{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:41:28Z","timestamp":1787161288771,"version":"build-2736575974"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Prolonged wakefulness increases sleep drive and is normally compensated for by increased sleep\n                    <jats:sup>1\u20133<\/jats:sup>\n                    . This homeostatic regulation of sleep shapes our lives profoundly, but the underlying neural circuit mechanisms remain poorly understood. Here, we identify wake-activated neurons that regulate sleep drive in mice, using whole-brain activity mapping, targeted neuronal manipulations and electrophysiology. By comparing whole-brain responses to sleep deprivation, recovery sleep and circadian behaviour, we identify the anterior medial preoptic area and the median raphe as candidate regions that encode sleep deficit. Activating sleep-deprivation-responsive cells in these regions induces increases in sleep duration and intensity that resemble recovery sleep. Conversely, inhibiting deprivation-responsive cells reduces sleep and abolishes the increased sleep propensity usually observed during deprivation. Neurons in the median raphe that are responsive to sleep deprivation project to subcortical sleep-associated regions and act through the preoptic hypothalamus. These deprivation-sensitive cells include serotonergic neurons and a distinct population of GABAergic neurons, whose intrinsic excitability increases during sleep deprivation. Co-activation of GABAergic and serotonergic neurons synergistically promotes sleep, whereas co-inhibition chronically decreases sleep by nearly 70%. Remarkably, most mice survive despite this marked reduction in sleep, without the compensatory increases in sleep drive or the behavioural deficits typically associated with severe sleep deprivation. Together, these results define neuronal populations that are activated during wakefulness and are crucial for sleep drive.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10928-3","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T15:23:59Z","timestamp":1787153039000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Wake-activated neuronal populations that regulate sleep drive"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2856-8372","authenticated-orcid":false,"given":"William","family":"Joo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3753-2492","authenticated-orcid":false,"given":"Clare","family":"Diester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1731-9910","authenticated-orcid":false,"given":"Vassilis","family":"Bitsikas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3621-0507","authenticated-orcid":false,"given":"Myrto","family":"Panopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Hidalgo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Ntemos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9010-2830","authenticated-orcid":false,"given":"Rodrigo C. G.","family":"Pena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabia","family":"Imhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Odstrcil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0732-1654","authenticated-orcid":false,"given":"Flavio","family":"Donato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Fucile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-4972","authenticated-orcid":false,"given":"Daniel","family":"Kroeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-8558","authenticated-orcid":false,"given":"Thomas E.","family":"Scammell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7645-5325","authenticated-orcid":false,"given":"Alexander F.","family":"Schier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"10928_CR1","first-page":"195","volume":"1","author":"AA Borbely","year":"1982","unstructured":"Borbely, A. A. A two process model of sleep regulation. Hum. Neurobiol. 1, 195\u2013204 (1982).","journal-title":"Hum. Neurobiol."},{"key":"10928_CR2","doi-asserted-by":"publisher","first-page":"311","DOI":"10.5665\/sleep.2440","volume":"36","author":"T Curie","year":"2013","unstructured":"Curie, T. et al. Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. Sleep 36, 311\u2013323 (2013).","journal-title":"Sleep"},{"key":"10928_CR3","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41583-023-00764-z","volume":"25","author":"P Franken","year":"2024","unstructured":"Franken, P. & Dijk, D. J. Sleep and circadian rhythmicity as entangled processes serving homeostasis. Nat. Rev. Neurosci. 25, 43\u201359 (2024).","journal-title":"Nat. Rev. Neurosci."},{"key":"10928_CR4","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/j.neuron.2017.01.014","volume":"93","author":"TE Scammell","year":"2017","unstructured":"Scammell, T. E., Arrigoni, E. & Lipton, J. O. Neural circuitry of wakefulness and sleep. Neuron 93, 747\u2013765 (2017).","journal-title":"Neuron"},{"key":"10928_CR5","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/nature19773","volume":"538","author":"F Weber","year":"2016","unstructured":"Weber, F. & Dan, Y. Circuit-based interrogation of sleep control. Nature 538, 51\u201359 (2016).","journal-title":"Nature"},{"key":"10928_CR6","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1126\/science.abi8372","volume":"374","author":"NP Franks","year":"2021","unstructured":"Franks, N. P. & Wisden, W. The inescapable drive to sleep: overlapping mechanisms of sleep and sedation. Science 374, 556\u2013559 (2021).","journal-title":"Science"},{"key":"10928_CR7","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1126\/science.adh8285","volume":"382","author":"AR Adamantidis","year":"2023","unstructured":"Adamantidis, A. R. & de Lecea, L. Sleep and the hypothalamus. Science 382, 405\u2013412 (2023).","journal-title":"Science"},{"key":"10928_CR8","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1146\/annurev-genom-121222-120306","volume":"25","author":"X Zou","year":"2024","unstructured":"Zou, X., Ptacek, L. J. & Fu, Y. H. The genetics of human sleep and sleep disorders. Annu.Rev. Genomics Hum. Genet. 25, 259\u2013285 https:\/\/doi.org\/10.1146\/annurev-genom-121222-120306 (2024).","journal-title":"Annu.Rev. Genomics Hum. Genet."},{"key":"10928_CR9","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/s41586-019-1034-5","volume":"568","author":"A Kempf","year":"2019","unstructured":"Kempf, A., Song, S. M., Talbot, C. B. & Miesenbock, G. A potassium channel \u03b2-subunit couples mitochondrial electron transport to sleep. Nature 568, 230\u2013234 (2019).","journal-title":"Nature"},{"key":"10928_CR10","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/s41586-018-0218-8","volume":"558","author":"Z Wang","year":"2018","unstructured":"Wang, Z. et al. Quantitative phosphoproteomic analysis of the molecular substrates of sleep need. Nature 558, 435\u2013439 (2018).","journal-title":"Nature"},{"key":"10928_CR11","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.conb.2013.02.010","volume":"23","author":"T Porkka-Heiskanen","year":"2013","unstructured":"Porkka-Heiskanen, T. Sleep homeostasis. Curr. Opin. Neurobiol. 23, 799\u2013805 (2013).","journal-title":"Curr. Opin. Neurobiol."},{"key":"10928_CR12","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a027730","volume":"9","author":"R Allada","year":"2017","unstructured":"Allada, R., Cirelli, C. & Sehgal, A. Molecular mechanisms of sleep homeostasis in flies and mammals. Cold Spring Harb. Perspect. Biol. 9, a027730 (2017).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"10928_CR13","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.neuron.2011.11.027","volume":"73","author":"T Liu","year":"2012","unstructured":"Liu, T. et al. Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73, 511\u2013522 (2012).","journal-title":"Neuron"},{"key":"10928_CR14","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1016\/j.molmet.2014.07.002","volume":"3","author":"K Tan","year":"2014","unstructured":"Tan, K., Knight, Z. A. & Friedman, J. M. Ablation of AgRP neurons impairs adaption to restricted feeding. Mol. Metab. 3, 694\u2013704 (2014).","journal-title":"Mol. Metab."