalian brain.

Item Type:Article
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URLURL TypeDescription ReadCube access CentralArticle
Pool, Allan-Hermann0000-0002-0811-9861
Chance, Rebecca K.0000-0001-7059-6119
Lee, Sangjun0000-0002-0846-8252
Ngai, John0000-0002-1191-8971
Oka, Yuki0000-0003-2686-0677
Additional Information:© 2020 Springer Nature. Received 29 January 2020. Accepted 16 July 2020. Published 14 October 2020. We thank the members of the Oka laboratory, D. J. Anderson, M. Thomson and S. Chen for helpful discussion and comments; B. Ho and A. Koranne for maintaining and genotyping animal lines; J. Park and the Single-Cell Profiling Center (SPEC) in the Beckman Institute at Caltech for technical assistance with scRNA-seq; B. Lowell and M. Krashes for generously sharing Pdyn-Cre mice; and L. Luo for a generous gift of TRAP2 mice. This work was supported by Startup funds from the President and Provost of the 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 McKnight Foundation, the Klingenstein-Simons Foundation, the New York Stem Cell Foundation and the NIH (R56MH113030 and R01NS109997). J.N. is supported by the NIH (U19MH114830). Data availability. The behavioural and histological data that support the findings are available from the corresponding author on reasonable request. Raw and fully processed scRNA-seq data are available at the NCBI Gene Expression Omnibus (GEO accession no. GSE154048). Code availability. The R code used to perform the scRNA-seq analysis is available from the corresponding author on reasonable request. Author Contributions. A.-H.P. and Y.O. conceived the research programme and designed experiments. A.-H.P. and T.W. carried out the experiments and analysed the data. J.N., R.K.C. and D.A.S. generated and characterized Rxfp1-2A–Cre mice. S.L. maintained and characterized Pdyn–Cre mice. A.-H.P. and Y.O. wrote the paper. Y.O. supervised the entire work. The authors declare no competing interests. Peer review information. Nature thanks Benjamin R. Arenkiel, Charles W. Bourque and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Group:Tianqiao and Chrissy Chen Institute for Neuroscience
Funding AgencyGrant Number
President and Provost of CaltechUNSPECIFIED
Caltech Division of Biology and Biological EngineeringUNSPECIFIED
Searle Scholars ProgramUNSPECIFIED
Edward Mallinckrodt, Jr. FoundationUNSPECIFIED
McKnight FoundationUNSPECIFIED
Klingenstein-Simons FoundationUNSPECIFIED
New York Stem Cell FoundationUNSPECIFIED
Subject Keywords:Feeding behaviour; Molecular neuroscience; Neural circuits
Issue or Number:7836
PubMed Central ID:PMC7718410
Record Number:CaltechAUTHORS:20200706-085818688
Persistent URL:
Official Citation:Pool, AH., Wang, T., Stafford, D. et al. The cellular basis of distinct thirst modalities. Nature 588, 112–117 (2020).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104221
Deposited By: George Porter
Deposited On:14 Oct 2020 17:01
Last Modified:16 Nov 2021 18:29

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