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

我们都经历过压力，无论是因为我们参加考试还是经历可怕的情况。事实上，一点点的压力对我们是有好处的，可以让我们应对现代生活的需求。然而，如果我们长期处于压力之下，这可能会导致严重的健康问题，包括肥胖、糖尿病、心脏病，以及无法集中注意力、学习新技能或应对日常生活。当我们感到压力时，身体会向血液中释放强大的糖皮质激素，控制身体机能的许多方面。这种糖皮质激素的释放是由位于大脑底部豌豆大小的垂体前叶的皮质滋养细胞的电活动控制复杂地调节的。应激时大脑释放的激素刺激促肾上腺皮质激素的电活动，导致应激激素ACTH向血液中的释放增加，以控制糖皮质激素的合成和肾上腺的释放。正常情况下，糖皮质激素本身的作用是关闭促皮质细胞的电活动，以阻止ACTH的释放，从而最终降低释放到体内的糖皮质激素水平。然而，当我们长期处于应激状态时，促皮质细胞变得过度兴奋，释放更多的促肾上腺皮质激素，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，在慢性应激下，控制促皮质细胞电兴奋性的许多不同蛋白质（离子孔）的表达被上调或下调。利用数学模型，我们可以预测这种兴奋性是如何改变的，从而使我们能够确定新的治疗目标，以限制慢性压力的影响。在这个项目中，我们将利用我们的数学模型，并将其与小鼠和分离细胞中皮质性电兴奋性和ACTH释放的实验分析相结合。综上所述，我们将揭示慢性应激控制垂体前皮质功能的机制，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.