High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin
Serotonergic psychedelics are emerging therapeutics for psychiatric disorders, yet their underlying mechanisms of action in the brain remain largely elusive. Here, we developed a wide-field behavioral tracking system for larval zebrafish and investigated the effects of psilocybin, a psychedelic sero...
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| Veröffentlicht in: | Molecular psychiatry 2024-04, Vol.29 (4), p.1046-1062 |
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| creator | Braun, Dotan Rosenberg, Ayelet M. Rabaniam, Elad Haruvi, Ravid Malamud, Dorel Barbara, Rani Aiznkot, Tomer Levavi-Sivan, Berta Kawashima, Takashi |
| description | Serotonergic psychedelics are emerging therapeutics for psychiatric disorders, yet their underlying mechanisms of action in the brain remain largely elusive. Here, we developed a wide-field behavioral tracking system for larval zebrafish and investigated the effects of psilocybin, a psychedelic serotonin receptor agonist. Machine learning analyses of precise body kinematics identified latent behavioral states reflecting spontaneous exploration, visually-driven rapid swimming, and irregular swim patterns following stress exposure. Using this method, we found that acute psilocybin treatment has two behavioral effects: [i] facilitation of spontaneous exploration (“stimulatory”) and [ii] prevention of irregular swim patterns following stress exposure (“anxiolytic”). These effects differed from the effect of acute SSRI treatment and were rather similar to the effect of ketamine treatment. Neural activity imaging in the dorsal raphe nucleus suggested that psilocybin inhibits serotonergic neurons by activating local GABAergic neurons, consistent with psychedelic-induced suppression of serotonergic neurons in mammals. These findings pave the way for using larval zebrafish to elucidate neural mechanisms underlying the behavioral effects of serotonergic psychedelics. |
| doi_str_mv | 10.1038/s41380-023-02391-7 |
| format | Article |
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Here, we developed a wide-field behavioral tracking system for larval zebrafish and investigated the effects of psilocybin, a psychedelic serotonin receptor agonist. Machine learning analyses of precise body kinematics identified latent behavioral states reflecting spontaneous exploration, visually-driven rapid swimming, and irregular swim patterns following stress exposure. Using this method, we found that acute psilocybin treatment has two behavioral effects: [i] facilitation of spontaneous exploration (“stimulatory”) and [ii] prevention of irregular swim patterns following stress exposure (“anxiolytic”). These effects differed from the effect of acute SSRI treatment and were rather similar to the effect of ketamine treatment. Neural activity imaging in the dorsal raphe nucleus suggested that psilocybin inhibits serotonergic neurons by activating local GABAergic neurons, consistent with psychedelic-induced suppression of serotonergic neurons in mammals. These findings pave the way for using larval zebrafish to elucidate neural mechanisms underlying the behavioral effects of serotonergic psychedelics.</description><identifier>ISSN: 1359-4184</identifier><identifier>ISSN: 1476-5578</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/s41380-023-02391-7</identifier><identifier>PMID: 38233467</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/47 ; 13/51 ; 631/154 ; 631/378 ; 631/443 ; 64 ; 64/116 ; 96/63 ; Animals ; Anti-Anxiety Agents - pharmacology ; Anxiety - drug therapy ; Behavior, Animal - drug effects ; Behavioral Sciences ; Biological Psychology ; Brain - drug effects ; Danio rerio ; Dorsal raphe nucleus ; Dorsal Raphe Nucleus - drug effects ; Exploration ; GABAergic Neurons - drug effects ; Hallucinogens - pharmacology ; Immediate Communication ; Ketamine ; Ketamine - pharmacology ; Kinematics ; Larva - drug effects ; Medicine ; Medicine & Public Health ; Mental disorders ; Neuroimaging ; Neurons ; Neurosciences ; Pharmacotherapy ; Psilocybin ; Psilocybin - pharmacology ; Psychedelic drugs ; Psychiatry ; Raphe nuclei ; Selective Serotonin Reuptake Inhibitors - pharmacology ; Serotonergic Neurons - drug effects ; Serotonin Receptor Agonists - pharmacology ; Serotonin uptake inhibitors ; Swimming ; Zebrafish ; γ-Aminobutyric acid</subject><ispartof>Molecular psychiatry, 2024-04, Vol.29 (4), p.1046-1062</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-52da62d82480f0e84dd1bc576e1f32320fb4be767b4ca5ba1dbb5a96c7aacfcd3</citedby><cites>FETCH-LOGICAL-c475t-52da62d82480f0e84dd1bc576e1f32320fb4be767b4ca5ba1dbb5a96c7aacfcd3</cites><orcidid>0000-0002-3575-5871 ; 0000-0001-7741-3995</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41380-023-02391-7$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41380-023-02391-7$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38233467$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Braun, Dotan</creatorcontrib><creatorcontrib>Rosenberg, Ayelet M.</creatorcontrib><creatorcontrib>Rabaniam, Elad</creatorcontrib><creatorcontrib>Haruvi, Ravid</creatorcontrib><creatorcontrib>Malamud, Dorel</creatorcontrib><creatorcontrib>Barbara, Rani</creatorcontrib><creatorcontrib>Aiznkot, Tomer</creatorcontrib><creatorcontrib>Levavi-Sivan, Berta</creatorcontrib><creatorcontrib>Kawashima, Takashi</creatorcontrib><title>High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><addtitle>Mol Psychiatry</addtitle><description>Serotonergic psychedelics are emerging therapeutics for psychiatric disorders, yet their underlying mechanisms of action in the brain remain largely elusive. Here, we developed a wide-field behavioral tracking system for larval zebrafish and investigated the effects of psilocybin, a psychedelic serotonin receptor agonist. Machine learning analyses of precise body kinematics identified latent behavioral states reflecting spontaneous exploration, visually-driven rapid swimming, and irregular swim patterns following stress exposure. Using this method, we found that acute psilocybin treatment has two behavioral effects: [i] facilitation of spontaneous exploration (“stimulatory”) and [ii] prevention of irregular swim patterns following stress exposure (“anxiolytic”). These effects differed from the effect of acute SSRI treatment and were rather similar to the effect of ketamine treatment. Neural activity imaging in the dorsal raphe nucleus suggested that psilocybin inhibits serotonergic neurons by activating local GABAergic neurons, consistent with psychedelic-induced suppression of serotonergic neurons in mammals. These findings pave the way for using larval zebrafish to elucidate neural mechanisms underlying the behavioral effects of serotonergic psychedelics.</description><subject>101/47</subject><subject>13/51</subject><subject>631/154</subject><subject>631/378</subject><subject>631/443</subject><subject>64</subject><subject>64/116</subject><subject>96/63</subject><subject>Animals</subject><subject>Anti-Anxiety Agents - pharmacology</subject><subject>Anxiety - drug therapy</subject><subject>Behavior, Animal - drug effects</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Brain - drug effects</subject><subject>Danio rerio</subject><subject>Dorsal raphe nucleus</subject><subject>Dorsal Raphe Nucleus - drug effects</subject><subject>Exploration</subject><subject>GABAergic Neurons - drug effects</subject><subject>Hallucinogens - pharmacology</subject><subject>Immediate Communication</subject><subject>Ketamine</subject><subject>Ketamine - pharmacology</subject><subject>Kinematics</subject><subject>Larva - drug effects</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mental disorders</subject><subject>Neuroimaging</subject><subject>Neurons</subject><subject>Neurosciences</subject><subject>Pharmacotherapy</subject><subject>Psilocybin</subject><subject>Psilocybin - pharmacology</subject><subject>Psychedelic drugs</subject><subject>Psychiatry</subject><subject>Raphe