Abstract The zebrafish is increasingly being employed as an experimental platform to model neuropsychiatric diseases and to screen for novel neuro-active compounds. While the superb genetic and optical access that this system offers has long been recognized, these features have not been fully exploited to investigate disease mechanisms and possible therapeutic interventions. Here we introduce a light-sheet imaging and graph-theoretical analysis pipeline to determine the effects of the known or suspected antidepressant compounds fluoxetine, ketamine and cycloserine on brain-wide neural activity patterns. We imaged the brains of both wildtype fish and gr s357 mutants, which harbor a missense mutation that abolishes glucocorticoid receptor transcriptional activity. The gr s357 mutation results in a chronically elevated stress axis together with behavioral endophenotypes of depression. Consistent with broad expression of the glucocorticoid receptor throughout the brain, we show that the mutant fish exhibit an altered correlational structure of resting-state brain activity. Intriguingly, in gr s357 mutant fish, an increased ‘modularity’, which represents the degree of segregation of the network into highly clustered modules, was restored by acute fluoxetine administration to wildtype levels. Ketamine and cycloserine also normalized specific parameters of the graph. Fluoxetine altered network function in the same direction in mutant and wildtype, while ketamine and cycloserine had effects that were opposite for the two genotypes. We propose that light-sheet imaging, followed by graph analysis, is a content-rich and scalable first-pass approach for studying the neural consequences of drug effects and drug x genotype interactions in zebrafish models of psychiatric disorders.

Light-sheet imaging and graph analysis of antidepressant action in the larval zebrafish brain network