{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T05:47:55Z","timestamp":1767851275724,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Propofol belongs to a class of molecules that are known to block learning and memory in mammals, including rodents and humans. Interestingly, learning and memory are not tied to the presence of a nervous system. There are several lines of evidence indicating that single-celled organisms also have the capacity for learning and memory which may be considered as basal intelligence. Here, we introduce a new experimental model for testing the learning ability of Physarum polycephalum, a model organism frequently used to study single-celled \u201cintelligence\u201d. In this study, the impact of propofol on Physarum\u2019s \u201cintelligence\u201d was tested. The model consists of a labyrinth of subsequent bifurcations in which food (oat flakes soaked with coconut oil-derived medium chain triglycerides [MCT] and soybean oil-derived long chain triglycerides [LCT]) or propofol in MCT\/LCT) is placed in one of each Y-branch. In this setting, it was tested whether Physarum memorized the rewarding branch. We saw that Physarum was a quick learner when capturing the first bifurcations of the maze; thereafter, the effect decreased, perhaps due to reaching a state of satiety. In contrast, when oat flakes were soaked with propofol, Physarum\u2019s preference for oat flakes declined significantly. Several possible actions, including the blocking of gamma-aminobutyric acid (GABA) receptor signaling, are suggested to account for this behavior, many of which can be tested in our new model.<\/jats:p>","DOI":"10.3390\/ijms24076287","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T07:32:09Z","timestamp":1679902329000},"page":"6287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Learning in the Single-Cell Organism Physarum polycephalum: Effect of Propofol"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6157-6773","authenticated-orcid":false,"given":"Stefan","family":"Kippenberger","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon","family":"Pipa","sequence":"additional","affiliation":[{"name":"Institute of Cognitive Science, University Osnabr\u00fcck, 49074 Osnabr\u00fcck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katja","family":"Steinhorst","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2438-2747","authenticated-orcid":false,"given":"Nadja","family":"Z\u00f6ller","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Kleemann","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deniz","family":"\u00d6zistanbullu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergy, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertram","family":"Scheller","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, St. Josefs-Hospital, 65189 Wiesbaden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.tim.2004.06.006","article-title":"Bacterial linguistic communication and social intelligence","volume":"12","author":"Becker","year":"2004","journal-title":"Trends Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.tim.2005.02.001","article-title":"Bacterial observations: A rudimentary form of intelligence?","volume":"13","author":"Hellingwerf","year":"2005","journal-title":"Trends Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2466\/pr0.98.3.705-711","article-title":"Discrimination learning and extinction in paramecia (P. caudatum)","volume":"98","author":"Armus","year":"2006","journal-title":"Psychol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20160155","DOI":"10.1098\/rsif.2016.0155","article-title":"A ciliate memorizes the geometry of a swimming arena","volume":"13","author":"Kunita","year":"2016","journal-title":"J. R. Soc. Interface R. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/35035159","article-title":"Maze-solving by an amoeboid organism","volume":"407","author":"Nakagaki","year":"2000","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1126\/science.1177894","article-title":"Rules for Biologically Inspired Adaptive Network Design","volume":"327","author":"Tero","year":"2010","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biosystems.2013.01.008","article-title":"Amoeba-based computing for traveling salesman problem: Long-term correlations between spatially separated individual cells of Physarum polycephalum","volume":"112","author":"Zhu","year":"2013","journal-title":"Biosystems"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"018101","DOI":"10.1103\/PhysRevLett.100.018101","article-title":"Amoebae anticipate periodic events","volume":"100","author":"Saigusa","year":"2008","journal-title":"Phys. Rev. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.nancom.2011.05.002","article-title":"An associative learning experiment using the plasmodium of Physarum polycephalum","volume":"2","author":"Shirakawa","year":"2011","journal-title":"Nano Commun. Netw."},{"key":"ref_10","first-page":"913","article-title":"Construction of a Molecular Learning Network","volume":"17","author":"Shirakawa","year":"2013","journal-title":"J. Adv. Comput. Intell."