A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia
Open accessAbstract
One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Shaker potassium channel mutants in fruit flies show a 25-50% right-shift in volatile anesthetic dose-response and can exit anesthesia at doses where wild-type siblings remain anesthetized and immobile.
“These flies display a resistant, right-shift in their volatile anesthetic dose-response curves of roughly 25%−50% but, more remarkably, are capable of exiting states of anesthesia at doses in which their wild-type siblings remain fully anesthetized and immobile [54–57].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [54]
The shared circuits hypothesis between sleep and anesthesia has been replicated across invertebrates to mammals.
“This shared circuits hypothesis has been replicated across divergent species spanning invertebrates to mammals [54, 58, 82, 98, 99, 101].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [54]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The sleep switch: hypothalamic control of sleep and wakefulness
Saper, C. B., Chou, T. C., & Scammell, T. E. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)02002-6 · Cited by 1,656 · see citing works
Correlates of Sleep and Waking in Drosophila melanogaster
Shaw, P. J., Cirelli, C., Greenspan, R. J., & Tononi, G. (2000) · Science · doi:10.1126/science.287.5459.1834 · Cited by 1,300 · see citing works
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal
Franks, N. P. (2008) · Nature reviews. Neuroscience · doi:10.1038/nrn2372 · Cited by 1,266 · see citing works
Alkire, M. T., Hudetz, A. G., & Tononi, G. (2008) · Science · doi:10.1126/science.1149213 · Cited by 1,245 · see citing works
Rest in Drosophila is a sleep-like state
Hendricks, J. C., Finn, S. M., Panckeri, K. A., Chavkin, J., Williams, J. A., Sehgal, A., & Pack, A. I. (2000) · Neuron · doi:10.1016/s0896-6273(00)80877-6 · Cited by 1,050 · see citing works
Self-citationThe neural correlate of (un)awareness: lessons from the vegetative state
Laureys, S. (2005) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2005.10.010 · Cited by 813 · see citing works
Molecular and neuronal substrates for general anaesthetics
Rudolph, U., & Antkowiak, B. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1496 · Cited by 771 · see citing works
Hysteresis and hierarchies: Dynamics of disorder-driven first-order phase transformations
Sethna, J. P., Dahmen, K. A., Kartha, S., KRUMHANSL, J. A., Roberts, B. W., & Shore, J. D. (1993) · Physical Review Letters · doi:10.1103/physrevlett.70.3347 · Cited by 723 · see citing works
Vincze, G., Barner, J. C., Linn, W. D., Johnsrud, M. T., Shepherd, M. D., & Wilson, J. P. (2015) · doi:10.1002/9781119183617.ch8 · Cited by 600 · see citing works
Noradrenaline is essential for mouse fetal development
THOMAS, S. A., Matsumoto, A. M., & Palmiter, R. D. (1995) · Nature · doi:10.1038/374643a0 · Cited by 534 · see citing works
Self-citationIdentification of sleep-promoting neurons in vitro
Gallopin, T., Fort, P., Eggermann, E., Cauli, B., Luppi, P.-H., Rossier, J., Audinat, E., Mühlethaler, M., & Serafin, M. (2000) · Nature · doi:10.1038/35010109 · Cited by 504 · see citing works
Reduced sleep in Drosophila Shaker mutants
Cirelli, C., Bushey, D., Hill, S., Huber, R., Kreber, R. A., Ganetzky, B., & Tononi, G. (2005) · Nature · doi:10.1038/nature03486 · Cited by 474 · see citing works
Tassi, P., & Muzet, A. (2000) · Sleep Medicine Reviews · doi:10.1053/smrv.2000.0098 · Cited by 458 · see citing works
Sleep in Drosophila is regulated by adult mushroom bodies
Joiner, W. J., Crocker, A. J., White, B. H., & Sehgal, A. (2006) · Nature · doi:10.1038/nature04811 · Cited by 455 · see citing works
Self-citationElastic energy storage in tendons: mechanical differences related to function and age
Shadwick, R. E. (1990) · Journal of Applied Physiology · doi:10.1152/jappl.1990.68.3.1033 · Cited by 362 · see citing works
An essential role for orexins in emergence from general anesthesia
Kelz, M. B., Sun, Y., Chen, J., Cheng Meng, Q., Moore, J. T., Veasey, S. C., Dixon, S., Thornton, M., Funato, H., & Yanagisawa, M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707146105 · Cited by 341 · see citing works
