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

我们都经历过压力，无论是因为我们在考试，还是因为我们经历了一种可怕的情况。事实上，一点点压力对我们是有好处的，可以让我们应付现代生活的需求。然而，如果我们长期承受压力，这可能会导致严重的健康问题，包括肥胖、糖尿病、心脏问题以及无法集中注意力、学习新技能或处理日常生活。当我们承受压力时，身体会向血液中释放强大的糖皮质激素，控制身体功能的许多方面。糖皮质激素的释放受到皮质激素细胞电活动的复杂调控，皮质激素细胞位于豌豆大小的脑垂体前叶，位于大脑的底部。促肾上腺皮质激素的电活动是在应激期间从大脑释放的激素刺激的，导致应激激素ACTH释放到血液中，以控制糖皮质激素的合成和从肾上腺释放。正常情况下，糖皮质激素本身会关闭促肾上腺皮质激素细胞的电活动，以防止ACTH释放，从而最终减少释放到体内的糖皮质激素水平。然而，当我们长期应激时，促肾上腺皮质细胞过度兴奋，释放更多的ACTH，导致糖皮质激素水平升高。此外，糖皮质激素不再有效地关闭促肾上腺皮质激素的活性。我们最近确定，在慢性应激中，许多控制促肾上腺皮质激素电兴奋性的不同蛋白质(离子孔)的表达受到上调或下调。使用数学模型，我们可以预测这种兴奋性可能如何改变，从而允许我们定义新的治疗目标，以限制慢性应激的影响。在这个项目中，我们将开发我们的数学模型，并将其与小鼠和分离细胞中促肾上腺皮质激素释放的电兴奋性和ACTH释放的实验分析相结合。综上所述，我们将揭开慢性应激控制垂体前叶促肾上腺皮质激素功能的机制，并确定潜在治疗策略的机制和目标，以限制慢性应激的有害影响。

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.