The zebrafish-based research in Aggressotype aims to understand the genetic changes that can lead to aggression and to identify novel drug treatments for this behaviour.

Zebrafish are an excellent model organism in which to carry out this work. They are small, easy to maintain in a laboratory and have a short life-cycle meaning that large numbers of fish can be generated at any one time. Zebrafish are easy to manipulate genetically and there are well-established protocols to measure their behaviour. Zebrafish are also ideal for chemical screens because drugs can be applied by immersion thus removing the need for potentially painful injections. Furthermore, their genetic similarity to other vertebrates will make it easy to translate information generated by this research to other animals.

The research to be carried out in the first part of this project will be based upon genes identified by studying human patients that exhibit heightened aggression. We will create zebrafish that lack the function of these aggression-related genes and quantify changes to their behaviour including aggression levels and impulsivity. Aggression will be measured by recording a fish’s interaction with its mirror image and impulsivity by a simple choice task in which a fish has to wait before pressing a button to receive a food reward. Once we have shown that genes have a similar behavioural function in fish as in humans we will characterise the related alterations to brain function. This will lead to a better understanding of how the brain controls aggression levels.

The second zebrafish project within Aggressotype will identify novel drug treatments for aggression. We will first develop a high-throughput model of zebrafish aggression by examining the behaviour of young fish. This approach will allow us to speed up the acquisition and analysis of behavioural data permitting us study a larger number of novel drugs. We will treat zebrafish with either a control treatment or a carefully selected compound of interest and quantify the changes to behaviour that are triggered. Promising drugs will be analysed over a range of different doses and then re-tested in mouse models of aggression to make sure that our data is not only related to zebrafish.

This research represents a first step towards developing improved therapeutic treatments for human aggression.

Details will follow soon.

Most pharmacological agents that are used to treat neuropsychiatric disorders were discovered “by accident” more than 50 years ago. This is also true for treatment of aggression symptoms a part of an underlying psychiatric disorder. Although these agents have been used for decades, we have still limited knowledge of their mode of action. Furthermore, all known treatments for neuropsychiatric disorders are often ineffective or may have serious side effects. Thus, there is an urgent need to develop new treatments that could either be novel pharmacological agents or psychological/behavioral interventions (also see section on Trials and Therapies).

In this work package, we will use genetic data that are generated by genomic analyses of large patient cohorts to search for new genes and biological mechanisms involved in conduct disorders and ADHD (by Aggressotype investigators and other researchers). Where structural details are available for possible candidate proteins, they can be tested for ligand binding using high-throughput in silico and in vitro screening procedures. Typical binding ligands may be enzyme or receptor inhibitors, or pharmacological chaperones, i.e. small molecules that bind to and stabilize proteins, including proteins that have acquired destabilizing mutations. Such screening procedures are a first step towards identifying new compounds that can be tested in intact cells or organisms. If the active pharmacological agents already have been tested in humans for other medical conditions, promising drugs may even be repurposed for treatment of neuropsychiatric disorders. However, such future applications are beyond the scope of Aggressotype.

To date, many genes have been associated with the development of pathological aggression and genome-wide association and family studies have led to the discovery of several gene variants accounting for an increased risk of aggressive behaviour. While the common variants of those genes have a rather small effect on aggression, rare gene variants have a greater impact on aggressive behaviour. The products of some of those genes have known functions, for example the Serotonin-transporter; in others the function of the coded protein is still elusive.

To gain more knowledge about the function of risk gene variants of aggressive behaviour, induced pluripotent stem cells will be obtained from skin biopsy-derived fibroblasts of patients with rare risk gene variants. Those stem cells will be differentiated into neuronal cells and will be functionally characterized using biochemical, molecular and electrophysiological readouts. Recently it has been shown that differentiated cells generated from human induced pluripotent stem cells are a good model to investigate the pathologic mechanisms of genetic disorders, for example in genetic forms of Parkinson’s disease.

In disorders where various common gene variants probably increase the risk of disorders synergistically, it is now possible to insert several risk gene variants by a transcription activator-like effector nucleases (TALENs) system. Also it is possible to correct or disrupt the genetic risk variants in the cell lines by TALEN technology, exploring the possibility of gene therapy in the future. Taken together, these studies will help to understand the functional role of common and rare variants in risk genes for aggression, and will improve our understanding of the possible molecular mechanisms underlying pathological aggression.