Larval Zebrafish as a Model for Mechanistic Discovery in Mental Health

Abstract

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.

Osmotic Stress Uncovers Correlations and Dissociations Between Larval Zebrafish Anxiety Endophenotypes

“…In fact, these arguments emphasize another benefit of examining multiple endophenotypes in parallel -to help rule out possible confounds that could explain observed behaviors. Finally, it would be interesting to examine how social avoidance or orienting endophenotypes are affected by osmotic stress, or relate to other group behaviors such as feeding, since they were not analyzed in this study (Tan et al, 2022).…”

“…Our results illustrate the many-to-many relationship between endophenotypes, behaviors, and underlying biological mechanisms. Therefore, cross-examination of endophenotypes via multiple behavioral assays is important to achieve a holistic understanding of stress and anxiety behaviors and their underlying mechanisms (Tan et al, 2022). There may be valuable insights drawn from the correlations and dissociations of endophenotypes that we can exploit in therapeutic approaches to treating stress-related mental disorders.…”

“…Importantly, they also share similar neuroanatomy and physiology, including the HPA stress response, with humans (Kalueff et al, 2014;Stewart et al, 2014Stewart et al, , 2015. Multiple behavioral endophenotypes have been described in the literature on zebrafish stress and anxiety (Tan et al, 2022). Thigmotaxis, or the propensity to stay close to the wall of the testing arena, is thought to be a proxy of anxiety behavior in animals (Wagle et al, 2017).…”

“…Additionally, locomotion during light-dark (L-D) transitions has been used to represent an anxiety endophenotype (Faught and Vijayan, 2022;Sveinsdóttir et al, 2022). The correlations or dissociations between these anxiety endophenotypes, as well as others such as sleep, startle, and feeding are not completely known and may vary according to stressor identity or intensity (Tan et al, 2022).…”

High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin

“…It has a conserved raphe serotonergic system in the hind/midbrain [32][33][34][35][36][37][38][39] in addition to teleost-specific serotonergic nuclei in the hypothalamus 32,33,40 , that allow detailed investigation of the working principles of serotonergic neurons during behavior. Larval zebrafish has also been used to screen the behavioral effect of stress exposure, antidepressants, and genetic mutations [41][42][43][44] . However, few published studies have examined the behavioral effects of psychedelics in larval zebrafish [45][46][47] , and, to date, there have been no published data on the effects of psilocybin.…”