},{"key":"10928_CR15","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/nature14108","volume":"520","author":"Y Oka","year":"2015","unstructured":"Oka, Y., Ye, M. & Zuker, C. S. Thirst driving and suppressing signals encoded by distinct neural populations in the brain. Nature 520, 349\u2013352 (2015).","journal-title":"Nature"},{"key":"10928_CR16","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1126\/science.aan6747","volume":"357","author":"WE Allen","year":"2017","unstructured":"Allen, W. E. et al. Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357, 1149\u20131155 (2017).","journal-title":"Science"},{"key":"10928_CR17","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/s41586-020-2821-8","volume":"588","author":"AH Pool","year":"2020","unstructured":"Pool, A. H. et al. The cellular basis of distinct thirst modalities. Nature 588, 112\u2013117 (2020).","journal-title":"Nature"},{"key":"10928_CR18","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/nn.3957","volume":"18","author":"Z Zhang","year":"2015","unstructured":"Zhang, Z. et al. Neuronal ensembles sufficient for recovery sleep and the sedative actions of \u03b12 adrenergic agonists. Nat. Neurosci. 18, 553\u2013561 (2015).","journal-title":"Nat. Neurosci."},{"key":"10928_CR19","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1126\/science.271.5246.216","volume":"271","author":"JE Sherin","year":"1996","unstructured":"Sherin, J. E., Shiromani, P. J., McCarley, R. W. & Saper, C. B. Activation of ventrolateral preoptic neurons during sleep. Science 271, 216\u2013219 (1996).","journal-title":"Science"},{"key":"10928_CR20","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1016\/j.cell.2019.03.041","volume":"177","author":"Z Zhang","year":"2019","unstructured":"Zhang, Z. et al. An excitatory circuit in the perioculomotor midbrain for non-REM sleep control. Cell 177, 1293\u20131307 (2019).","journal-title":"Cell"},{"key":"10928_CR21","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1038\/s41593-023-01430-4","volume":"26","author":"K Tossell","year":"2023","unstructured":"Tossell, K. et al. Somatostatin neurons in prefrontal cortex initiate sleep-preparatory behavior and sleep via the preoptic and lateral hypothalamus. Nat. Neurosci. 26, 1805\u20131819 (2023).","journal-title":"Nat. Neurosci."},{"key":"10928_CR22","doi-asserted-by":"publisher","DOI":"10.1126\/science.aea3381","volume":"391","author":"K Yamashita","year":"2025","unstructured":"Yamashita, K. et al. A whole-brain single-cell atlas of circadian neural activity in mice. Science 391, eaea3381 https:\/\/doi.org\/10.1126\/science.aea3381 (2025).","journal-title":"Science"},{"key":"10928_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3003472","volume":"23","author":"G Sun","year":"2025","unstructured":"Sun, G. et al. A framework to determine active neurons and networks within the mouse brain reveals how brain activity changes over the course of the day. PLoS Biol. 23, e3003472 (2025).","journal-title":"PLoS Biol."},{"key":"10928_CR24","doi-asserted-by":"publisher","unstructured":"Swaney, J. et al. Scalable image processing techniques for quantitative analysis of volumetric biological images from light-sheet microscopy. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/576595 (2019).","DOI":"10.1101\/576595"},{"key":"10928_CR25","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1007\/s12021-020-09490-8","volume":"19","author":"J Perens","year":"2021","unstructured":"Perens, J. et al. An optimized mouse brain atlas for automated mapping and quantification of neuronal activity using iDISCO+ and light sheet fluorescence microscopy. Neuroinformatics 19, 433\u2013446 (2021).","journal-title":"Neuroinformatics"},{"key":"10928_CR26","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.neuron.2020.08.001","volume":"108","author":"B Collins","year":"2020","unstructured":"Collins, B. et al. Circadian VIPergic neurons of the suprachiasmatic nuclei sculpt the sleep\u2013wake cycle. Neuron 108, 486\u2013499 (2020).","journal-title":"Neuron"},{"key":"10928_CR27","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/S0306-4522(02)00308-1","volume":"115","author":"SE Gaus","year":"2002","unstructured":"Gaus, S. E., Strecker, R. E., Tate, B. A., Parker, R. A. & Saper, C. B. Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species. Neuroscience 115, 285\u2013294 (2002).","journal-title":"Neuroscience"},{"key":"10928_CR28","doi-asserted-by":"publisher","first-page":"3830","DOI":"10.1523\/JNEUROSCI.20-10-03830.2000","volume":"20","author":"J Lu","year":"2000","unstructured":"Lu, J., Greco, M. A., Shiromani, P. & Saper, C. B. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J. Neurosci. 20, 3830\u20133842 (2000).","journal-title":"J. Neurosci."},{"key":"10928_CR29","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nature22350","volume":"545","author":"S Chung","year":"2017","unstructured":"Chung, S. et al. Identification of preoptic sleep neurons using retrograde labelling and gene profiling. Nature 545, 477\u2013481 (2017).","journal-title":"Nature"},{"key":"10928_CR30","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.1016\/j.cub.2019.07.087","volume":"29","author":"Y Ma","year":"2019","unstructured":"Ma, Y. et al. Galanin neurons unite sleep homeostasis and \u03b12-adrenergic sedation. Curr. Biol. 29, 3315\u20133322 (2019).","journal-title":"Curr. Biol."},{"key":"10928_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06590-7","volume":"9","author":"D Kroeger","year":"2018","unstructured":"Kroeger, D. et al. Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice. Nat. Commun. 9, 4129 (2018).","journal-title":"Nat. Commun."},{"key":"10928_CR32","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.neuron.2019.08.026","volume":"104","author":"P Zhong","year":"2019","unstructured":"Zhong, P. et al. Control of non-REM sleep by midbrain neurotensinergic neurons. Neuron 104, 795\u2013809 (2019).","journal-title":"Neuron"},{"key":"10928_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32461-3","volume":"13","author":"S Teng","year":"2022","unstructured":"Teng, S. et al. Control of non-REM sleep by ventrolateral medulla glutamatergic neurons projecting to the preoptic area. Nat. Commun. 13, 4748 (2022).","journal-title":"Nat. Commun."},{"key":"10928_CR34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0006-8993(98)00828-2","volume":"816","author":"A Morien","year":"1999","unstructured":"Morien, A., Garrard, L. & Rowland, N. E. Expression of Fos immunoreactivity in rat brain during dehydration: effect of duration and timing of water deprivation. Brain Res. 816, 1\u20137 (1999).","journal-title":"Brain Res."},{"key":"10928_CR35","doi-asserted-by":"publisher","first-page":"7743","DOI":"10.1523\/JNEUROSCI.20-20-07743.2000","volume":"20","author":"E Watanabe","year":"2000","unstructured":"Watanabe, E. et al. Nav2\/NaG channel is involved in control of salt-intake behavior in the CNS. J. Neurosci. 20, 7743\u20137751 (2000).","journal-title":"J. Neurosci."},{"key":"10928_CR36","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/S1054-3589(08)60326-9","volume":"6","author":"M Jouvet","year":"1968","unstructured":"Jouvet, M. Insomnia and decrease of cerebral 5-hydroxytryptamine after destruction of the raphe system in the cat. Adv. Pharmacol. 6, 265\u2013279 (1968).","journal-title":"Adv. Pharmacol."},{"key":"10928_CR37","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/0361-9230(79)90033-9","volume":"4","author":"T Yamamoto","year":"1979","unstructured":"Yamamoto, T., Watanabe, S., Oishi, R. & Ueki, S. Effects of midbrain raphe stimulation and lesion on EEG activity in rats. Brain Res. Bull. 4, 491\u2013495 (1979).","journal-title":"Brain Res. Bull."},{"key":"10928_CR38","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1016\/j.neuron.2019.05.038","volume":"103","author":"G Oikonomou","year":"2019","unstructured":"Oikonomou, G. et al. The serotonergic raphe promote sleep in zebrafish and mice. Neuron 103, 686\u2013701 (2019).","journal-title":"Neuron"},{"key":"10928_CR39","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00535","volume":"12","author":"K Iwasaki","year":"2018","unstructured":"Iwasaki, K. et al. Ablation of central serotonergic neurons decreased REM sleep and attenuated arousal response. Front. Neurosci. 