Using the zebrafish model to understand the effects of inflammation on behaviour

Abstract

The relationship between the brain, immune system, and inflammation is a complex and vital aspect of maintaining brain health throughout one’s lifespan. Peripheral immune responses have been shown to play a significant role in the pathophysiology of many neuropsychiatric disorders, including depression, which represents a significant cause of disability worldwide. Given that current antidepressant medications have limited efficacy in achieving full remission for many patients, there is a need for the development of new biomarkers and treatments. Understanding the causal link between inflammatory responses and disease outcomes is crucial for the development of effective treatments for mental health disorders associated with chronic inflammation. While rodent models have been valuable in shedding light on the immunological and mechanistic aspects of this relationship, animal behaviour is highly variable, and many animals are needed to investigate this complex biological phenomenon, carrying high ethical and financial costs. This thesis aimed to investigate the hypothesis that inflammation can disrupt zebrafish (Danio rerio) larvae behaviour and that the inflammation-behaviour relationship observed in mammalian models is also present in zebrafish. While the causal relationship between immune dysfunction and the pathophysiology of depression remains unclear, antidepressants have been shown to affect both immune cells and signalling molecules, leading to both immunomodulatory and pro/antiinflammatory effects. In this project, it’s also hypothesized that the therapeutic effects of antidepressants may be partially attributed to their immunomodulatory properties. To address these hypotheses, experimental and computational were integrated. Zebrafish were exposed to proinflammatory stimuli and in vivo imaging techniques were used to investigate the effects of various treatments on the trafficking of two innate immune cells. These data were linked to the behaviour displayed by zebrafish larvae using automated tracking software. To understand the immune-modulating properties of antidepressants large-scale transcriptomic datasets were used, and the computational observations in vivo were validated using the zebrafish inflammation model developed in this project. This thesis contributes to a growing body of research that explores the relationship between inflammation, behaviour and mental health disorders. These findings support the widely reported hypothesis that inflammation is associated with behavioural alterations and that antidepressant drugs may exert their effects, at least in part, through modulating immune pathways. The zebrafish model developed in this thesis is a valuable tool for investigating this relationship and for identifying potential therapeutic targets. Furthermore, this work also revealed that different classes of antidepressants interact with various immune pathways, and even within the same class, immunomodulatory action can vary, demonstrating the potential of drug-induced perturbation databases for computational drug discovery approaches. However, there are still many unanswered questions, and further studies are necessary to validate the findings presented. This thesis serves as a stepping stone for future studies aimed at elucidating the precise mechanisms underlying the relationship between inflammation and behaviour, and for identifying new therapeutic targets for mental health disorders.