Investigating the role of pulsatile hypothalamic signals in regulating the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis

下丘脑-垂体-肾上腺（HPA）轴是使生物体能够迅速有效地应对压力的主要激素系统。这种复杂的神经内分泌网络调节肾上腺分泌重要的糖皮质激素，其功能的一个关键方面是激素释放的超昼夜振荡（即脉动模式）。整个中枢神经系统的神经元都暴露于这些糖皮质激素脉冲。例如，在海马细胞中，糖皮质激素水平的快速变化调节基因转录和突触传递。值得注意的是，这些振荡的改变与各种生理和病理条件有关，包括衰老和慢性应激。阐明调节这种搏动活动的机制不仅有助于理解应激轴的正常生理功能，而且有助于理解这种功能在疾病中是如何改变的，尽管糖皮质激素脉冲很重要，但HPA轴产生和调节这种搏动活动的机制仍然很大程度上未知。长期以来的假设是，系统中的脉动活动是由下丘脑内的神经“脉冲发生器”控制的，但最近的研究表明，该系统产生振荡的方式更为复杂。最重要的是，最近的研究表明，垂体肾上腺系统可以产生自己的脉动活动独立于下丘脑脉冲。这表明，从系统中出现的脉动活动是两个振荡组件之间的动态相互作用的结果：一个脉动的下丘脑神经网络和内源性脉动的垂体-肾上腺系统。我们的假设是，这种动态相互作用的变化将导致中断的激素脉动出现从系统。在这个项目中，我们将通过考虑两个关键问题来探索这个想法：（1）下丘脑释放的激素脉冲的幅度，频率和平均浓度如何影响垂体-肾上腺系统的脉动活动？(2)下丘脑的脉动糖皮质激素反馈如何影响系统的动力学？为了回答这些问题，我们将采用一系列的技术：在体内（整个动物，大鼠）实验生理学和体外电生理学/成像，以评估下丘脑脉动对垂体-肾上腺系统的影响，以及糖皮质激素反馈对下丘脑的影响;和数学建模，以解开这些组件之间的动态相互作用。这种多学科的方法将使我们能够在多个尺度上研究系统的动力学，并了解支撑振荡激素释放的关键机制。

The major hormonal system that enables an organism to respond rapidly and effectively to stressful situations is the hypothalamic-pituitary-adrenal (HPA) axis. This complex neuroendocrine network regulates the secretion of vital glucocorticoid hormones from the adrenal glands, and a critical aspect of its function is an ultradian oscillation (i.e. pulsatile pattern) in hormone release. Neurons throughout the central nervous system are exposed to these glucocorticoid pulses. In hippocampal cells, for example, these rapid changes in glucocorticoid levels regulate gene transcription and modulate synaptic transmission. Significantly, alterations in these oscillations are associated with a wide variety of physiological and pathological conditions, including ageing and chronic stress. Elucidating the mechanisms regulating this pulsatile activity will not only help to understand the normal physiological function of the stress axis, but will also help to understand how this function is altered in disease.Despite the importance of glucocorticoid pulses, the mechanisms through which the HPA axis generates and regulates this pulsatile activity remain largely unknown. The long-held hypothesis has been that pulsatile activity in the system is controlled by a neural "pulse generator" within the hypothalamus, but recent studies have shown that the way in which this system generates oscillations is more complex. Most significantly, recent work has now shown that the pituitary-adrenal system can generate its own pulsatile activity independently of hypothalamic pulses. This suggests that the pulsatile activity emerging from the system is the result of a dynamic interaction between two oscillatory components: a pulsatile hypothalamic neural network and an endogenously-pulsatile pituitary-adrenal system.Our hypothesis is that changes in this dynamic interaction will result in disrupted hormone pulsatility emerging from the system. In this project, we will explore this idea by considering two key questions:(1) How does the amplitude, frequency and mean concentration of hormone pulses released from the hypothalamus influence the pulsatile activity of the pituitary-adrenal system?(2) How does pulsatile glucocorticoid feedback at the hypothalamus influence the system's dynamics?To answer these questions, we will employ an array of techniques: in vivo (whole animal, rat) experimental physiology and in vitro electrophysiology/imaging to assess the effects of hypothalamic pulsatility on the pituitary-adrenal system, and the effects of glucocorticoid feedback on hypothalamus; and mathematical modelling to untangle the dynamic interactions between these components. This multidisciplinary approach will enable us to study the dynamics of the system at multiple scales, and to understand the key mechanisms underpinning oscillatory hormone release.