Cited by 390Regulation of Appetite and ObesityNeurotransmitter Receptor Influence on BehaviorNeuroscience of respiration and sleep

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Thirst-associated preoptic neurons encode an aversive motivational drive.

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Allen, William E., DeNardo, Laura A., Chen, Michael Z., Liu, Cindy D., Loh, Kyle M., Fenno, Lief E., Ramakrishnan, Charu, Deisseroth, Karl, Luo, Liqun·2017·Science

DOI 10.1126/science.aan6747PMC PMC5723384

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Abstract

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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Background
Progesterone Receptor Activation Regulates Sensory Sensitivity and Migraine Susceptibility
Joshi, S., Williamson, J., Moosa, S., & Kapur, J. (2023) · Journal of Pain · doi:10.1016/j.jpain.2023.09.017 · Cited by 16
Activation of organum vasculosum neurones and water intake in mice by vasopressin neurones in the suprachiasmatic nucleus
Gizowski, C., Zaelzer, C. A., & Bourque, C. W. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12577 · Cited by 16
Neural populations for maintaining body fluid balance
Ichiki, T., Augustine, V., & Oka, Y. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.01.014 · Cited by 18
Neurobiology of Thirst and Hunger Drives
Encarnacion-Rivera, L., Deisseroth, K. A., & Luo, L. (2025) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-112723-032328 · Cited by 16
The median preoptic nucleus: A major regulator of fluid, temperature, sleep, and cardiovascular homeostasis
McKinley, M. J., Pennington, G. L., & Ryan, P. J. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-819975-6.00028-5 · Cited by 15
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst
Zagmutt, S., Mera, P., González‐García, I., Ibeas, K., Romero, M. D. M., Obri, A., Martín‐Mur, B., Esteve‐Codina, A., Soler‐Vázquez, M. C., Bastías-Pérez, M., et al. (2023) · Biology of Sex Differences · doi:10.1186/s13293-023-00498-8 · Cited by 14
Natural product P57 induces hypothermia through targeting pyridoxal kinase
Wang, R., Xiao, L., Pan, J., Bao, G., Zhu, Y., Zhu, D., Wang, J., Pei, C., Ma, Q., Fu, X., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41435-y · Cited by 15
“Further study combing TRAP mouse line 59 and optogenetic/chemogenetic tools may help us dissect the speci ﬁ c MPA neuron and neural circuit involved in the P57-induced hypothermia.”
Redundancy and multifunctionality among spinal locomotor networks
Pham, B., Luo, J., Anand, H., Kola, O., Salcedo, P., Nguyen, C., Gaunt, S., Zhong, H., Garfinkel, A., Tillakaratne, N. J. K., et al. (2020) · Journal of Neurophysiology · doi:10.1152/jn.00338.2020 · Cited by 15
“Thus far, FosTRAP has been used to probe network activity from somatosensory and visual stimuli in the brain along with fear-conditioning paradigms (Allen et al. 2017; Cazzulino et al. 2016; Chatzi et al. 2019; DeNardo et al. 2019; Girasole et al. 2018; Guenthner et al. 2013; Joshi and Panicker…”
BackgroundMethod
EphB2 receptor cell-autonomous forward signaling mediates auditory memory recall and learning-driven spinogenesis
Talebian, A., & Henkemeyer, M. J. (2019) · Communications Biology · doi:10.1038/s42003-019-0625-x · Cited by 15
Functional MRI of large scale activity in behaving micePreprint
Fonseca, M. S., Bergomi, M. G., Mainen, Z. F., & Shemesh, N. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.16.044941 · Cited by 15
“activation of neurons in the medial, also known as median, preoptic nucleus of the hypothalamus promotes operant lever pressing for water rewards at rates that scale with stimulation frequency (Allen et al., 2017).”
BackgroundResult
Increasing resolution in stress neurobiology: from single cells to complex group behaviors
Miranda, L., Bordes, J., Gasperoni, S., & López, J. P. (2023) · Stress · doi:10.1080/10253890.2023.2186141 · Cited by 15
“More specifically, using TRAP2 mice, Koutlas and colleagues showed that stress-activated neurons in the ventral tegmental area have different electrophysiological properties, as compared to non-activated neurons in the same region (Koutlas et al., 2022).”
BackgroundInfluential
Regulation of REM sleep in mice: The role of dopamine and serotonin function in the basolateral amygdala
Hasegawa, E., Li, Y., & Sakurai, T. (2023) · Neuroscience Research · doi:10.1016/j.neures.2023.09.003 · Cited by 14
