STRESS recovery

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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. Many people are able to cope with chronic stress, whilst others are more susceptible, possibly because of their genetic background or other life experiences. Why some are more affected by long-term stress are unclear and this project will address this question and possibly identify strategies and drugs that may allow these people to become more resilient. When we are stressed the body releases powerful glucocorticoid hormones from an organ just above the kidneys, the adrenal gland, into the blood stream and these control many aspects of body function that are important for responding to stress. This release of glucocorticoids is intricately controlled by the brain, which regulates the electrical activity of corticotrophs, cells that are located in the pea-sized anterior pituitary gland, at the base of the brain. Stimulation of corticotroph cells by hormones released from the brain during stress results in release of the stress hormone ACTH that is released 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 over excited and release more ACTH resulting in elevated glucocorticoid levels. It had been largely assumed that once the period of chronic stress was over the behaviour of the corticotrophs simply returned to the normal "pre-stress" level.However, our remarkable recent findings reveal that corticotrophs undergo a persistent change in both their properties as well as the portfolio of genes they express. These persistent changes last for weeks after the stress is over suggesting that that the behaviour of the cells is altered and that stress regulation through their interaction with the brain and adrenal glands may then be different. This may help explain the variable ways people respond to new stressful situations after a period of chronic stress and the reason why some are resilient, while others susceptible, to the development of stress-related disorders. An important technical development means that for the first time we are now able to measure how corticotrophs behave in real-time in the living animal. We will combine this with powerful techniques that allow us to measure corticotroph activity and make predictions about how corticotrophs and their hormone output are regulated, so that we can understand how this may be modified by chronic stress. 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.