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Thirst-associated preoptic neurons encode an aversive motivational drive.
Open accessAbstract
Water deprivation produces a drive to seek and consume water. How neural activity creates this motivation remains poorly understood. We used activity-dependent genetic labeling to characterize neurons activated by water deprivation in the hypothalamic median preoptic nucleus (MnPO). Single-cell transcriptional profiling revealed that dehydration-activated MnPO neurons consist of a single excitatory cell type. After optogenetic activation of these neurons, mice drank water and performed an operant lever-pressing task for water reward with rates that scaled with stimulation frequency. This stimulation was aversive, and instrumentally pausing stimulation could reinforce lever-pressing. Activity of these neurons gradually decreased over the course of an operant session. Thus, the activity of dehydration-activated MnPO neurons establishes a scalable, persistent, and aversive internal state that dynamically controls thirst-motivated behavior.
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“These thirst-study authors found that artificial stimulation of neurons in the hypothalamus made mice drink, but that mice would work to turn off the stimulation if given a choice, thus leading the authors to suggest that thirst is essentially aversive.”
From Evolving Concepts of Emotion and Motivation (2018) · cites this paper as Allen et al., 2017
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Multiregion neuronal activity: the forest and the trees
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“Activation of SFONOS1 or identified thirst-related MnPO neurons also led to conditioned place aversion [80, 81].”
BackgroundHippocampal representation during collective spatial behaviour in bats
Forli, A., & Yartsev, M. M. (2023) · Nature · doi:10.1038/s41586-023-06478-7 · Cited by 58
Engram Size Varies with Learning and Reflects Memory Content and Precision
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“In order to test this possibility, we used the TRAP2 mouse line to permanently label neurons active after conditioning at either a 30 or 720 s PSI (Allen et al., 2017; DeNardo et al., 2019).”
MethodThirst and Drinking Paradigms: Evolution from Single Factor Effects to Brainwide Dynamic Networks
Armstrong, L. E., & Kavouras, S. A. (2019) · Nutrients · doi:10.3390/nu11122864 · Cited by 63
“Thus, both the unpleasant effect of thirst and the pleasant effect of drinking regulate water consumption [82] and ultimately total body water balance (Figure 2).”
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Jagot, F., Gaston-Breton, R., Choi, A. J., Pascal, M., Bourhy, L., Dorado-Doncel, R., Conzelmann, K., Lledo, P., Lepousez, G., & Eberl, G. (2023) · Neuron · doi:10.1016/j.neuron.2023.05.009 · Cited by 57
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Sensory input, sex and function shape hypothalamic cell type development
Kaplan, H. S., Logeman, B. L., Zhang, K., Yawitz, T. A., Santiago, C., Sohail, N., Talay, M., Seo, C., Naumenko, S., Sui, S. J. H., et al. (2025) · Nature · doi:10.1038/s41586-025-08603-0 · Cited by 51
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Experience-dependent mechanisms in the regulation of parental care
Stolzenberg, D. S., & Mayer, H. S. (2019) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.04.002 · Cited by 55
“Despite its critical role in the onset and maintenance of caregiving behavior, it should be noted that the MPOA is comprised of a highly heterogenous population of cells, some of which regulate other behaviors such as sexual behavior, thermoregulation, and thirst (Allen et al., 2017; Dominguez and Hull, 2005; Tan et a…”
BackgroundDrug-activated cells: From immediate early genes to neuronal ensembles in addiction
Salery, M., Godino, A., & Nestler, E. J. (2021) · Advances in pharmacology · doi:10.1016/bs.apha.2020.09.006 · Cited by 50
Imaging and analysis of genetically encoded calcium indicators linking neural circuits and behaviors
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Cellular populations and thermosensing mechanisms of the hypothalamic thermoregulatory center
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“expression of discrete neuropeptides and receptors, such as cholecystokinin, corticotropin-releasing hormone, tachykinin 1 (regulating sleep [19]), gonadotropin-releasing hormone (GnRH), kisspeptin (regulating fertility—[42]), prostagalandin EP3 recepter (controlling fever—[58]), and PACAP & BDNF (identified in thirst…”
BackgroundPetzold, A., van den Munkhof, H. E., Figge-Schlensok, R., & Korotkova, T. M. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.02.008 · Cited by 55
A forebrain neural substrate for behavioral thermoregulation
Jung, S., Lee, M., Kim, D., Son, C., Ahn, B. H., Heo, G., Park, J., Kim, M., Park, H., Koo, D.-J., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.09.039 · Cited by 49
Neurons in the Dorsomedial Hypothalamus Promote, Prolong, and Deepen Torpor in the Mouse
Ambler, M., Hitrec, T., Wilson, A., Cerri, M., & Pickering, A. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.2102-21.2022 · Cited by 48
“Female TRAP2 (Allen et al., 2017; DeNardo et al., 2019), Ai14 (Madisen et al., 2010), and C57BL/6J mice, at least 8 weeks of age with mean body weight 22.9 (2.8) grams on experiment entry were used.”
InfluentialCentral regulation of body fluid homeostasis
Noda, M., & Matsuda, T. (2022) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.98.016 · Cited by 48
Rijsketic, D. R., Casey, A. B., Barbosa, D. A. N., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M. B., Halpern, C. H., Williams, L. M., Malenka, R. C., et al. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01613-4 · Cited by 46
“Moreover, we performed c-Fos mapping in TRAP2 (Targeted Recombination in Active Populations; Fos::c-Fos-2A-iCre); Ai14 (Rosa-CAG-LSL::tdTomato) mice to determine if identified ensembles might be amenable to control by functionally defined genetic recombination in future studies [19, 20].”
