Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance

Marc Duque¹, Alex B Chen², Eric Hsu³, Sujatha Narayan⁴, Altyn Rymbek⁵, Shahinoor Begum⁶, Gesine Saher⁷, Adam E Cohen⁶, David E Olson⁸, Yulong Li⁹, David A Prober⁵, Dwight E Bergles¹⁰, Mark C Fishman¹¹, Florian Engert¹², Misha B Ahrens¹³

Affiliations

¹ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address: mduqueramirez@g.harvard.edu.
² Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address: abchen@g.harvard.edu.
³ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
⁵ Tianqiao and Chrissy Chen Institute for Neuroscience, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁶ Department of Physics, Harvard University, Cambridge, MA 02138, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
⁷ Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37075, Germany.
⁸ Department of Chemistry, University of California, Davis, Davis, CA 95616, USA; Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA; Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA 95616, USA.
⁹ State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China; PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China.
¹⁰ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
¹¹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
¹² Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
¹³ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address: ahrensm@janelia.hhmi.org.

PMID: 39694033
PMCID: PMC11889991 (available on 2026-02-05)
DOI: 10.1016/j.neuron.2024.11.011

Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance

Marc Duque et al. Neuron. 2025.

. 2025 Feb 5;113(3):426-443.e5.

doi: 10.1016/j.neuron.2024.11.011. Epub 2024 Dec 17.

Authors

Affiliations

¹ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address: mduqueramirez@g.harvard.edu.
² Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address: abchen@g.harvard.edu.
³ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
⁵ Tianqiao and Chrissy Chen Institute for Neuroscience, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁶ Department of Physics, Harvard University, Cambridge, MA 02138, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
⁷ Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37075, Germany.
⁸ Department of Chemistry, University of California, Davis, Davis, CA 95616, USA; Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA; Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA 95616, USA.
⁹ State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China; PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China.
¹⁰ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
¹¹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
¹² Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
¹³ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address: ahrensm@janelia.hhmi.org.

PMID: 39694033
PMCID: PMC11889991 (available on 2026-02-05)
DOI: 10.1016/j.neuron.2024.11.011

Abstract

Transient exposure to ketamine can trigger lasting changes in behavior and mood. We found that brief ketamine exposure causes long-term suppression of futility-induced passivity in larval zebrafish, reversing the "giving-up" response that normally occurs when swimming fails to cause forward movement. Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit responsible for passivity. After ketamine washout, this circuit exhibits hyposensitivity to futility, leading to long-term increased perseverance. Pharmacological, chemogenetic, and optogenetic manipulations show that norepinephrine and astrocytes are necessary and sufficient for ketamine's long-term perseverance-enhancing aftereffects. In vivo calcium imaging revealed that astrocytes in adult mouse cortex are similarly activated during futility in the tail suspension test and that acute ketamine exposure also induces astrocyte hyperactivation. The cross-species conservation of ketamine's modulation of noradrenergic-astroglial circuits and evidence that plasticity in this pathway can alter the behavioral response to futility hold promise for identifying new strategies to treat affective disorders.

Keywords: astrocytes; behavioral states; brain states; circuits; glia; ketamine; mood-altering compounds; noradrenaline; norepinephrine; zebrafish.

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Conflict of interest statement

Declaration of interests D.E.O. is a co-founder of Delix Therapeutics, Inc., serves as the Chief Innovation Officer and Head of the Scientific Advisory Board, and has sponsored research agreements with Delix Therapeutics. Delix Therapeutics has licensed technology from the University of California, Davis. A.E.C. is a co-founder of Q-State Biosciences.

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Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance

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Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance

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