“1(cre)Bkmn/J; ID# 006660, Jaxson Laboratory (B ¨ ackman et al., 2006) and ePet1-Cre (B6.”
MethodInfluential
Embryonically active piriform cortex neurons promote intracortical recurrent connectivity during development
Wang, D. C., Santos-Valencia, F., Song, J. H., Franks, K. M., & Luo, L. (2024) · Neuron · doi:10.1016/j.neuron.2024.06.007 · Cited by 14
Selectively Inhibiting the Median Preoptic Nucleus Attenuates Angiotensin II and Hyperosmotic-Induced Drinking Behavior and Vasopressin Release in Adult Male Rats
Marciante, A. B., Wang, L. A., Farmer, G. E., & Cunningham, J. T. (2019) · eNeuro · doi:10.1523/eneuro.0473-18.2019 · Cited by 14
“A recent study by Allen et al. (2017) used a new technique involving the induction of Fos in neurons, a measurement for acute neuronal activation, co-transfected with TRAP creating an in-frame fusion to characterize MnPO neurons based on their activation by water deprivation or changes in body…”
Method
Progression of human subjective perceptions during euhydration, mild dehydration, and drinking
Armstrong, L. E., Giersch, G. E. W., Colburn, A. T., Lopez, V., Sekiguchi, Y., Muñoz, C. X., & Lee, E. C. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.113211 · Cited by 14
“First, although decades of human [2,7,20,36] and animal studies [3,4,9] have focused on thirst as the primary impetus for seeking and consuming water, and have regarded thirst as an adequate stimulus for fluid replacement during sedentary daily activities [20], correlation matrix 6C and Tables 2-4 show that the percep…”
Remote Optogenetics Using Up/Down-Conversion Phosphors
Matsubara, T., & Yamashita, T. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.771717 · Cited by 14
“Optogenetics has been widely used to interrogate the causal functions of the activity and plasticity of specific neuronal circuits in behaviors and neurological diseases (e.g., Adamantidis et al., 2007; Tsai et al., 2009; Kravitz et al., 2010; Aponte et al., 2011; Liu et al., 2012; Nabavi et al., 2014; Ramirez et al.,…”
Method
Limbic progesterone receptors regulate spatial memory
Joshi, S., Williams, C. L., & Kapur, J. (2023) · Scientific Reports · doi:10.1038/s41598-023-29100-2 · Cited by 15
“An advanced version of TRAP mice described in our earlier study was also used (Allen et al., 2017).”
MethodInfluential
Ketamine Evokes Acute Behavioral Effects Via μ Opioid Receptor–Expressing Neurons of the Central Amygdala
Pomrenze, M. B., Vaillancourt, S., Llorach, P., Rijsketic, D. R., Casey, A. B., Gregory, N. S., Zhao, W., Girard, T. E., Mattox, K. T., Salgado, J. S., et al. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.04.020 · Cited by 14
A brain center that controls consummatory responses
Canovas, J. A., Wang, L., Mohamed, A. A. M., Abbott, L. F., & Zuker, C. S. (2025) · Cell · doi:10.1016/j.cell.2025.08.021 · Cited by 15
Anesthesia in mice activates discrete populations of neurons throughout the brain
Yatziv, S.-L., Yudco, O., Vaso, K., Mizrahi, A., & Devor, M. G. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24950 · Cited by 13
“To confirm the presence of the knock- in allele, mice were genotyped using primers for iCre as described in Allen et al. (2017).”
BackgroundMethod
Genetic Access to Gustatory Disgust-Associated Neurons in the Interstitial Nucleus of the Posterior Limb of the Anterior Commissure in Male Mice
Tanaka, D. H., Li, S., Mukae, S., & Tanabe, T. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.06.021 · Cited by 13
The how and why of sleep: Motor theory and catecholamine hypothesis
Ma, C., & Dan, Y. (2025) · Neuron · doi:10.1016/j.neuron.2025.08.017 · Cited by 13
All IEGs Are Not Created Equal—Molecular Sorting Within the Memory Engram
Yelhekar, T. D., Meng, M., Doupe, J., & Lin, Y. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-62983-9_6 · Cited by 12
Thirst-driven hygrosensory suppression promotes water seeking in Drosophila
Chu, L., Tai, C., & Chiang, A. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2404454121 · Cited by 12
Aldosterone-induced salt appetite requires HSD2 neurons
Gasparini, S., Peltekian, L., McDonough, M. C., Mitchell, C. J. A., Hefti, M. M., Resch, J. M., & Geerling, J. C. (2024) · JCI Insight · doi:10.1172/jci.insight.175087 · Cited by 14
Short-term social isolation acts on hypothalamic neurons to promote social behavior in a sex- and context-dependent manner
