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Published February 17, 2022 | Supplemental Material
Journal Article Open

Sensory representation and detection mechanisms of gut osmolality change


Ingested food and water stimulate sensory systems in the oropharyngeal and gastrointestinal areas before absorption. These sensory signals modulate brain appetite circuits in a feed-forward manner. Emerging evidence suggests that osmolality sensing in the gut rapidly inhibits thirst neurons upon water intake. Nevertheless, it remains unclear how peripheral sensory neurons detect visceral osmolality changes, and how they modulate thirst. Here we use optical and electrical recording combined with genetic approaches to visualize osmolality responses from sensory ganglion neurons. Gut hypotonic stimuli activate a dedicated vagal population distinct from mechanical-, hypertonic- or nutrient-sensitive neurons. We demonstrate that hypotonic responses are mediated by vagal afferents innervating the hepatic portal area (HPA), through which most water and nutrients are absorbed. Eliminating sensory inputs from this area selectively abolished hypotonic but not mechanical responses in vagal neurons. Recording from forebrain thirst neurons and behavioural analyses show that HPA-derived osmolality signals are required for feed-forward thirst satiation and drinking termination. Notably, HPA-innervating vagal afferents do not sense osmolality itself. Instead, these responses are mediated partly by vasoactive intestinal peptide secreted after water ingestion. Together, our results reveal visceral hypoosmolality as an important vagal sensory modality, and that intestinal osmolality change is translated into hormonal signals to regulate thirst circuit activity through the HPA pathway.

Additional Information

© 2022 Nature Publishing Group. Received 15 April 2021; Accepted 15 December 2021; Published 26 January 2022. We thank the members of the Oka laboratory, S. D. Liberles and C. S. Zuker for helpful discussion and comments; B. Ho and A. Koranne for maintaining and genotyping mouse lines; T. Zhang, W. Han and I. E. Araujo for technical advice on surgical techniques; L. Luebbert for initial imaging analysis; T. Karigo for technical help; X. Chen and V. Gradinaru for advice on virus development and tissue clearing; and J. Parker for sharing the qPCR machine. 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 New York Stem Cell Foundation, NIH (R01NS109997, R01NS123918), Alfred P. Sloan Foundation, and Heritage Medical Research Institute. T.I. is supported by the Japan Society for the Promotion of Science. Data availability: Additional data that support the finding of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper. Code availability: The MATLAB code used to perform the imaging analysis is modified from the CalmAn code at https://github.com/flatironinstitute/CaImAn-MATLAB, and is available at https://github.com/Oka-Lab/Imaging-analysis. Author Contributions: T.I. and Y.O. conceived the research programme and designed experiments. T.I. performed the experiments and analysed the data, with help from T.W. A.K., and D.J.A. wrote the code for the imaging analysis and provided advice on the data analysis. A.-H.P. analysed the single-cell RNA sequencing data. H.E. performed and analysed chemogenetic experiments. T.I. and Y.O. wrote the paper. Y.O. supervised the entire work. The authors declare no competing interests. Peer review information: Nature thanks Richard Palmiter and the other, anonymous reviewers for their contribution to the peer review of this work.

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August 22, 2023
December 22, 2023