High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin

Dotan Braun; Ayelet M. Rosenberg; Elad Rabaniam; Ravid Haruvi; Dorel Malamud; Rani Barbara; Tomer Aiznkot; Berta Levavi-Sivan; Takashi Kawashima

doi:10.1038/s41380-023-02391-7

High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin

Dotan Braun, Ayelet M. Rosenberg, Elad Rabaniam, Ravid Haruvi, Dorel Malamud, Rani Barbara, Tomer Aiznkot, Berta Levavi-Sivan, Takashi Kawashima^*

^*Corresponding author for this work

Department of Brain Sciences

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1046-1062
Number of pages	17
Journal	Molecular Psychiatry
Volume	29
Issue number	4
DOIs	https://doi.org/10.1038/s41380-023-02391-7
Publication status	Published Online - 17 Jan 2024

Bibliographical note

We thank Inbal Shainer, Jonathan Toledano and other members of Kawashima laboratories for experimental help, members of Veterinary Resource at Weizmann Institute of Science for animal care, Armin Bahl, Herwig Baier, Marta Moita, Yavin Shaham and Ziv Williams for helpful discussion on the project, and Gil Levkowitz, Misha Ahrens, and Sasha Devore for critical reading of the manuscript. This research is supported by Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center (R.H.), Moshe Meir Horwitz Fund (R.H.), Azrieli faculty fellowship (T.K.), Israel Science Foundation Individual Grant (688/22), Binational Science Foundation (NSF-BSF CNCRS, #2021746), Dan Lebas & Ruth Sonnewend (T.K.), Jonathan Birnbach (T.K.), and Internal grant from the Center for New Scientists at Weizmann Institute of Science (T.K.) and Irene and Jared M. Drescher Center for Research on Mental and Emotional Health (T.K).
Publisher Copyright:
© 2024, The Author(s).

All Science Journal Classification (ASJC) codes

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/s41380-023-02391-7Licence: CC BY

Cite this

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title = "High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin",

abstract = "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.",

author = "Dotan Braun and Rosenberg, {Ayelet M.} and Elad Rabaniam and Ravid Haruvi and Dorel Malamud and Rani Barbara and Tomer Aiznkot and Berta Levavi-Sivan and Takashi Kawashima",

note = "We thank Inbal Shainer, Jonathan Toledano and other members of Kawashima laboratories for experimental help, members of Veterinary Resource at Weizmann Institute of Science for animal care, Armin Bahl, Herwig Baier, Marta Moita, Yavin Shaham and Ziv Williams for helpful discussion on the project, and Gil Levkowitz, Misha Ahrens, and Sasha Devore for critical reading of the manuscript. This research is supported by Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center (R.H.), Moshe Meir Horwitz Fund (R.H.), Azrieli faculty fellowship (T.K.), Israel Science Foundation Individual Grant (688/22), Binational Science Foundation (NSF-BSF CNCRS, #2021746), Dan Lebas & Ruth Sonnewend (T.K.), Jonathan Birnbach (T.K.), and Internal grant from the Center for New Scientists at Weizmann Institute of Science (T.K.) and Irene and Jared M. Drescher Center for Research on Mental and Emotional Health (T.K). Publisher Copyright: {\textcopyright} 2024, The Author(s).",

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AU - Rabaniam, Elad

AU - Haruvi, Ravid

AU - Malamud, Dorel

AU - Barbara, Rani

AU - Aiznkot, Tomer

AU - Levavi-Sivan, Berta

AU - Kawashima, Takashi

N1 - We thank Inbal Shainer, Jonathan Toledano and other members of Kawashima laboratories for experimental help, members of Veterinary Resource at Weizmann Institute of Science for animal care, Armin Bahl, Herwig Baier, Marta Moita, Yavin Shaham and Ziv Williams for helpful discussion on the project, and Gil Levkowitz, Misha Ahrens, and Sasha Devore for critical reading of the manuscript. This research is supported by Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center (R.H.), Moshe Meir Horwitz Fund (R.H.), Azrieli faculty fellowship (T.K.), Israel Science Foundation Individual Grant (688/22), Binational Science Foundation (NSF-BSF CNCRS, #2021746), Dan Lebas & Ruth Sonnewend (T.K.), Jonathan Birnbach (T.K.), and Internal grant from the Center for New Scientists at Weizmann Institute of Science (T.K.) and Irene and Jared M. Drescher Center for Research on Mental and Emotional Health (T.K). Publisher Copyright: © 2024, The Author(s).

PY - 2024/1/17

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N2 - 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.

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JF - Molecular Psychiatry

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ER -

High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin

Abstract

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