STRESS recovery

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精力、学习新技能或处理日常生活。许多人能够应对慢性压力，而其他人则更容易受到影响，可能是因为他们的遗传背景或其他生活经历。为什么有些人更容易受到长期压力的影响还不清楚，这个项目将解决这个问题，并可能找到可能使这些人变得更有弹性的策略和药物。当我们感到压力时，身体会从肾脏上方的器官--肾上腺--释放出强大的糖皮质激素，进入血流，这些激素控制着身体功能的许多方面，这些方面对应对压力非常重要。糖皮质激素的释放由大脑复杂地控制，大脑调节促肾上腺皮质激素的电活动，促肾上腺皮质激素细胞位于豌豆大小的脑垂体前叶，位于大脑底部。应激期间从大脑释放的激素刺激促肾上腺皮质激素细胞，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。人们在很大程度上认为，一旦慢性应激期结束，促肾上腺皮质激素细胞的行为就会简单地恢复到正常的“压力前”水平。然而，我们最近引人注目的发现表明，促肾上腺皮质激素细胞的性质以及它们表达的基因组合都经历了持续的变化。这些持续的变化在压力结束后持续数周，这表明细胞的行为发生了变化，通过它们与大脑和肾上腺的相互作用进行的压力调节可能会有所不同。这可能有助于解释人们在经历了一段时间的慢性压力后对新的压力情况做出不同反应的方式，以及为什么有些人对压力相关障碍的发展具有韧性，而另一些人则容易患上与压力相关的障碍。一项重要的技术发展意味着，我们现在第一次能够实时测量促肾上腺皮质激素在活体动物中的行为。我们将把它与强大的技术结合起来，这些技术允许我们测量促肾上腺皮质激素的活动，并预测促肾上腺皮质激素及其荷尔蒙输出是如何调节的，这样我们就可以了解慢性应激可能如何改变这一点。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. 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.