The cellular basis of distinct thirst modalities
Abstract
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.
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.Attached Files
Accepted Version - nihms-1613354.pdf
Supplemental Material - 41586_2020_2821_Fig10_ESM.jpg
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Additional details
- PMCID
- PMC7718410
- Eprint ID
- 104221
- Resolver ID
- CaltechAUTHORS:20200706-085818688
- President and Provost of Caltech
- Caltech Division of Biology and Biological Engineering
- Searle Scholars Program
- Edward Mallinckrodt, Jr. Foundation
- McKnight Foundation
- Klingenstein-Simons Foundation
- New York Stem Cell Foundation
- NIH
- R56MH113030
- NIH
- R01NS109997
- NIH
- U19MH114830
- Created
-
2020-10-14Created from EPrint's datestamp field
- Updated
-
2021-11-16Created from EPrint's last_modified field
- Caltech groups
- Tianqiao and Chrissy Chen Institute for Neuroscience, Division of Biology and Biological Engineering