Functional role(s) of oestrogen signalling on neuronal progenitor cell development and fate in the brain

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Nerve cells (called neurons) form in the brain principally during embryo development but they can also be synthesised in the adult brain. Defects in the process of neuron synthesis (neurogenesis) have been linked with various brain diseases, psychiatric illnesses and addictions. Neurogenesis is also critically involved in the repair of an injured brain. One type of cell, called radial glial cells (RGCs) can give rise to all types of neurons in the cerebral cortex of the brain but how this is controlled is not well understood. Recently, hormones, called oestrogens, have been indicated to play important roles in RGCs and in neurogenesis.In this project we will apply genetically engineered zebrafish models to investigate the roles of oestrogen in neurogenesis and brain development, investigating also for sex related differences. We are using zebrafish for this work because of the relative ease to create transgenic animals and the fact that there is a high neurogenic activity in the brain throughout life. We have already successfully developed one genetically engineered (transgenic) zebrafish in which cells responsive to oestrogen produce a green fluorescent protein (GFP) that can be detected using imaging methods in living animals and in real time. Using this model we will establish the role of oestrogens in the RGCs in the telecephalon and identify the different cells in the brain responsive to oestrogens and how they develop. We will also apply a method called two-photon microscopy to selectively remove the oestrogen responsive RGCs in the telecephalon and investigate subsequent effects on brain development to help establish their function. We will then develop a new transgenic zebrafish model with a different genetic insert that prolongs the green fluorescent signal generated in response to oestrogen exposure. This will enable us to follow the fate of the oestrogen responsive RGCs and other neural cells of early life in the brain of juvenile and adult fish. We will also use this model to investigate for differences that occur between males and females.We will develop a further, more complex (triple), transgenic zebrafish that will enable us to identify activity in oestrogen responding neurons. This model includes two fluorescent colours, red identifying oestrogen responsive neurons and green identifying when these cells are active (produced in response to increased levels of calcium in the cell). Using this fish we will investigate the roles of oestrogen responding neurons in smell, including assessing for sex related differences. We will also apply a technique to block oestrogen action responsive neurons in the telecephalon during early life to establish how this affects their subsequent development and function in smell.Applying these transgenic models, finally we will initiate studies into the effects of exposure to so called endocrine disrupting chemicals (EDCs), for which there is widespread health concern, on oestrogen responding neurons and their subsequent fate and function. The research will be significant interest to a diverse audience including academic and industry researchers, and the medical profession, by provision of new models to study neurogenesis and the roles of an important group of environmental chemicals on human health. It will also be of strong interest to industry and government regulatory bodies, as the models develop could be applied for advancing risk assessment of chemicals with oestrogenic activity, supporting evidence-based decision-making for those chemicals. The wider public will benefit also from this research from improved understanding of neurological conditions and better evidence of chemical effects that may affect their own health. The models developed will provide more integrative systems for chemical effects analysis with great potential for reducing the numbers of vertebrate animals used in testing.