Hypothalamic-pituitary modulation of corticosterone pulsatility

下丘脑-垂体-肾上腺轴对维持生命至关重要，是保护身体应对压力的主要荷尔蒙系统。这个系统的一个非常重要的方面是，它必须能够对紧急情况做出快速反应。我们想要调查，维持这种快速反应的一个重要因素是否是荷尔蒙水平总是以一种极端的方式变化的事实，这防止了系统脱敏或下调。我们认为这种极端的节律性实际上是建立在垂体和肾上腺相互作用的方式中的--既有前馈调节，也有反馈调节，来自下丘脑的激活只是增加了这个系统的内在脉动性。我们将通过给予不同的CRF模式和浓度来人工改变下丘脑的驱动力来测试这一点。我们还提出，ACTH的超常节律性对于维持肾上腺对应激的反应性至关重要。此外，我们认为这种反应性将在一天中以一种依赖于肾上腺交感神经创新活动的方式变化。我们将通过在一天的不同时间给出不同的ACTH模式来研究这一点，并测量参与皮质酮合成和皮质酮释放到血浆中的肾上腺内酶。这些研究应该能够提供关于下丘脑-垂体轴如何能够对应激情况做出快速反应的重要信息，并将为了解在许多疾病(如抑郁症)中发现的HPA功能异常提供基础，并提供为什么使用合成类固醇治疗可能会产生特别糟糕的副作用的理论基础。关于BBSRC的战略优先事项，我们的建议使用系统方法来研究HPA活性振荡活动的潜在机制及其对神经内分泌系统对内外应激刺激做出快速反应的有效性的影响。因此，使用我们的自动化全动物输液和采样系统来回答有关下丘脑-垂体-肾上腺相互作用的问题，非常符合BBSRC的战略优先事项“生物研究的系统方法”。

The hypothalamic-pituitary-adrenal axis is critical for the maintenance of life, and is the major hormonal system that protects the body in response to stress. A very important aspect of this system is that is must be able to respond rapidly to emergency situations. We should like to investigate whether an important factor in maintaining this rapid reactivity is the fact that hormone levels are always changing in an ultradian manner, which prevents the system from desensitising or downregulating. We propose that this ultradian rhythmicity is actually built into the way the pituitary and the adrenal glands interact - in both feedforward and feedback regulation, and that the activation from the hypothalamus simply increases the built-in pulsatility of this system. This we shall test by artificially altering hypothalamic drive by giving different patterns and concentrations of CRF. We also propose that the ultradian rhythmicity of ACTH is critical for maintaining adrenal gland responsiveness to stress. Furthermore we believe that this responsiveness will vary over the day in a manner dependent upon the activity of the sympathetic innovation to the adrenal gland. We shall investigate this by giving differential patterns of ACTH at different times of day and measuring both the intra-adrenal enzymes involves in corticosterone synthesis and the release of corticosterone into the plasma. These studies should provide important information as to how the hypothalamic-pituitary axis is able to respond rapidly to stressful situations and will provide the basis for understanding abnormalities of HPA function which have been detected in a number of diseases such as depression, as well as providing a rationale why treatment with synthetic steroids might have particularly bad side effects. With respect to BBSRC strategic priorities, our proposal uses a systems approach to investigate the mechanisms underlying the oscillatory activity of HPA activity and its impact on the effectiveness of this neuroendocrine system to react rapidly to internal and external stress stimuli. The use of our automated whole animal infusion and sampling systems to answer questions about hypothalamic-pituitary-adrenal interactions, is therefore closely in line with the BBSRC strategic priority 'Systems Approach to Biological Research'.