Ketamine modulates a norepinephrine-astroglial circuit to persistently suppress futility-induced passivity
Marc Duque, Alex B. Chen, Eric Hsu, Sujatha Narayan, Altyn Rymbek, Shahinoor Begum, Gesine Saher, Adam E. Cohen, David E. Olson, David A. Prober, Dwight E. Bergles, Mark C. Fishman, Florian Engert, Misha B. Ahrens
bioRxiv Preprint Server December 29, 2022 preprint DOI: 10.1101/2022.12.29.522099 via bioRxiv
Summary
AI-generated from the abstractKetamine, a mood-altering compound, suppresses passivity induced by futility in larval zebrafish, similar to effects in rodent learned helplessness models. Brain-wide imaging in behaving zebrafish shows ketamine elevates intracellular calcium in astroglia for many minutes, followed by persistent calcium downregulation after washout. This calcium elevation depends on astroglial α1-adrenergic receptors and is required for suppression of passivity. Chemo- and optogenetic experiments show that the aftereffects of glial calcium elevation are sufficient to suppress passivity by inhibiting neuronal-astroglial integration of behavioral futility. Imaging in mouse cortex reveals ketamine elevates astroglial calcium through conserved pathways, suggesting ketamine exerts its behavioral effects by persistently modulating evolutionarily ancient neuromodulatory systems spanning neurons and astroglia.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Larval zebrafish and mice |
| Intervention | Ketamine |
| Keywords | Ketamine dissociative anesthetic Mood-altering compound Astroglia astrocytes Star-shaped brain cells Glial cells |
| Citations | 1 |
| Key finding | Ketamine elevates astroglial calcium through conserved pathways, and this elevation is required for suppressing futility-induced passivity by inhibiting neuronal-astroglial integration of behavioral futility. |
Abstract
Mood-altering compounds hold promise for the treatment of many psychiatric disorders, such as depression, but connecting their molecular, circuit, and behavioral effects has been challenging. Here we find that, analogous to effects in rodent learned helplessness models, ketamine pre-exposure persistently suppresses futility-induced passivity in larval zebrafish. While antidepressants are thought to primarily act on neurons, brain-wide imaging in behaving zebrafish showed that ketamine elevates intracellular calcium in astroglia for many minutes, followed by persistent calcium downregulation post-washout. Calcium elevation depends on astroglial α1-adrenergic receptors and is required for suppression of passivity. Chemo-/optogenetic perturbations of noradrenergic neurons and astroglia demonstrate that the aftereffects of glial calcium elevation are sufficient to suppress passivity by inhibiting neuronal-astroglial integration of behavioral futility. Imaging in mouse cortex reveals that ketamine elevates astroglial calcium through conserved pathways, suggesting that ketamine exerts its behavioral effects by persistently modulating evolutionarily ancient neuromodulatory systems spanning neurons and astroglia.