A very popular drug, ketamine, has gone mainstream as a miraculous treatment for severe depression. Everyone has questions, and researchers believe that translucent zebrafish may provide answers. Because the zebrafish are so small and translucent, their entire animal brain can be imaged to see what the drug is doing to it, say researchers.
Unlike humans, zebrafish aren’t depressed, but scientists use the little sea creature as a model for what happens when this creature shows a ‘giving-up’ attitude which mimics the depression, for example when it realizes it’s not getting anywhere and stops swimming. A bunch of researchers from HHMI’s Janelia Research Campus, Harvard, and Johns Hopkins discovered that ketamine acts in the zebrafish brain: At supporting cells, instead, astroglia. They concluded this by examining this depression behavior by the zebrafish, scientist holds the potential to x-ray the zebrafish’s whole cerebrum, along with a distinct practical real-life set-up.
Janelia scientists had shown in previous work that astroglia, one of two members of a neural circuit, signal to the zebrafish when to stop. The harder the fish swims, the more astroglial activity increases, indicating to the fish that it isn’t receiving an influx of oxygen.
These findings explain that in mice, these astrocytes get activated which shows us how an antidepressant drug would be working to get more safe and effective treatment options against depression.
This paper proposes that these astroglia, non-neural cell groups, are making a crucial contribution and that very few of the distinct effects of these antidepressant drugs arise through modification of astroglial physiology, according to the lead author Alex Chen.
This study explains that brief exposure to ketamine leads to long-term control of futility-induced passivity in larval zebrafish, changing the typical “giving-up” response when swimming fails to produce forward movement.
Whole-brain imaging revealed that ketamine hyperactivates the norepinephrine-astroglia circuit, which governs passivity. Following ketamine washout, this circuit shows decreased sensitivity to futility, causing sustained rises in perseverance. Using pharmacological, chemogenetic, and optogenetic approaches, the authors proved that norepinephrine and astrocytes are both necessary and sufficient for ketamine’s long-term effects on perseverance.
In-vivo calcium imaging in adult mice revealed similar astrocyte activation during futility in the tail suspension test, with acute ketamine exposure causing comparable astrocyte hyperactivation. The cross-species conservation of ketamine’s effects on noradrenergic-astroglial circuits and evidence of plasticity in this pathway offer confirming insights for utilizing novel treatments for affective disorders.
Previous Ahrens Lab research established a radial astrocyte connection to the giving-up action. Short or quick increases in astroglia calcium may cause giving up behavior, but this is offset by after-effects of the ketamine-stimulated calcium flood accompanying giving up, such that fish are less responsive to the signaling of giving up in the future. “As with ketamine, the beauty of it is that it’s desensitized,” Misha Ahrens, Janelia Senior Group Leader and senior author of the paper, points out. “You get out, it’s like a cold shower, you kind of get a little bit sensitive to the cold, but at a cellular, molecular level.”
Although they don’t understand ketamine’s exact brain path, this study is clear that it is the astrocytes that are acted upon, by increasing the norepinephrine levels and no one understands how this happens nor its effect on neuronal and astroglial physiology, according to Boorman. These findings, however, do offer a possibility for astroglia cells to be involved in depression as well as providing a focal into where the researchers could direct their knowledge of the disease.
Reference: Duque M, Chen AB, Hsu E, et al. Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance. Neuron. 2024;112(11). doi:10.1016/j.neuron.2024.11.011
