Larval Zebrafish as a Model for Mechanistic Discovery in Mental Health

Animal models are essential for the discovery of mechanisms and treatments for neuropsychiatric disorders. However, complex mental health disorders such as depression and anxiety are difficult to fully recapitulate in these models. Borrowing from the field of psychiatric genetics, we reiterate the framework of 'endophenotypes' - biological or behavioral markers with cellular, molecular or genetic underpinnings - to reduce complex disorders into measurable behaviors that can be compared across organisms. Zebrafish are popular disease models due to the conserved genetic, physiological and anatomical pathways between zebrafish and humans. Adult zebrafish, which display more sophisticated behaviors and cognition, have long been used to model psychiatric disorders. However, larvae (up to 1 month old) are more numerous and also optically transparent, and hence are particularly suited for high-throughput screening and brain-wide neural circuit imaging. A number of behavioral assays have been developed to quantify neuropsychiatric phenomena in larval zebrafish. Here, we will review these assays and the current knowledge regarding the underlying mechanisms of their behavioral readouts. We will also discuss the existing evidence linking larval zebrafish behavior to specific human behavioral traits and how the endophenotype framework can be applied. Importantly, many of the endophenotypes we review do not solely define a diseased state but could manifest as a spectrum across the general population. As such, we make the case for larval zebrafish as a promising model for extending our understanding of population mental health, and for identifying novel therapeutics and interventions with broad impact.