The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Neurons for hunger and thirst transmit a negative-valence teaching signal
Open accessAbstract
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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“A potentially similar function has been described for arcuate nucleus AgRP neurons and nitric oxide synthase 1 (NOS1) neurons in the subfornical organ (SFO). These neurons show heightened activity during hunger (AgRP) and thirst (NOS1), their activity elicits an aversive state (place avoidance), and they are essential for driving feeding and drinking behaviors, respectively21,227.”
From Neural mechanisms of social homeostasis (2019) · cites this paper as [227]
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“However, AgRP activity is rapidly suppressed on sensory detection of food227,228,230, which, surprisingly, suggests that ongoing AgRP activity is dispensable for food consumption.”
From Neural mechanisms of social homeostasis (2019) · cites this paper as [227]
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“AgRP neurons are activated in a state of energy deficit228, and their optical stimulation can voraciously promote food consumption, but also elicits real-time place avoidance (indicative of an aversive state) in the absence of food173,227,229.”
From Neural mechanisms of social homeostasis (2019) · cites this paper as [227]
In the citing paper
“However, a mouse may subsequently avoid a flavor that was paired with the AgRP neuronal stimulation that made it eat, leading some authors to suggest that stimulated hunger is necessarily an aversive drive that the mouse later associates with the flavor (Betley et al., 2015).”
From Evolving Concepts of Emotion and Motivation (2018) · cites this paper as Betley et al., 2015
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Kim, D. H., Lee, M. J., Lee, S. H., Kim, J. Y., Bae, J. H., Khang, A. R., Kang, Y. H., & Yi, D. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27219514
Orexin and pupillary modulation for hunger control
Kosar, S., Bracey, E. F., Grujic, N., Du, Y., Peleg‐Raibstein, D., & Burdakov, D. (2026) · Proceedings of the National Academy of Sciences · doi:10.1101/2025.03.07.642010 · Cited by 1
Metadata
- Authors
- Betley, J. N., Xu, S., Cao, Z. F. H., Gong, R., Magnus, C. J., Yu, Y., & Sternson, S. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sternson, Scott M.
- ORCID
- Venue
- Nature
- Published
- 2015-04-27
- Volume
- 521
- Issue
- 7551
- Pages
- 180-185
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4567040
- OpenAlex
- W2101995469
- Cited by
- 704
- References
- 49
- Citations by year
- 2026: 32 · 2025: 73 · 2024: 70 · 2023: 68 · 2022: 50 · 2021: 72 · 2020: 65 · 2019: 73 · 2018: 64 · 2017: 62 · 2016: 54 · 2015: 21
- FWCI
- 37.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- hunger, thirst, homeostasis, AgRP neurons, subfornical organ, negative valence, teaching signal, motivation in learning, avoidance conditioning, energy homeostasis, fluid homeostasis
- MeSH terms
- Animals, Cues, Dehydration, Drinking, Eating, Food, Food Preferences, Homeostasis, Hunger, Hypothalamus, Male, Neurons, Starvation, Thirst, Models, Animal, Mice, Agouti-Related Protein
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