Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance.
Marc Duque, Alex B. Chen, Eric Hsu, Sujatha Narayan, Altyn Rymbek, Shahinoor Begum, Gesine Saher, Adam E Cohen, David E. Olson, Yulong Li, David A. Prober, Dwight E. Bergles, Mark C. Fishman, Florian Engert, Misha B. Ahrens
Neuron February 5, 2025 DOI: 10.1016/j.neuron.2024.11.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Larval zebrafish and adult mice |
| Intervention | Ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Astrocytes Behavioral states Brain states Circuits Glia Mood-altering compounds Noradrenaline Norepinephrine Zebrafish Psychopharmacology Behavioral neuroscience Antidepressants Motivation |
| Citations | 27 |
| Key findings | Brief ketamine exposure causes long-term suppression of futility-induced passivity by hyperactivating and then desensitizing a norepinephrine-astroglia circuit, a mechanism conserved across zebrafish and mice. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 5
- A multi-institutional investigation of psilocybin’s effects on mouse behavior bioRxiv (Cold Spring Harbor Laboratory) April 9, 2025
- Narrating the psychoneuroimmunomodulatory properties of serotonin 5-HT2A receptor psychedelics from a transdiagnostic perspective. Acta Neuropsychiatrica July 25, 2025
- The Emerging Crisis in Non-Prescribed Ketamine Use: A Rapid Attenuation of Depression in Face of Abuse and "Chill-out" or Escapism Drug. Substance Use & Misuse February 1, 2026
- Neuroscience: Special K gets an 'A'. Current Biology April 21, 2025
- Research Progress on the Mechanism of Ketamine in Neuropathic Pain Comorbid Depression Neuropsychiatric Disease and Treatment August 9, 2025
Cites 19
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
and 14 more in the library