PhD Studentship: The short fuse of stress - understanding the molecular mechanisms of stress malada

Environmental stress is a frequently encountered experience that can erode homeostatic mechanisms and disrupt the integrity of whole organ systems. Humans and animals have complex adaptive responses to stress, which alter behaviour and overall physiological pathways. A key regulator of these adaptive responses is the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA-axis leads to synthesis of cortisol and promotes adaptation. The response of the HPA-axis is controlled by negative feedback via circulating cortisol. However, the set-point of this negative feedback circuit can be reprogrammed to result in maladaptive responses that consequently result in serious health problems including depression and anxiety. Furthermore, stress responses are modulated by an individual’s genomic constitution, which makes a distinct contribution to the individual’s susceptibility to psychiatric disorders. The majority of the steroidogenic genes expressed in the adrenal glands are also detectable in the brain. We have established the presence of the entire enzymatic pathway to cortisol biosynthesis in the hypothalamus and other areas of the brain crucial to the response to stress and brain remodelling in zebrafish. Furthermore, it has been established that the brain not only responds to peripheral steroid hormones but also that the brain actively synthesises neurosteroids. However, the regulation steroidogenic enzymes expressed in the brain and their role in the regulation of the response to stress remains elusive. Therefore, we have generated several glucocorticoid-deficient zebrafish lines (cyp11a2, cyp21a2, cyp17a2, fdx1b null alleles) differentially disrupting cortisol biosynthesis, and begun to compare their phenotypes to that of a mutant exhibiting glucocorticoid resistance and hypercortisolaemia (defective glucocorticoid receptor, nc3r1 mutants). These in vivo models will be used to explore the pathophysiologic mechanisms involved in maladaptation to stress responses.

Firstly, this project will explore the dynamic regulation of steroidogenic enzymes expression in the brain in response to environmental stress and genetic disruption. Secondly, the effects of stress on the activity of steroidogenic pathway enzymes in the hypothalamus will be analysed. Finally, the impact of stress on proliferation of neural progenitors in the CNS will be explored. We will employ quantitative PCR, in situ hybridisation, cell proliferation, apoptosis assays, as well as bright-field and fluorescence microscopy. Thus, this project will address exciting research questions and provide a wide range of transferrable skills to the PhD student.

Overall, this project combines cutting-edge technology with cross-cutting research questions to discover important novel physiological mechanisms. These studies will also provide novel insights into pathophysiologic changes in the central-nervous system that may underlie stress-linked affective disorders.

Funding Notes

The Faculty Scholarships for Medicine, Dentistry & Health cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.