12, 535 (2018).","journal-title":"Front. Neurosci."},{"key":"10928_CR40","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1038\/s41593-018-0318-7","volume":"22","author":"LA DeNardo","year":"2019","unstructured":"DeNardo, L. A. et al. Temporal evolution of cortical ensembles promoting remote memory retrieval. Nat. Neurosci. 22, 460\u2013469 (2019).","journal-title":"Nat. Neurosci."},{"key":"10928_CR41","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.cell.2014.04.045","volume":"158","author":"PE Rothwell","year":"2014","unstructured":"Rothwell, P. E. et al. Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell 158, 198\u2013212 (2014).","journal-title":"Cell"},{"key":"10928_CR42","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1038\/s41593-021-00894-6","volume":"24","author":"LB Krone","year":"2021","unstructured":"Krone, L. B. et al. A role for the cortex in sleep\u2013wake regulation. Nat. Neurosci. 24, 1210\u20131215 (2021).","journal-title":"Nat. Neurosci."},{"key":"10928_CR43","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1007\/s00429-014-0924-4","volume":"221","author":"A Muzerelle","year":"2016","unstructured":"Muzerelle, A., Scotto-Lomassese, S., Bernard, J. F., Soiza-Reilly, M. & Gaspar, P. Conditional anterograde tracing reveals distinct targeting of individual serotonin cell groups (B5\u2013B9) to the forebrain and brainstem. Brain Struct. Funct. 221, 535\u2013561 (2016).","journal-title":"Brain Struct. Funct."},{"key":"10928_CR44","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65502","volume":"10","author":"Z Xu","year":"2021","unstructured":"Xu, Z. et al. Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in the mouse dorsal and median raphe nuclei. eLife 10, e65502 (2021).","journal-title":"eLife"},{"key":"10928_CR45","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1523\/JNEUROSCI.16-06-02097.1996","volume":"16","author":"EL Meyer-Bernstein","year":"1996","unstructured":"Meyer-Bernstein, E. L. & Morin, L. P. Differential serotonergic innervation of the suprachiasmatic nucleus and the intergeniculate leaflet and its role in circadian rhythm modulation. J. Neurosci. 16, 2097\u20132111 (1996).","journal-title":"J. Neurosci."},{"key":"10928_CR46","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/s41586-024-07692-7","volume":"632","author":"G Maddaloni","year":"2024","unstructured":"Maddaloni, G., Chang, Y. J., Senft, R. A. & Dymecki, S. M. Adaptation to photoperiod via dynamic neurotransmitter segregation. Nature 632, 147\u2013156 (2024).","journal-title":"Nature"},{"key":"10928_CR47","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/s00429-016-1217-x","volume":"222","author":"KE Sos","year":"2017","unstructured":"Sos, K. E. et al. Cellular architecture and transmitter phenotypes of neurons of the mouse median raphe region. Brain Struct. Funct. 222, 287\u2013299 (2017).","journal-title":"Brain Struct. Funct."},{"key":"10928_CR48","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay8746","volume":"366","author":"A Szonyi","year":"2019","unstructured":"Szonyi, A. et al. Median raphe controls acquisition of negative experience in the mouse. Science 366, eaay8746 (2019).","journal-title":"Science"},{"key":"10928_CR49","doi-asserted-by":"publisher","first-page":"E5464","DOI":"10.1073\/pnas.1700983114","volume":"114","author":"A Vassalli","year":"2017","unstructured":"Vassalli, A. & Franken, P. Hypocretin (orexin) is critical in sustaining theta\/gamma-rich waking behaviors that drive sleep need. Proc. Natl Acad. Sci. USA 114, E5464\u2013E5473 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10928_CR50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2101580118","volume":"118","author":"T Yamagata","year":"2021","unstructured":"Yamagata, T. et al. The hypothalamic link between arousal and sleep homeostasis in mice. Proc. Natl Acad. Sci. USA 118, e2101580118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10928_CR51","doi-asserted-by":"publisher","first-page":"9687","DOI":"10.1523\/JNEUROSCI.23-29-09687.2003","volume":"23","author":"CM McDermott","year":"2003","unstructured":"McDermott, C. M. et al. