Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance
Year: 2024
Type: article
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.
Source: Neuron
Institutions: Howard Hughes Medical Institute, Harvard University, Janelia Research Campus, Johns Hopkins University, Johns Hopkins Medicine, California Institute of Technology, Max Planck Institute for Multidisciplinary Sciences, University of California, Davis, Peking University, State Key Laboratory of Membrane Biology
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $9,350
Funders: National Science Foundation, Howard Hughes Medical Institute, Simons Foundation, Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, National Institutes of Health, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: G1312049534, G3372546951, Two-Photon All-Optical Electrophysiology in Behaving Mice, JHU Center for Neuroscience Research, CRCNS US-German Research Proposal: Neural Computations Underlying Mechanical -Flow Sensing in Zebrafish, Graduate Research Fellowship Program (GRFP), G5684227621, G5867770422, Genetic and Neuronal Mechanisms that Regulate Zebrafish Sleep, Graduate Research Fellowship Program (GRFP), G7411043898, Design, Synthesis, and Evaluation of Neural Plasticity-Promoting Analogs of Iboga and Ergoline Alkaloids, Signaling to and from the Synapse, G878320519, Training Program in Neuroscience, G9000074102, The Heart and the Mind: An Integrative Approach to Brain-Body Interactions in the Zebrafish, Genetic and neural mechanisms underlying emerging social behavior in zebrafish
OpenAlex ID: W4405496609