Zebrafish Tools for Deciphering Habenular Network-Linked Mental Disorders

SIMPLE SUMMARY: Everything that we think, feel or do depends on the function of neural networks in the brain. These are highly complex structures made of cells (neurons) and their interconnections (axons), which develop dependent on precisely coordinated interactions of genes. Any gene mutation can result in unwanted alterations in neural network formation and concomitant brain disorders. The habenula neural network is one of these important circuits, which has been linked to autism, schizophrenia, depression and bipolar disorder. Studies using the zebrafish have uncovered genes involved in the development of this network. Intriguingly, some of these genes have also been identified as risk genes of human brain disorders highlighting the power of this animal model to link risk genes and the affected network to human disease. But can we use the advantages of this model to identify new targets and compounds with ameliorating effects on brain dysfunction? In this review, we summarise the current knowledge on techniques to manipulate the habenula neural network to study the consequences on behavior. Moreover, we give an overview of existing behavioral test to mimic aspects of mental disorders and critically discuss the applicability of the zebrafish model in this field of research. ABSTRACT: The prevalence of patients suffering from mental disorders is substantially increasing in recent years and represents a major burden to society. The underlying causes and neuronal circuits affected are complex and difficult to unravel. Frequent disorders such as depression, schizophrenia, autism, and bipolar disorder share links to the habenular neural circuit. This conserved neurotransmitter system relays cognitive information between different brain areas steering behaviors ranging from fear and anxiety to reward, sleep, and social behaviors. Advances in the field using the zebrafish model organism have uncovered major genetic mechanisms underlying the formation of the habenular neural circuit. Some of the identified genes involved in regulating Wnt/beta-catenin signaling have previously been suggested as risk genes of human mental disorders. Hence, these studies on habenular genetics contribute to a better understanding of brain diseases. We are here summarizing how the gained knowledge on the mechanisms underlying habenular neural circuit development can be used to introduce defined manipulations into the system to study the functional behavioral consequences. We further give an overview of existing behavior assays to address phenotypes related to mental disorders and critically discuss the power but also the limits of the zebrafish model for identifying suitable targets to develop therapies.