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J. Neurosci. 23, 9687\u20139695 (2003).","journal-title":"J. Neurosci."},{"key":"10928_CR52","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2014.00389","volume":"8","author":"VC Rossi","year":"2014","unstructured":"Rossi, V. C. et al. Effects of sleep deprivation on different phases of memory in the rat: dissociation between contextual and tone fear conditioning tasks. Front. Behav. Neurosci. 8, 389 (2014).","journal-title":"Front. Behav. Neurosci."},{"key":"10928_CR53","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1101\/lm.48803","volume":"10","author":"LA Graves","year":"2003","unstructured":"Graves, L. A., Heller, E. A., Pack, A. I. & Abel, T. Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learn Mem. 10, 168\u2013176 (2003).","journal-title":"Learn Mem."},{"key":"10928_CR54","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.bbi.2017.04.007","volume":"64","author":"GC Kincheski","year":"2017","unstructured":"Kincheski, G. C. et al. Chronic sleep restriction promotes brain inflammation and synapse loss, and potentiates memory impairment induced by amyloid-\u03b2 oligomers in mice. Brain Behav. Immun. 64, 140\u2013151 (2017).","journal-title":"Brain Behav. Immun."},{"key":"10928_CR55","doi-asserted-by":"publisher","first-page":"10227","DOI":"10.1073\/pnas.0803125105","volume":"105","author":"D Gerashchenko","year":"2008","unstructured":"Gerashchenko, D. et al. Identification of a population of sleep-active cerebral cortex neurons. Proc. Natl Acad. Sci. USA 105, 10227\u201310232 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10928_CR56","doi-asserted-by":"publisher","first-page":"20272","DOI":"10.1073\/pnas.1314762110","volume":"110","author":"SR Morairty","year":"2013","unstructured":"Morairty, S. R. et al. A role for cortical nNOS\/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity. Proc. Natl Acad. Sci. USA 110, 20272\u201320277 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10928_CR57","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1038\/nn.4377","volume":"19","author":"A Eban-Rothschild","year":"2016","unstructured":"Eban-Rothschild, A., Rothschild, G., Giardino, W. J., Jones, J. R. & de Lecea, L. VTA dopaminergic neurons regulate ethologically relevant sleep\u2212wake behaviors. Nat. Neurosci. 19, 1356\u20131366 (2016).","journal-title":"Nat. Neurosci."},{"key":"10928_CR58","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1016\/j.cub.2016.05.078","volume":"26","author":"A Venner","year":"2016","unstructured":"Venner, A., Anaclet, C., Broadhurst, R. Y., Saper, C. B. & Fuller, P. M. A novel population of wake-promoting GABAergic neurons in the ventral lateral hypothalamus. Curr. Biol. 26, 2137\u20132143 (2016).","journal-title":"Curr. Biol."},{"key":"10928_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9744","volume":"6","author":"C Anaclet","year":"2015","unstructured":"Anaclet, C. et al. Basal forebrain control of wakefulness and cortical rhythms. Nat. Commun. 6, 8744 (2015).","journal-title":"Nat. Commun."},{"key":"10928_CR60","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.nbscr.2018.02.001","volume":"5","author":"TE Bjorness","year":"2018","unstructured":"Bjorness, T. E. & Greene, R. W. Dose response of acute cocaine on sleep\/waking behavior in mice. Neurobiol. Sleep Circadian Rhythms 5, 84\u201393 (2018).","journal-title":"Neurobiol. Sleep Circadian Rhythms"},{"key":"10928_CR61","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.neulet.2012.02.040","volume":"513","author":"MA Schmidt","year":"2012","unstructured":"Schmidt, M. A. & Wisor, J. P. Interleukin 1 receptor contributes to methamphetamine- and sleep deprivation-induced hypersomnolence. Neurosci. Lett. 513, 209\u2013213 (2012).","journal-title":"Neurosci. Lett."