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激素系统。这一系统的一个非常重要的方面是，它必须能够对紧急情况作出迅速反应。我们想研究维持这种快速反应的一个重要因素是否是激素水平总是以超昼夜方式变化的事实，这会阻止系统脱敏或下调。我们认为，这种超昼夜节律实际上是建立在垂体和肾上腺相互作用的方式中的-在前馈和反馈调节中，下丘脑的激活只是增加了这个系统的内在脉动。我们将通过给予不同模式和浓度的CRF来人为改变下丘脑驱动来测试这一点。我们还提出，超昼夜节律的促肾上腺皮质激素是至关重要的维持肾上腺反应的压力。此外，我们相信，这种反应性将在一天中以依赖于交感神经对肾上腺的创新活动的方式变化。我们将通过给出一天中不同时间的ACTH差异模式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来研究这一点。这些研究应该提供重要的信息，下丘脑-垂体轴是如何能够迅速应对压力的情况下，并将提供基础，了解异常的HPA功能已被检测到的一些疾病，如抑郁症，以及提供一个合理的理由，为什么用合成类固醇治疗可能有特别坏的副作用。关于BBSRC的战略重点，我们的建议使用系统的方法来调查HPA活动的振荡活动的机制及其对神经内分泌系统的有效性的影响，以迅速应对内部和外部的压力刺激。因此，使用我们的自动化整体动物输注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，与BBSRC的战略优先事项“生物研究的系统方法”密切相关。

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'.