Remodelling of corticotroph excitability in chronic stress: an integrated physiological and modelling analysis

点击翻译按钮获取中文摘要

We all experience stress whether it is because we are taking an exam or experience a frightening situation. In fact, a little bit of stress is good for us and allows us to cope with the demands of modern life. However, if we are chronically stressed this can lead to major health problems including obesity, diabetes, heart problems and inability to concentrate, learn new skills or cope with everyday life.When we are stressed the body releases powerful glucocorticoid hormones into the blood stream that control many aspects of body function. This release of glucocorticoids is intricately regulated by the control of the electrical activity of corticotroph cells, located in the pea-sized anterior pituitary gland, at the base of the brain. The electrical activity of corticotrophs is stimulated by hormones released from the brain during stress, resulting in increased release of the stress hormone ACTH into the blood to control glucocorticoid synthesis and release from the adrenal gland. Normally, the glucocorticoids themselves act to switch off the electrical activity of the corticotroph cell to prevent ACTH release and thus ultimately reducing levels of glucocorticoid released into the body. However, when we are chronically stressed the corticotroph cells become overexcited and release more ACTH resulting in elevated glucocorticoid levels. Furthemore, the glucocorticoids no longer efficiently switch off the activity of the corticotrophs.We have recently determined that in chronic stress the expression of many different proteins (ion pores) that control the electrical excitability of corticotrophs are up or down regulated. Using a mathematical model, we can make predictions of how this excitability may be changed and thus allow us to define new therapeutic targets to limit the effects of chronic stress. In this project we will exploit our mathematical model and combine this with experimental analysis of corticotroph electrical excitability and ACTH release in mice and in isolated cells. Taken together we will unravel the mechanisms by which chronic stress controls anterior pituitary corticotroph function and define mechanisms and targets for potential therapeutic strategies to limit the deleterious effects of chronic stress.