},{"key":"10928_CR62","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/S0306-4522(00)00518-2","volume":"102","author":"D Aeschbach","year":"2001","unstructured":"Aeschbach, D. et al. Evidence from the waking electroencephalogram that short sleepers live under higher homeostatic sleep pressure than long sleepers. Neuroscience 102, 493\u2013502 (2001).","journal-title":"Neuroscience"},{"key":"10928_CR63","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1523\/JNEUROSCI.2182-17.2018","volume":"38","author":"HR Smith","year":"2018","unstructured":"Smith, H. R. et al. Dorsal raphe serotonin neurons mediate CO2-induced arousal from sleep. J. Neurosci. 38, 1915\u20131925 (2018).","journal-title":"J. Neurosci."},{"key":"10928_CR64","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsz231","volume":"43","author":"A Venner","year":"2020","unstructured":"Venner, A., Broadhurst, R. Y., Sohn, L. T., Todd, W. D. & Fuller, P. M. Selective activation of serotoninergic dorsal raphe neurons facilitates sleep through anxiolysis. Sleep 43, zsz231 (2020).","journal-title":"Sleep"},{"key":"10928_CR65","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/s41586-025-08672-1","volume":"641","author":"M Ahmadlou","year":"2025","unstructured":"Ahmadlou, M. et al. A subcortical switchboard for perseverative, exploratory and disengaged states. Nature 641, 151\u2013161 (2025).","journal-title":"Nature"},{"key":"10928_CR66","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/j.neuron.2010.11.032","volume":"68","author":"CB Saper","year":"2010","unstructured":"Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J. & Scammell, T. E. Sleep state switching. Neuron 68, 1023\u20131042 (2010).","journal-title":"Neuron"},{"key":"10928_CR67","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.neuron.2014.07.002","volume":"83","author":"I Pollak Dorocic","year":"2014","unstructured":"Pollak Dorocic, I. et al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron 83, 663\u2013678 (2014).","journal-title":"Neuron"},{"key":"10928_CR68","doi-asserted-by":"publisher","DOI":"10.1126\/science.adm8203","volume":"388","author":"SS Lee","year":"2025","unstructured":"Lee, S. S. et al. Sleep need-dependent plasticity of a thalamic circuit promotes homeostatic recovery sleep. Science 388, eadm8203 (2025).","journal-title":"Science"},{"key":"10928_CR69","doi-asserted-by":"publisher","first-page":"2823","DOI":"10.1016\/j.cub.2026.04.059","volume":"36","author":"W Ba","year":"2026","unstructured":"Ba, W. et al. Wake-active brainstem GABA neurons signal sleep pressure by upregulating AMPA receptors to drive recovery sleep. Curr. Biol. 36, 2823\u20132839 (2026).","journal-title":"Curr. Biol."},{"key":"10928_CR70","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.cell.2016.04.013","volume":"165","author":"S Liu","year":"2016","unstructured":"Liu, S., Liu, Q., Tabuchi, M. & Wu, M. N. Sleep drive is encoded by neural plastic changes in a dedicated circuit. Cell 165, 1347\u20131360 (2016).","journal-title":"Cell"},{"key":"10928_CR71","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1016\/j.cell.2011.07.039","volume":"146","author":"Y Yang","year":"2011","unstructured":"Yang, Y., Atasoy, D., Su, H. H. & Sternson, S. M. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992\u20131003 (2011).","journal-title":"Cell"},{"key":"10928_CR72","doi-asserted-by":"publisher","first-page":"5376","DOI":"10.1016\/j.cell.2024.07.047","volume":"187","author":"G Wu","year":"2024","unstructured":"Wu, G. et al. Opposing GPCR signaling programs protein intake setpoint in Drosophila. Cell 187, 5376\u20135392 (2024).","journal-title":"Cell"},{"key":"10928_CR73","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41586-024-08164-8","volume":"637","author":"SX Zhang","year":"2025","unstructured":"Zhang, S. X. et al. Stochastic neuropeptide signals compete to calibrate the rate of satiation. Nature 637, 137\u2013144 https:\/\/doi.org\/10.1038\/s41586-024-08164-8 (2025).","journal-title":"Nature"},{"key":"10928_CR74","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.molcel.2020.12.029","volume":"81","author":"SC