Primary Supervisor: Dr Will Norton, Department of Neuroscience, Psychology and Behaviour

Secondary supervisor: Dr Jonathan McDearmid

PhD project title: Interrogating the neural circuit that controls aggression

University of Registration: University of Leicester

Project outline:

Interrogating the neural circuit that controls aggression

The aim of this project is to develop transgenic tools to characterise the neural circuit that controls aggression in the vertebrate brain.

To do this we will use the zebrafish, a leading model for neuroscience studies, to investigate the genes and neural circuits that control aggression and other social interactions. In a recent study we carried out a screen to identify novel drugs that can reduce aggression (Carreño Gutierrez et al., 2019). Two of the most interesting drugs that we identified by this approach, caffeine and sildenafil, both activate the same areas of the zebrafish brain: Purkinje cells in the cerebellum and the eminentia thalami (ET, the zebrafish homologue of the globus pallidus in other vertebrates). We have recently confirmed these findings by imaging the entire neural network in the adult zebrafish brain that controls aggressive behaviour (Reichmann et al., 2020).

The aim of this PhD project is to build upon these exciting findings by generating tools to directly manipulate neural activity in the cerebellum and ET, and measure changes to aggression and related behaviours. We will 1) identify genes that are uniquely expressed in Purkinje cells or the ET, building upon results from our drug screen and published studies; 2) create transgenic lines expressed in these brain areas to allow optical or chemical manipulation of neural activity; and 3) measure changes to neural activity (by electrophysiology), aggression and related behaviours in zebrafish with- and without activation of Purkinje cells or the ET.

This project will combine a large range of techniques to address this question including zebrafish husbandry and maintenance; molecular techniques (cloning genes, in situ hybridisation, creating transgenic constructs); imaging of neural activity in the whole brain; electrophysiology to assess circuit manipulation; and behavioural analysis of novel zebrafish lines.

This is project is very timely because we recently identified key nodes of the neural circuit in the zebrafish brain that controls aggression. Since zebrafish are vertebrates with highly conserved brain structure, this information can be translated across species with the potential to inform us about human diseases that include aggression as a symptom.

References:

1. Carreno Guteierrez et al., 2020. Screening for drugs to reduce zebrafish aggression identifies caffeine and sildenafil. Eur Neuropsychopharmacol Jann;30:17-29. doi: 10.1016/j.euroneuro.2019.10.005. Epub 2019 Nov 1.
2. Reichmann et al., 2020. The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity. Acta Physiol (Oxf) e13543. doi: 10.1111/apha.13543. Online ahead of print.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour

Techniques that will be undertaken during the project:

The student will gain extensive experience in a wide range of skills across multiple disciplines. This will include in vivo experiments required for behavioural testing, maintenance and husbandry of zebrafish. In addition, the student will acquire comprehensive experience of molecular biology techniques (e.g. qPCR, in situ hybridisation), immunohistochemistry, microscopy techniques (including fluorescent and confocal laser scanning microscopy) and image analysis methods as well as electrophysiological recording.

Contact: Dr Will Norton, University of Leicester