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“Injection 4-hydroxytamoxifen (4-OHT) into TRAP2*Ai14 double transgenic mice just before stimulation results in permanent labeling of transiently activated neurons.(73) Using this method, we observed the labeling of the accessory olfactory bulb (AOB) and the olfactory bulb (OB) after exposure to maternal bedding (Figur…”
MethodStriatal dopamine integrates cost, benefit, and motivation
Eshel, N., Touponse, G. C., Wang, A. R., Osterman, A. K., Shank, A. N., Groome, A. M., Taniguchi, L., Pinto, D. F. C., Tucciarone, J., Bentzley, B. S., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.10.038 · Cited by 51
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Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures
Brodovskaya, A., Shiono, S., & Kapur, J. (2021) · Brain · doi:10.1093/brain/awab119 · Cited by 44
“mice, modified to a new generation TRAP2 that utilizes the activity of immediate early gene c-Fos to drive Cre expression.(13,14) 4-OHT injection translocates Cre inside the nucleus that relieves the repression from tdTomato, which labels activated cells.”
BackgroundAn mPOA-ARCAgRP pathway modulates cold-evoked eating behavior
Yang, S., Tan, Y. L., Wu, X., Wang, J., Sun, J., Liu, A., Gan, L., Shen, B., Zhang, X., Fu, Y., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109502 · Cited by 44
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Layers of signals that regulate appetite
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“These signals are remarkably diverse—spanning, for example, the smell of food, the nutrient content of the gut, and the level of body fat reserves—yet are seamlessly integrated within individual neurons to track changes in bodily state.”
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Connect-seq to superimpose molecular on anatomical neural circuit maps
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Obesity and responsibility: Is it time to rethink agency?
Grannell, A., Fallon, F., Al‐Najim, W., & le Roux, C. W. (2021) · Obesity Reviews · doi:10.1111/obr.13270 · Cited by 47
“Indeed this information is detected similarly to hunger by subcortical regions of the brain within the hypothalamus.(37) Given that we experience a sensation of thirst that motivates us to seek fluid and subsides with the consummatory act of drinking, there is a part of the brain the hypothalamus projects to,”
BackgroundGu, X., Wu, Y., Zhang, Z., Zhu, J., Wu, X., Wang, Q., Yi, X., Lin, Z.-J., Jiao, Z.-H., Xu, M., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01684-7 · Cited by 39
Neural landscape diffusion resolves conflicts between needs across time
Richman, E. B., Ticea, N., Allen, W. E., Deisseroth, K. A., & Luo, L. (2023) · Nature · doi:10.1038/s41586-023-06715-z · Cited by 41
“11), suggesting that the broadly distributed goal state activity could function as a shared initial condition to coordinate the population neural dynamics of distinct regions in the production of specific behavioural outcomes.”
BackgroundStults‐Kolehmainen, M. (2023) · Frontiers in Psychology · doi:10.3389/fpsyg.2023.1134049 · Cited by 53
“Likewise, thirst is a motivation state, a condition, resulting from deficient water intake, associated with the feeling of being thirsty (see Table 1; Allen et al., 2017).”
BackgroundResultInfluentialNeural circuit control of innate behaviors
Wei, X., Jiao, Z., Senol, E., Yao, J., Zhao, M., Zhao, Z., Chen, X., Cao, P., Fu, Y., Gao, Z., et al. (2021) · Science China Life Sciences · doi:10.1007/s11427-021-2043-2 · Cited by 40
“dition, activity-dependent genetic labeling mouse lines (FosTRAP2) may be used to specifically label the huntingassociated neurons in the rlPAG (Allen et al., 2017).”
Background
Metadata
- Authors
- Allen, W. E., DeNardo, L. A., Chen, M. Z., Liu, C. D., Loh, K. M., Fenno, L. E., Ramakrishnan, C., Deisseroth, K., & Luo, L.
- Affiliations
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Stanford Medicine (US)
- Corresponding author
- Allen, William E.
- DeNardo, Laura A.
- Chen, Michael Z.
- Deisseroth, Karl
- Luo, Liqun
- ORCID
- Venue
- Science
- Published
- 2017-09-15
- Volume
- 357
- Issue
- 6356
- Pages
- 1149-1155
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5723384
- OpenAlex
- W2754841759
- Cited by
- 390
- References
- 52
- Citations by year
- 2026: 41 · 2025: 67 · 2024: 67 · 2023: 39 · 2022: 32 · 2021: 38 · 2020: 43 · 2019: 35 · 2018: 23 · 2017: 3
- FWCI
- 17.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (award315464, 1546612)
- National Institutes of Health (award315463, TR01-MH099642, award340292, R01-NS50835)
- Howard Hughes Medical Institute (Hughes Collaborative Innovation Award, award315462)
- 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 › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- thirst, water deprivation, median preoptic nucleus, hypothalamus, aversive motivation, optogenetic stimulation, internal state
- MeSH terms
- Animals, Cell Line, Dehydration, Drinking Behavior, Motivation, Neurons, Preoptic Area, Thirst, Gene Expression Profiling, TNF Receptor-Associated Factor 2, Mice, Single-Cell Analysis, Optogenetics
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