Self-citationOrexin neuronal circuitry: Role in the regulation of sleep and wakefulness
Ohno, K., & Sakurai, T. (2007) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2007.08.001 · Cited by 269 · see citing works
Sleep, Anesthesiology, and the Neurobiology of Arousal State Control
Lydic, R., & Baghdoyan, H. A. (2005) · Anesthesiology · doi:10.1097/00000542-200512000-00024 · Cited by 251 · see citing works
Siegel, J. M. (1999) · Cell · doi:10.1016/s0092-8674(00)81969-8 · Cited by 235 · see citing works
McCormick, D. A., Pape, H.-C., & Williamson, A. (1991) · Progress in Brain Research · doi:10.1016/s0079-6123(08)63817-0 · Cited by 209 · see citing works
Restoration of Norepinephrine and Reversal of Phenotypes in Mice Lacking Dopamine β‐Hydroxylase
THOMAS, S. A., Marck, B. T., Palmiter, R. D., & Matsumoto, A. M. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70062468.x · Cited by 188 · see citing works
Self-citationBruhn, J., Röpcke, H., Rehberg, B., Bouillon, T. W., & Hoeft, A. (2000) · Anesthesiology · doi:10.1097/00000542-200010000-00018 · Cited by 161 · see citing works
Berridge, C. W., & Foote, S. L. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-21-06999.1996 · Cited by 151 · see citing works
Alternating vigilance states: new insights regarding neuronal networks and mechanisms
Fort, P., Bassetti, C. L., & Luppi, P. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06722.x · Cited by 148 · see citing works
Drosophila tracheal morphogenesis: intricate cellular solutions to basic plumbing problems
Uv, A. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(03)00083-7 · Cited by 140 · see citing works
Modelling general anaesthesia as a first-order phase transition in the cortex
Steyn‐Ross, M. L., Steyn‐Ross, D. A., & Sleigh, J. W. (2004) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2004.02.001 · Cited by 137 · see citing works
Elastic pressure-volume curves: what information do they convey?
Jonson, B., & Svantesson, C. (1999) · Thorax · doi:10.1136/thx.54.1.82 · Cited by 118 · see citing works
Miller, R. D., Way, W. L., & Eger, E. I. (1968) · Anesthesiology · doi:10.1097/00000542-196811000-00012 · Cited by 115 · see citing works
Ouyang, M., Hellman, K. M., Abel, T. G., & THOMAS, S. A. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00226.2004 · Cited by 111 · see citing works
Self-citationAlkire, M. T., Asher, C. D., Franciscus, A. M., & Hahn, E. L. (2009) · Anesthesiology · doi:10.1097/aln.0b013e31819c461c · Cited by 105 · see citing works
Campbell, J. L., & Nash, H. A. (2001) · Journal of Neurobiology · doi:10.1002/neu.10009 · Cited by 87 · see citing works
Keifer, J. C., Baghdoyan, H. A., & Lydic, R. (1996) · Anesthesiology · doi:10.1097/00000542-199604000-00023 · Cited by 82 · see citing works
McKay, I. D. H., Voss, L. J., Sleigh, J. W., Barnard, J. P. M., & Johannsen, E. K. (2005) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000184825.65124.24 · Cited by 72 · see citing works
Drosophila melanogaster as a Model for Study of General Anesthesia
Allada, R., & Nash, H. A. (1993) · Anesthesia & Analgesia · doi:10.1213/00000539-199307000-00005 · Cited by 62 · see citing works
Roizen, M. F., White, P. F., Eger, E. I., & Brownstein, M. (1978) · Anesthesiology · doi:10.1097/00000542-197810000-00005 · Cited by 60 · see citing works
Steyn‐Ross, D. A., Steyn‐Ross, M. L., Wilcocks, L. C., & SLEIGH, J. W. (2001) · Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics · doi:10.1103/physreve.64.011918 · Cited by 60 · see citing works
Kreuer, S., Wilhelm, W., Grundmann, U., et al. (2004) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000103182.78466.ef · Cited by 59 · see citing works
Tweaking biological switches through a better understanding of bistability behavior
Chatterjee, A., Kaznessis, Y. N., & Hu, W. (2008) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2008.08.010 · Cited by 48 · see citing works
van Swinderen, B., & Waldowski, R. A. (2003) · Behavioural Processes · doi:10.1016/s0376-6357(03)00131-1 · Cited by 42 · see citing works
High throughput modular chambers for rapid evaluation of anesthetic sensitivity
