Zebrafish Tools for Deciphering Habenular Network-Linked Mental Disorders

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.

Keywords: Wnt; asymmetry; behavior; compound; habenula; mental disorder; neurogenesis; pharmacology; zebrafish.

Figure 1

Overview of zebrafish habenular network manipulations. Dorsal view on the head of a 4-day old embryo labelled for anti-acetylated tubulin, anterior to the top (central picture). Highlighted are the pineal complex and the dorsal habenula including their efferent projections to the interpeduncular nucleus (IPN) only. Efferent axons from the lateral (green) and the medial (yellow) habenular neurons project to the dorsal and ventral IPN, respectively. Manipulation strategies to change laterality of asymmetry of the habenulae are shown on the top and those causing symmetry on the left and right. For silencing dHbl neuron-IPN transmission, Tg(narp:GALVP16); Tg(UAS:TeNT); Tg(brn3a-hsp70:GFP) (dHbl neurons) transgenic lines are used, while Tg(gpr151:GAL4VP16); Tg(brn3a-hsp70:GFP-Cre); Tg(UAS:loxP-DsRed-loxP-GFP-TeNT) are used for silencing of the dHbm-IPN information flow (lower pictures [62]). op, olfactory placode; P, Pineal; pp, parapineal; tec, tectum.