Ketamine modulates a norepinephrine-astroglial circuit to persistently suppress futility-induced passivity
bioRxiv Preprint Server – December 29, 2022
Source: bioRxiv
Summary
Ketamine's antidepressant-like effects may surprisingly stem from its action on star-shaped brain cells called astroglia, not just neurons. Traditionally, mood-altering compounds are thought to primarily affect neurons. Research in zebrafish and mice revealed that ketamine elevates calcium within astroglia, a crucial step for persistently suppressing passive, futile behaviors. This suggests ketamine effectively combats passivity by modulating ancient brain pathways involving both neurons and astroglia, offering a novel understanding of its positive impact.
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.