Zhao, X., Chae, Y. C., Smith, D., Chen, V., DeFelipe, D., Sokol, J. W., Sadangi, A., & Tschida, K. (2024) · eLife · doi:10.7554/elife.94924.3 · Cited by 13
TMEM63B functions as a mammalian hyperosmolar sensor for thirst
Zou, W., Deng, S., Chen, X., Ruan, J., Wang, H., Zhan, W., Wang, J., Liu, Z., & Yan, Z. (2025) · Neuron · doi:10.1016/j.neuron.2025.02.012 · Cited by 12
Engagement of basal amygdala‐nucleus accumbens glutamate neurons in the processing of rewarding or aversive social stimuli
Poggi, G., Bergamini, G., Dulinskas, R., Madur, L., Greter, A., Ineichen, C., Dagostino, A., Kúkeľová, D., Sigrist, H., Bornemann, K. D., et al. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16272 · Cited by 12
“Whilst the efficacy of the TRAP-ing method is somewhat limited (Allen et al., 2017; Sanders et al., 2019), the literature indicates it to be adequate for current purposes given the inclusion of appropriate control groups.”
Method
Neural Circuitry for Stress Information of Environmental and Internal Odor Worlds
Mori, K., & Sakano, H. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.943647 · Cited by 13
Characterizing and TRAPing a Social Stress-Activated Neuronal Ensemble in the Ventral Tegmental Area
Koutlas, I., Linders, L. E., van der Starre, S. E., Wolterink‐Donselaar, I. G., Adan, R. A. H., & Meye, F. J. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.936087 · Cited by 13
“There are notable differences between TRAP1 and TRAP2 as an approach, with the latter being less disruptive for endogenous Fos levels and having a more efficient form of Cre (Guenthner et al., 2013; Allen et al., 2017; DeNardo et al., 2019).”
Background
Brain circuits for retching-like behavior
Huo, L., Ye, Z., Liu, M., He, Z., Huang, M., Li, D., Wu, Q., Wang, Q., Wang, X., Cao, P., et al. (2023) · National Science Review · doi:10.1093/nsr/nwad256 · Cited by 13
“To test this hypothesis, we used the FosTRAP ( FosCreER mice) strategy [27 ] to genetically activate NTS neurons that were active during B. cereus -induced retching-like behavior.”
Method
Engagement of the brain orexin system in activity-based anorexia behaviour in mice
Schéle, E., Stoltenborg, I., Xie, A., Peris‐Sampedro, F., Adan, R. A. H., & Dickson, S. L. (2023) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2023.02.014 · Cited by 12
Suppression of neurons in circumventricular organs enables months-long survival without water in thirteen-lined ground squirrels
Junkins, M. S., Feng, N. Y., Merriman, D. K., Bagriantsev, S. N., & Gracheva, E. O. (2024) · Science · doi:10.1126/science.adp8358 · Cited by 10
Neural networks of the mouse visceromotor cortex
Hintiryan, H., Zhu, M., Zhao, P., Zhang, M., Barry, J., Nanda, S., Rudd, M., Wong, A., Miller, S. M., Gou, L., et al. (2025) · Nature · doi:10.1038/s41586-025-09360-w · Cited by 17
Capturing activated neurons and synapses
Choi, J., Kim, J., & Kim, J. (2019) · Neuroscience Research · doi:10.1016/j.neures.2019.12.020 · Cited by 11
Long‐lasting tagging of neurons activated by seizures or cocaine administration in Egr1‐CreER T2 transgenic mice
Longueville, S., Nakamura, Y., Brami‐Cherrier, K., Coura, R., Hervé, D., & Girault, J. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.15060 · Cited by 10
Rational regulation of water-seeking effort in rodents
Reinagel, P. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111742118 · Cited by 10
Motivation and Engagement during Visually Guided Behavior
Ortiz, A. V., Aziz, D. J., & Hestrin, S. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108272 · Cited by 9
“In support of this view, recent recordings in hypothalamic nuclei have shown that activity of thirst-sensitive neurons is reduced gradually over a course of 10 min and is correlated with the volume of water consumption (Allen et al., 2017).”
Influential

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: Allen, William E.
DeNardo, Laura A.
Chen, Michael Z.
Liu, Cindy D.
Loh, Kyle M.
Fenno, Lief E.
Ramakrishnan, Charu
Deisseroth, Karl
Luo, Liqun
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2017-09-15
Volume: 357
Issue: 6356
Pages: 1149-1155
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.aan6747
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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Thirst-associated preoptic neurons encode an aversive motivational drive.

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