nuclei</subject><subject>Selective Serotonin Reuptake Inhibitors - pharmacology</subject><subject>Serotonergic Neurons - drug effects</subject><subject>Serotonin Receptor Agonists - pharmacology</subject><subject>Serotonin uptake inhibitors</subject><subject>Swimming</subject><subject>Zebrafish</subject><subject>γ-Aminobutyric acid</subject><issn>1359-4184</issn><issn>1476-5578</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kUuLFDEUhQtRnHH0D7iQAjduSvNOaiUyqCMMuNF1yOOmO2N10iZVje2vN2WP42Ph4pLA-e5JDqfrnmL0EiOqXlWGqUIDInSdEQ_yXneOmRQD51Ldb3fKx4Fhxc66R7XeILSK_GF3RhWhlAl53pWruNkOBWqeljnm1M_FuC8xbfoc-iW5nEJM4PvvYIsJsW57C1tziLn0BQ5gptrXOe6Wycy5HHuTfJtvMU_HOboeQgA319VrX-OU3dHG9Lh7ENoePLk9L7rP795-urwarj--_3D55npwTPJ54MQbQbwiTKGAQDHvsXVcCsCBEkpQsMyCFNIyZ7g12FvLzSicNMYF5-lF9_rku1_sDryD1LJNel_izpSjzibqv5UUt3qTDxpjLAWSqjm8uHUo-esCdda7WB1Mk0mQl6rJiAVDfBxZQ5__g97kpaSWT1MkJBeUqJUiJ8qVXGuBcPcbjPTaqT51qluf-menWralZ3_muFv5VWID6AmoTUobKL_f_o_tDy5bsTw</recordid><startdate>20240401</startdate><enddate>20240401</enddate><creator>Braun, Dotan</creator><creator>Rosenberg, Ayelet M.</creator><creator>Rabaniam, Elad</creator><creator>Haruvi, Ravid</creator><creator>Malamud, Dorel</creator><creator>Barbara, Rani</creator><creator>Aiznkot, Tomer</creator><creator>Levavi-Sivan, Berta</creator><creator>Kawashima, Takashi</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3575-5871</orcidid><orcidid>https://orcid.org/0000-0001-7741-3995</orcidid></search><sort><creationdate>20240401</creationdate><title>High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin</title><author>Braun, Dotan ; 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Here, we developed a wide-field behavioral tracking system for larval zebrafish and investigated the effects of psilocybin, a psychedelic serotonin receptor agonist. Machine learning analyses of precise body kinematics identified latent behavioral states reflecting spontaneous exploration, visually-driven rapid swimming, and irregular swim patterns following stress exposure. Using this method, we found that acute psilocybin treatment has two behavioral effects: [i] facilitation of spontaneous exploration (“stimulatory”) and [ii] prevention of irregular swim patterns following stress exposure (“anxiolytic”). These effects differed from the effect of acute SSRI treatment and were rather similar to the effect of ketamine treatment. Neural activity imaging in the dorsal raphe nucleus suggested that psilocybin inhibits serotonergic neurons by activating local GABAergic neurons, consistent with psychedelic-induced suppression of serotonergic neurons in mammals. These findings pave the way for using larval zebrafish to elucidate neural mechanisms underlying the behavioral effects of serotonergic psychedelics.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>38233467</pmid><doi>10.1038/s41380-023-02391-7</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-3575-5871</orcidid><orcidid>https://orcid.org/0000-0001-7741-3995</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 101/47 13/51 631/154 631/378 631/443 64 64/116 96/63 Animals Anti-Anxiety Agents - pharmacology Anxiety - drug therapy Behavior, Animal - drug effects Behavioral Sciences Biological Psychology Brain - drug effects Danio rerio Dorsal raphe nucleus Dorsal Raphe Nucleus - drug effects Exploration GABAergic Neurons - drug effects Hallucinogens - pharmacology Immediate Communication Ketamine Ketamine - pharmacology Kinematics Larva - drug effects Medicine Medicine & Public Health Mental disorders Neuroimaging Neurons Neurosciences Pharmacotherapy Psilocybin Psilocybin - pharmacology Psychedelic drugs Psychiatry Raphe nuclei Selective Serotonin Reuptake Inhibitors - pharmacology Serotonergic Neurons - drug effects Serotonin Receptor Agonists - pharmacology Serotonin uptake inhibitors Swimming Zebrafish γ-Aminobutyric acid |
| title | High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin |
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