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 via PubMed
Summary
AI-generated from the abstractA brief exposure to ketamine can produce lasting changes in behavior and mood. In larval zebrafish, a short ketamine treatment suppressed the passive "giving-up" response that normally occurs when swimming fails to produce forward movement. Whole-brain imaging showed that ketamine initially hyperactivates a circuit involving norepinephrine and astrocytes, which controls this passivity. After ketamine is removed, the same circuit becomes less sensitive to futility, resulting in long-term increased perseverance. Experiments using pharmacology, chemogenetics, and optogenetics confirmed that norepinephrine and astrocytes are both necessary and sufficient for this effect. In adult mice, astrocytes in the cortex were similarly activated during a futility test, and ketamine also caused astrocyte hyperactivation. The cross-species conservation of this mechanism suggests new strategies for treating affective disorders.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Larval zebrafish and adult mice |
| Intervention | Ketamine |
| Topics | Ketamine |
| Keywords | Astrocytes Behavioral states Brain states Circuits Glia |
| Citations | 27 |
| Key finding | 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.