Sun, Y., Chen, J., Pruckmayr, G. T., Baumgardner, J. E., Eckmann, D. M., Eckenhoff, R. G., & Kelz, M. B. (2006) · BMC Anesthesiology · doi:10.1186/1471-2253-6-13 · Cited by 41 · see citing works
Self-citationAnalysis of anesthetic action on the potassium channels of the Shaker mutant of Drosophila
TINKLENBERG, J. A., SEGAL, I. S., TIANZHI, G., & MAZE, M. (1991) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1991.tb33884.x · Cited by 39 · see citing works
Quantitative Autoradiography of Halothane Binding in Rat Brain
Eckenhoff, M. F., & Eckenhoff, R. G. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37402-6 · Cited by 39 · see citing works
Self-citationBerridge, C. W., & O'Neill, J. (2001) · Behavioral Neuroscience · doi:10.1037/0735-7044.115.1.165 · Cited by 38 · see citing works
Halothane-induced Hypnosis Is Not Accompanied by Inactivation of Orexinergic Output in Rodents
Gompf, H. S., Chen, J., Sun, Y., Yanagisawa, M., Aston‐Jones, G., & Kelz, M. B. (2009) · Anesthesiology · doi:10.1097/aln.0b013e3181b764b3 · Cited by 37 · see citing works
Self-citationMesa, A., Diaz, A. P., & Frosth, M. (2000) · Anesthesiology · doi:10.1097/00000542-200004000-00040 · Cited by 36 · see citing works
A succession of anesthetic endpoints in the <i>Drosophila</i> brain
van Swinderen, B. (2006) · Journal of Neurobiology · doi:10.1002/neu.20300 · Cited by 33 · see citing works
Mueller, R. A., Smith, R. D., Spruill, W. A., et al. (1975) · Anesthesiology · doi:10.1097/00000542-197502000-00006 · Cited by 32 · see citing works
Gating kinetics of ShakerK+ channels are differentially modified by general anesthetics
Correa, A. M. (1998) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1998.275.4.c1009 · Cited by 31 · see citing works
Postoperative outcome of patients with narcolepsy. A retrospective analysis
Burrow, B., Burkle, C. M., Warner, D. O., & Chini, E. N. (2005) · Journal of Clinical Anesthesia · doi:10.1016/j.jclinane.2004.03.007 · Cited by 29 · see citing works
Increased volatile anesthetic requirement in short-sleeping Drosophila mutants
Weber, B., Schaper, C., Bushey, D., Rohlfs, M., Steinfath, M., Tononi, G., Cirelli, C., Scholz, J., & Bein, B. (2009) · Anesthesiology · doi:10.1097/aln.0b013e3181942df2 · Cited by 26 · see citing works
Walcourt, A., Scott, R. L., & Nash, H. A. (2001) · Anesthesia & Analgesia · doi:10.1213/00000539-200102000-00047 · Cited by 20 · see citing works
Studies on Target Genes of General Anesthetics
Gamo, S. (2002) · Current Drug Targets · doi:10.2174/1389450023348118 · Cited by 13 · see citing works
Campbell, J. L., Gu, Q., Guo, D., & Nash, H. A. (2009) · Journal of Neurogenetics · doi:10.3109/01677060903177800 · Cited by 8 · see citing works
Respiratory Physiology: Strange Cycles and the Fruit-Fly's Tongue
Lighton, J. R. B. (2005) · Current Biology · doi:10.1016/j.cub.2005.11.020 · Cited by 2 · see citing works
Campbell, J., Gu, Q., Guo, D., et al. (2009) · Journal of Neurogenetics · doi:10.1080/01677060903177800 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Unresponsiveness ≠ unconsciousness
Sanders, R. D., Tononi, G., Laureys, S., Sleigh, J. W., & Warner, D. S. (2012) · Anesthesiology · doi:10.1097/aln.0b013e318249d0a7 · Cited by 474 · see citing works
Vazey, E. M., & Aston-Jones, G. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1310025111 · Cited by 279 · see citing works
Unraveling the evolutionary determinants of sleep
Joiner, W. J. (2016) · Current Biology · doi:10.1016/j.cub.2016.08.068 · Cited by 232 · see citing works
Self-citationReturning from oblivion: imaging the neural core of consciousness
Långsjö, J. W., Alkire, M. T., Kaskinoro, K., Hayama, H., Maksimow, A., Kaisti, K. K., Aalto, S., Aantaa, R., Jääskeläinen, S. K., Revonsuo, A., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.4962-11.2012 · Cited by 205 · see citing works
Neural correlates of unconsciousness in large-scale brain networks
Mashour, G. A., & Hudetz, A. G. (2018) · Trends in Neurosciences · doi:10.1016/j.tins.2018.01.003 · Cited by 189 · see citing works
Recovery of consciousness is mediated by a network of discrete metastable activity states
