Article | Published:

Neurons for hunger and thirst transmit a negative-valence teaching signal

Nature volume 521, pages 180185 (14 May 2015) | Download Citation

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Abstract

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

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Acknowledgements

This research was funded by the Howard Hughes Medical Institute. Z.F.H.C. was funded by the HHMI Janelia Farm Graduate Scholar program. We thank B. Balleine, M. Schnitzer, N. Ji, A. Lee, Z. Guo for suggestions on experimental design; H. Su for molecular biology; J. Rouchard, S. Lindo, K. Morris, M. McManus for mouse breeding and procedures; M. Copeland for histology; J. Osborne and C. Werner for apparatus design; K. Branson for automated mouse tracking software (Ctrax); J. Dudman, S. Eddy, H. Grill, N. Geary, U. Heberlein for comments on the manuscript.

Author information

Author notes

    • J. Nicholas Betley
    • , Shengjin Xu
    •  & Zhen Fang Huang Cao

    These authors contributed equally to this work.

Affiliations

  1. Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, Virginia 20147, USA

    • J. Nicholas Betley
    • , Shengjin Xu
    • , Zhen Fang Huang Cao
    • , Rong Gong
    • , Christopher J. Magnus
    • , Yang Yu
    •  & Scott M. Sternson

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Contributions

J.N.B. and S.M.S initiated the project. J.N.B., Z.F.H.C., S.X. and S.M.S. prepared the manuscript with comments from all authors. J.N.B., S.X., Z.F.H.C., R.G., C.J.M. and S.M.S. designed the experiments and analysed the data. J.N.B. and Z.F.H.C. performed conditioning experiments, S.X. performed in vivo calcium imaging experiments, R.G. and C.J.M. developed the SFO activation model for evoked water drinking, Y.Y. helped with image registration.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Scott M. Sternson.

Extended data

Supplementary information

Videos

  1. 1.

    Ghrelin injection increased calcium activity of AGRP neurons in vivo

    Left, baseline Ca2+ activity in AL-fed mouse before ghrelin injection; right, 4 min after ghrelin injection. Video is 3× speed.

  2. 2.

    Food rapidly reduced Ca2+ activity of AGRP neurons during food consumption of a mouse chow pellet.

    Food rapidly reduced Ca2+ activity of AGRP neurons during food consumption of a mouse chow pellet. Video is 3× speed.

  3. 3.

    GCaMP6f fluorescence in AGRP neurons was rapidly reduced by presenting inaccessible food pellets.

    GCaMP6f fluorescence in AGRP neurons was rapidly reduced by presenting inaccessible food pellets. Subsequent consumption of food also reduced AGRP neuron activity. Video is 3× speed.

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DOI

https://doi.org/10.1038/nature14416

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