Studies on the distinct control of free corticosterone levels in the brain

糖皮质激素(人体皮质醇)是一种荷尔蒙，对生物体的健康和福祉至关重要。它们在包括新陈代谢和生长在内的许多身体功能中起着至关重要的作用。重要的是，糖皮质激素还调节情绪、情绪和记忆等大脑功能。糖皮质激素最为人所知的是在有压力的情况下释放。因此，它们通常被称为“压力荷尔蒙”。在压力期间和之后，它们对于调动能量和支持所谓的压力应对和压力适应战略的各种过程是必不可少的。因此，糖皮质激素在抑郁症和焦虑症等精神疾病中发挥重要作用也就不足为奇了，这些疾病似乎涉及到对应激事件的不安应对。糖皮质激素是由肾上腺(位于肾脏上方)分泌的，在24小时的昼夜周期中表现出明显的节律，在动物和人类的活动期开始前达到最高水平。有趣的是，我们现在知道糖皮质激素并不是从肾上腺持续分泌到血液中，而是以一系列的脉冲形式分泌，每个脉冲持续大约一个小时。通过循环，糖皮质激素可以到达体内的所有器官和组织。然而，情况更加复杂，因为荷尔蒙的最大部分与血浆中存在的蛋白质结合在一起。只有一小部分荷尔蒙是自由的，重要的是，只有这种自由的部分才能被组织‘看到’，因此具有生物学活性。因此，几乎没有任何关于调节体内游离皮质酮水平的信息，这是非常令人惊讶的。此外，作为糖皮质激素作用的主要靶器官，大脑是否暴露在与循环中存在的相同水平的游离糖皮质激素中，这一点尚不清楚。在这方面，我们最近有了一个重要的发现。通过一种名为体内微透析的技术，我们直接测量了大鼠大脑中的游离糖皮质激素水平，即游离皮质酮的水平，我们发现大脑中维持了血液皮质酮的脉动节律。然而，我们也发现，与循环相比，皮质酮对压力的反应在大脑中严重延迟。因此，我们假设，大脑中的游离糖皮质激素水平与循环中的水平受到明显的调节，对大脑中各种糖皮质激素调节过程具有根本影响。因此，我们设计了这里提出的全面研究计划，在该计划中，我们将使用包括遗传方法在内的最先进技术来研究大鼠和小鼠大脑中游离皮质酮的调节。通过进行双微透析，我们将能够同时监测大脑和循环中的游离皮质酮水平和应激反应。因此，我们的项目将有益于应激的神经生物学的基本知识，因此，毫无疑问，有可能为改善人类和动物的福祉做出深远的贡献。

Glucocorticoids (in humans cortisol) are hormones which are crucial for the health and wellbeing of an organism. They play a vital role in many body functions including metabolism and growth. Importantly, glucocorticoid hormones also modulate brain functions such as mood, emotion and memory. Glucocorticoids are best known for their release during a stressful situation. Therefore, they are often called 'stress hormones'. During and after stress they are essential for the mobilisation of energy and for a wide variety of processes to support so-called stress coping and stress adaptation strategies. It is therefore not surprising that glucocorticoid hormones play an important role in psychiatric diseases such as depression and anxiety; diseases which seem to involve disturbed coping with stressful events. Glucocorticoid hormones are secreted by the adrenal glands (situated just above the kidneys) and show a clear rhythm over the 24-hour day/night cycle with highest levels reached just before the start of the active period in animals and man. Interestingly, we now know that glucocorticoids are not continuously secreted from the adrenal glands into the bloodstream but rather in a series of pulses, with every pulse lasting about one hour. Through the circulation the glucocorticoids can reach all organs and tissues in the body. However, the situation is even more complex as the largest part of the hormones is bound to proteins present in the plasma. Only a minor fraction of hormone is unbound (free) and, importantly, it is only this free fraction that is 'seen' by the tissues and is therefore biologically active. Thus, it is highly surprising that there is hardly any information available on the regulation of free corticosterone levels in the body. Furthermore, it is not known whether the brain, a principal target organ for glucocorticoid action, is exposed to the same levels of free glucocorticoid hormone as those present in the circulation. In this respect, we recently have made an important discovery. Measuring the levels of free glucocorticoid hormone directly in the brain of rats, i.e. free corticosterone - with a technique called in vivo microdialysis- we found that the pulsatile rhythm of blood corticosterone is maintained in the brain. However, we also found that the response of corticosterone to stress is profoundly delayed in the brain as compared to the circulation. We have therefore hypothesised that free glucocorticoid levels in the brain are regulated distinctly from those in the circulation having fundamental consequences for the wide variety of glucocorticoid-modulated processes in the brain. We therefore have designed the here proposed comprehensive research plan in which we will study the regulation of free corticosterone in the brain of rats and mice using state-of-the-art techniques including genetic approaches. By performing dual microdialysis we will be able to monitor free corticosterone levels and stress responses in the brain and circulation simultaneously. Thus, our project will benefit the basic knowledge of the neurobiology of stress and, therefore, has without doubt the potential to make a profound contribution to the improvement of both human and animal wellbeing.