Hudson, A. E., Calderon, D. P., Pfaff, D. W., & Proekt, A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408296111 · Cited by 178 · see citing works
Moore, J. T., Chen, J., Han, B., Meng, Q. C., Veasey, S. C., Beck, S. G., & Kelz, M. B. (2012) · Current Biology · doi:10.1016/j.cub.2012.08.042 · Cited by 171 · see citing works
Self-citationThe Biology of General Anesthesia from Paramecium to Primate
Kelz, M. B., & Mashour, G. A. (2019) · Current Biology · doi:10.1016/j.cub.2019.09.071 · Cited by 151 · see citing works
Self-citationEvolution of consciousness: Phylogeny, ontogeny, and emergence from general anesthesia
Mashour, G. A., & Alkire, M. T. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301188110 · Cited by 144 · see citing works
Anesthesia and the neurobiology of consciousness
Mashour, G. A. (2024) · Neuron · doi:10.1016/j.neuron.2024.03.002 · Cited by 127 · see citing works
Joiner, W. J., Friedman, E. B., Hung, H.-T., Koh, K., Sowcik, M., Sehgal, A., & Kelz, M. B. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003605 · Cited by 82 · see citing works
Self-citationRapid eye movement sleep debt accrues in mice exposed to volatile anesthetics
Pick, J., Chen, Y., Moore, J. T., Sun, Y., Wyner, A. J., Friedman, E. B., & Kelz, M. B. (2011) · Anesthesiology · doi:10.1097/aln.0b013e31822ddd72 · Cited by 79 · see citing works
Self-citationDirect modulation of microtubule stability contributes to anthracene general anesthesia
Emerson, D. J., Weiser, B. P., Psonis, J., Liao, Z., Taratula, O., Fiamengo, A., Wang, X., Sugasawa, K., Smith, A. B., Eckenhoff, R. G., et al. (2013) · Journal of the American Chemical Society · doi:10.1021/ja311171u · Cited by 63 · see citing works
Self-citationHu, F. Y., Hanna, G. M., Han, W., Mardini, F., Thomas, S. A., Wyner, A. J., & Kelz, M. B. (2012) · Anesthesiology · doi:10.1097/aln.0b013e3182700ab9 · Cited by 58 · see citing works
Self-citationIn vivo activation of azipropofol prolongs anesthesia and reveals synaptic targets
Weiser, B. P., Kelz, M. B., & Eckenhoff, R. G. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.413989 · Cited by 29 · see citing works
Self-citationWoll, K. A., Guzik-Lendrum, S., Bensel, B. M., Bhanu, N. V., Dailey, W. P., Garcia, B. A., Gilbert, S. P., & Eckenhoff, R. G. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002182 · Cited by 23 · see citing works
Self-citationTroup, M., Zalucki, O. H., Kottler, B. D., Karunanithi, S., Anggono, V., & van Swinderen, B. (2019) · Anesthesiology · doi:10.1097/aln.0000000000002850 · Cited by 21 · see citing works
Reduced Nav1.6 sodium channel activity in mice increases in vivo sensitivity to volatile anesthetics
Pal, D., Jones, J. M., Wisidagamage, S., Meisler, M. H., & Mashour, G. A. (2015) · PLOS ONE · doi:10.1371/journal.pone.0134960 · Cited by 17 · see citing works
- Authors
- Friedman, E. B., Sun, Y., Moore, J. T., Hung, H.-T., Meng, Q. C., Perera, P., Joiner, W. J., Thomas, S. A., Eckenhoff, R. G., Sehgal, A., & Kelz, M. B.
- Affiliations
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kelz, Max B.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-07-30
- Volume
- 5
- Issue
- 7
- Pages
- e11903
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2912772
- OpenAlex
- W2087748297
- Cited by
- 218
- References
- 55
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 11 · 2023: 8 · 2022: 7 · 2021: 16 · 2020: 15 · 2019: 18 · 2018: 19 · 2017: 16 · 2016: 15 · 2015: 9 · 2014: 18 · 2013: 14 · 2012: 21
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Foundation for Anesthesia Education and Research
- University of Pennsylvania
- Institute for Translational Medicine and Therapeutics
- National Institute of General Medical Sciences (K08GM077357, R01GM088156)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- general anesthesia, consciousness, loss of consciousness, wakefulness, emergence from anesthesia, anesthesia induction, sleep-wake states, single-gene mutations, dose-response relationship, Drosophila, mice, behavioral state transitions
- MeSH terms
- Anesthetics, Animals, Brain, Central Nervous System, Drosophila, Male, Mice, Inbred C57BL, Unconsciousness, Wakefulness, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
