Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance.
Neuron February 5, 2025 Marc Duque, Alex B Chen, Eric Hsu et al. 27 citations
A 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.