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20162382","DOI":"10.1098\/rspb.2016.2382","article-title":"Direct transfer of learned behaviour via cell fusion in non-neural organisms","volume":"283","author":"Vogel","year":"2016","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"28","DOI":"10.17085\/apm.20079","article-title":"Pharmacological strategies to prevent postoperative delirium: A systematic review and network meta-analysis","volume":"16","author":"Lee","year":"2021","journal-title":"Anesth. Pain Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cell.2018.08.031","article-title":"Propofol: Milk of Amnesia","volume":"175","author":"Walsh","year":"2018","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/gbe\/evv237","article-title":"The Physarum polycephalum Genome Reveals Extensive Use of Prokaryotic Two-Component and Metazoan-Type Tyrosine Kinase Signaling","volume":"8","author":"Schaap","year":"2015","journal-title":"Genome Biol. Evol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"625","DOI":"10.3389\/fpsyg.2013.00625","article-title":"Consciousness in humans and non-human animals: Recent advances and future directions","volume":"4","author":"Boly","year":"2013","journal-title":"Front. Psychol."},{"key":"ref_16","first-page":"248","article-title":"Prediction, perception and agency","volume":"83","author":"Friston","year":"2012","journal-title":"Int. J. Psychophysiol. Off. J. Int. Organ. Psychophysiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s001140100230","article-title":"How do general anaesthetics work?","volume":"88","author":"Antkowiak","year":"2001","journal-title":"Naturwissenschaften"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R1199","DOI":"10.1016\/j.cub.2019.09.071","article-title":"The Biology of General Anesthesia from Paramecium to Primate","volume":"29","author":"Kelz","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/j.1601-5223.1944.tb02739.x","article-title":"Colchicine mitosis, chromosome contraction, narcosis and protein chain folding","volume":"30","author":"Oestergren","year":"1944","journal-title":"Hereditas"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00018-016-2415-7","article-title":"\u03b3-Aminobutyric acid (GABA) signalling in plants","volume":"74","author":"Ramesh","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15280","DOI":"10.1074\/jbc.M112.427047","article-title":"Systematic analysis of \u03b3-aminobutyric acid (GABA) metabolism and function in the social amoeba Dictyostelium discoideum","volume":"288","author":"Wu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Craddock, T.J., Tuszynski, J.A., and Hameroff, S. (2012). Cytoskeletal signaling: Is memory encoded in microtubule lattices by CaMKII phosphorylation?. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002421"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1242\/jcs.100.3.509","article-title":"Physarum plasmodia do contain cytoplasmic microtubules!","volume":"100","author":"Moisand","year":"1991","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1242\/jcs.107.8.2071","article-title":"Microtubules are required in amoeba chemotaxis for preferential stabilization of appropriate pseudopods","volume":"107","author":"Ueda","year":"1994","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1016\/S0140-6736(68)91821-7","article-title":"Effects of general anaesthetics on microtubules: A possible mechanism of anaesthesia","volume":"2","author":"Allison","year":"1968","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9877","DOI":"10.1038\/s41598-017-09992-7","article-title":"Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction","volume":"7","author":"Craddock","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"244002","DOI":"10.1088\/1361-6463\/aac2b0","article-title":"A novel growth mode of Physarum polycephalum during starvation","volume":"51","author":"Lee","year":"2018","journal-title":"J. Phys. D Appl. Phys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1140\/epje\/i2010-10589-y","article-title":"Routing Physarum with repellents","volume":"31","author":"Adamatzky","year":"2010","journal-title":"Eur. Phys. J. E"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20180368","DOI":"10.1098\/rstb.2018.0368","article-title":"Memory inception and preservation in slime moulds: The quest for a common mechanism","volume":"374","author":"Boussard","year":"2019","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5136","DOI":"10.1073\/pnas.1618114114","article-title":"Mechanism of signal propagation in Physarum polycephalum","volume":"114","author":"Alim","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2007815118","DOI":"10.1073\/pnas.2007815118","article-title":"Encoding memory in tube diameter hierarchy of living flow network","volume":"118","author":"Kramar","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fnhum.2017.00191","article-title":"Acting without Central Agent-Considerations for a Self-Model at the Cellular Level","volume":"11","author":"Kippenberger","year":"2017","journal-title":"Front. Hum. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e61907","DOI":"10.7554\/eLife.61907","article-title":"Reconsidering the evidence for learning in single cells","volume":"10","author":"Gershman","year":"2021","journal-title":"eLife"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev.ph.28.030166.000543","article-title":"Comparative Physiology: Learning in Invertebrates","volume":"28","author":"McConnell","year":"1966","journal-title":"Annu. Rev. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1099\/00221287-143-4-1059","article-title":"Contact with a solid substratum induces cysts in axenic cultures of Physarum polycephalum amoebae: Mannitol-induced detergent-resistant cells are not true cysts","volume":"143","author":"Dee","year":"1997","journal-title":"Microbiology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:04:06Z","timestamp":1760123046000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,27]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24076287"],"URL":"https:\/\/doi.org\/10.3390\/ijms24076287","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,27]]}}}