Ketamine modulates a norepinephrine-astroglial circuit to persistently suppress futility-induced passivity

Abstract

Rapid-acting antidepressants like ketamine hold promise to change the approach to treatment of major depressive disorder (MDD), but their cellular and molecular targets remain unclear. Passivity induced by behavioral futility underlies learned helplessness, a process that becomes maladaptive in MDD. Antidepressants decrease futility-induced passivity (FIP) in rodent models such as the forced swimming or tail suspension tasks, but these models lack the throughput and accessibility for screening compounds and investigating their effects on the brain in vivo. Therefore, we adapted a recently discovered FIP behavior in the small and optically accessible larval zebrafish to create a scalable behavioral assay for antidepressant action. We found that rapid-acting antidepressants with diverse pharmacological targets demonstrated a suppression of FIP conserved between fish and rodents. While fast-acting antidepressants are thought to primarily target neurons, using brain-wide imaging in vivo we found, surprisingly, that ketamine, but not psychedelics or typical antidepressants, drove cytosolic calcium elevation in astroglia lasting many minutes. Blocking neural activity did not prevent ketamine's effects on FIP or astroglial calcium, suggesting an astroglia-autonomous mechanism of ketamine's action. Chemogenetic and optogenetic perturbations of astroglia reveal that the aftereffects of calcium elevation are sufficient to suppress FIP by inhibiting astroglial integration of futile swimming. In sum, our work provides evidence that ketamine exerts its antidepressant effects by inhibiting an astroglial population that integrates futility and changes behavioral state. Astroglia play central roles in modulating circuit dynamics, and our work argues that targeting astroglial signaling may be a fruitful strategy for designing new rapid-acting antidepressants.

Cilia-mediated cerebrospinal fluid flow modulates neuronal and astroglial activity in the zebrafish larval brain

“…In zebrafish, the majority of astroglia exhibit morphological traits reminiscent of mammalian radial glia, showcasing radial extensions that extend from the ventricular surface to the pial surface (29). Yet, increasing evidence support a role of zebrafish astroglia in neural circuit regulation (48,49,(82)(83)(84), similarly to mammalian astrocytes. Notably, molecules such as norepinephrine (85)(86)(87)(88), acetylcholine (89)(90)(91), and glutamate (92)(93)(94) have been proposed as primary triggers for activating astrocytes.…”

Norepinephrine changes behavioral state via astroglial purinergic signaling

“…Here we made use of our previously published behavioral assay for futilityinduced passivity in larval zebrafish 49,52 . Specifically, fish were immobilized in agarose and their tails freed.…”