Psychiatric disorders are highly prevalent brain pathologies that represent an urgent, unmet biomedical problem. Since reliable clinical diagnoses are essential for the treatment of psychiatric disorders, their animal models with robust, relevant behavioral and physiological endpoints become necessary. Zebrafish (Danio rerio) display well-defined, complex behaviors in major neurobehavioral domains which are evolutionarily conserved and strikingly parallel to those seen in rodents and humans. Although zebrafish are increasingly often used to model psychiatric disorders, there are also multiple challenges with such models as well. The field may therefore benefit from a balanced, disease-oriented discussion that considers the clinical prevalence, the pathological complexity, and societal importance of the disorders in question, and the extent of its detalization in zebrafish central nervous system (CNS) studies. Here, we critically discuss the use of zebrafish for modeling human psychiatric disorders in general, and highlight the topics for further in-depth consideration, in order to foster and (re)focus translational biological neuroscience research utilizing zebrafish. Recent developments in molecular biology research utilizing this model species have also been summarized here, collectively calling for a wider use of zebrafish in translational CNS disease modeling.

Anxiety is a complex and multifaceted neurobehavioral disorder that includes various forms of chronic pathological anxiety and fears, and is also the cause for various comorbid pathologies, such as depression or cardiovascular diseases. Behavioral testing of various model organisms, including the zebrafish (Danio rerio), is widely used to study neurobiological mechanisms of anxiety. Here, we discuss the novel tank test, the open field test, light-dark box and shoaling test that are widely used in translational biological psychiatry to characterize anxiety-related behavioral phenotypes in zebrafish.

T- and Y-shaped mazes are traditionally used to assess spatial learning and memory of zebrafish. In the installation of the T-shaped maze, the fish are taught to swim into the desired sleeve and not swim into the wrong one using both positive (for example, food reinforcement) and negative (for example, electric current) stimuli to form more persistent reflexes. The Y-shaped maze is based on the principle of spontaneous choice. Spontaneous choice behavior describes the tendency of animals to change their direction of rotation in a series of successive turns. Each choice statistically depends on the previous one, which indicates its mnestic origin. Unlike other types of memory tasks, testing in the Y-shaped maze does not require prior training or reinforcement (as in the T-shaped maze). Both aquatic mazes are becoming useful tools for assessing zebrafish cognitive phenotypes.

Social interactions between conspecifics are an important factor in normal development of an individual in a community, and their deficits correlate with multiple psychiatric disorders. Several methods for assessing social behavior and its deficits have been described for zebrafish (Danio rerio), and include tests for social preference and social interaction. These tests are commonly used to model a wide range of social phenotypes that are potentially relevant to studying depression, pathological aggression, schizophrenia, autism, and other brain diseases. An important and widely used method for determining social behavior is the shoaling test, based on the innate, genetically fixed feature of zebrafish to form shoals/schools, the density of which depends on many factors, such as the presence of a predator, the effect of pharmacological drugs, etc. Aggression, along with shoaling, is an important manifestation of social behavior, which is also a core symptoms of multiple brain diseases, such as control disorder and conduct disorder. Here, we discuss various methods for assessing aggressive behavior in zebrafish (e.g., the mirror reflection tests), and their shoaling agonistic behaviors.

Antimicrobial drugs represent a diverse group of widely utilized antibiotic, antifungal, antiparasitic and antiviral agents. Their growing use and clinical importance necessitate our improved understanding of physiological effects of antimicrobial drugs, including their potential effects on the central nervous system (CNS), at molecular, cellular, and behavioral levels. In addition, antimicrobial drugs can alter the composition of gut microbiota, and hence affect the gut–microbiota–brain axis, further modulating brain and behavioral processes. Complementing rodent studies, the zebrafish (Danio rerio) emerges as a powerful model system for screening various antimicrobial drugs, including probing their putative CNS effects. Here, we critically discuss recent evidence on the effects of antimicrobial drugs on brain and behavior in zebrafish, and outline future related lines of research using this aquatic model organism.

Depression is a widespread, severely debilitating mental disorder characterized by low mood, anhedonia, fatigue, decreased attention, suicidality and psychomotor retardation, accompanied by neuroendocrine and molecular disorders. Zebrafish have neuroendocrine and neurotransmitter systems similar to humans, as well as high genetic homology, and are rapidly becoming popular model organisms for modeling depressive-like conditions. Here, we discuss modern behavioral, pharmacological and genetic models of depression in zebrafish, their methodological applications and translational implications.