Thornquist","year":"2021","unstructured":"Thornquist, S. C., Pitsch, M. J., Auth, C. S. & Crickmore, M. A. Biochemical evidence accumulates across neurons to drive a network-level eruption. Mol. Cell 81, 675\u2013690 (2021).","journal-title":"Mol. Cell"},{"key":"10928_CR75","doi-asserted-by":"publisher","first-page":"6785","DOI":"10.1016\/j.cell.2024.09.030","volume":"187","author":"R Yan","year":"2024","unstructured":"Yan, R. et al. The multi-stage plasticity in the aggression circuit underlying the winner effect. Cell 187, 6785\u20136803 https:\/\/doi.org\/10.1016\/j.cell.2024.09.030 (2024).","journal-title":"Cell"},{"key":"10928_CR76","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13057-w","volume":"10","author":"U Chon","year":"2019","unstructured":"Chon, U., Vanselow, D. J., Cheng, K. C. & Kim, Y. Enhanced and unified anatomical labeling for a common mouse brain atlas. Nat. Commun. 10, 5067 (2019).","journal-title":"Nat. Commun."},{"key":"10928_CR77","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.jneumeth.2004.09.020","volume":"143","author":"X Zhuang","year":"2005","unstructured":"Zhuang, X., Masson, J., Gingrich, J. A., Rayport, S. & Hen, R. Targeted gene expression in dopamine and serotonin neurons of the mouse brain. J. Neurosci. Methods 143, 27\u201332 (2005).","journal-title":"J. Neurosci. Methods"},{"key":"10928_CR78","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.neuron.2011.05.028","volume":"71","author":"L Vong","year":"2011","unstructured":"Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142\u2013154 (2011).","journal-title":"Neuron"},{"key":"10928_CR79","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.cell.2014.10.010","volume":"159","author":"N Renier","year":"2014","unstructured":"Renier, N. et al. iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 159, 896\u2013910 (2014).","journal-title":"Cell"},{"key":"10928_CR80","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","volume":"8","author":"WE Johnson","year":"2007","unstructured":"Johnson, W. E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118\u2013127 (2007).","journal-title":"Biostatistics"},{"key":"10928_CR81","doi-asserted-by":"publisher","first-page":"2610","DOI":"10.1523\/JNEUROSCI.21-08-02610.2001","volume":"21","author":"P Franken","year":"2001","unstructured":"Franken, P., Chollet, D. & Tafti, M. The homeostatic regulation of sleep need is under genetic control. J. Neurosci. 21, 2610\u20132621 (2001).","journal-title":"J. Neurosci."},{"key":"10928_CR82","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3389\/fninf.2019.00075","volume":"13","author":"SC Yates","year":"2019","unstructured":"Yates, S. C. et al. QUINT: workflow for quantification and spatial analysis of features in histological images from rodent brain. Front. Neuroinform. 13, 75 (2019).","journal-title":"Front. Neuroinform."},{"key":"10928_CR83","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-017-0377-3","volume":"15","author":"Y Ben-Shaul","year":"2017","unstructured":"Ben-Shaul, Y. OptiMouse: a comprehensive open source program for reliable detection and analysis of mouse body and nose positions. BMC Biol. 15, 41 (2017).","journal-title":"BMC Biol."},{"key":"10928_CR84","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk0997","volume":"385","author":"VA Kveim","year":"2024","unstructured":"Kveim, V. A. et al. Divergent recruitment of developmentally defined neuronal ensembles supports memory dynamics. Science 385, eadk0997 (2024).","journal-title":"Science"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10928-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10928-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10928-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:02:30Z","timestamp":1787158950000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10928-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":84,"alternative-id":["10928"],"URL":"https:\/\/doi.org\/10.1038\/s41586-026-10928-3","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"assertion":[{"value":"17 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}