The regulation of circadian and ultradian rhythmicity of circulating glucocorticoid hormones and their role in the optimisation of limbic activity

生物节律对身体健康和许多生理系统的最佳功能至关重要。人体节律的日常昼夜调节是由下丘脑视交叉上核（SCN）中的一组细胞控制的。这些细胞使用一种特殊的分子机制，即所谓的时钟基因，它使用一种自我调节的反馈系统来维持大约24小时的活动节奏。这个中央时钟的活动受外部信号（如光线）的精细调节，调节多种生理系统，包括内分泌、代谢、心血管、认知和行为输出。时钟基因在大脑的其他区域和许多外周组织中也被发现，这一发现挑战了单个SCN起搏器的概念。然而，与SCN不同的是，这些其他区域的时钟基因并不一定表达独立的长期节律，而是需要SCN来引导和维持它们的节律。这立即要求我们解决SCN如何控制这些从振荡器的问题。作为SCN外生物钟基因的控制者，一个明显的候选者是肾上腺皮质分泌的糖皮质激素，它以昼夜节律分泌。这种节律是在SCN的控制下，我们最近表明，通过该系统的信号传递取决于其昼夜节律和其分泌的脉冲特征。此外，我们知道一个非常重要的时钟基因/周期1 (per 1) /具有允许其受糖皮质激素调节的分子特征。因此，在这个应用中，我们想要定义SCN如何影响糖皮质激素分泌动力学，以及这些动力学的变化如何改变大脑中对认知功能和焦虑行为至关重要的区域的时钟基因的调节。然后，我们将继续研究这些时钟基因的变化如何改变神经元相互作用的效率（突触可塑性），以及这反过来如何改变有意识动物的记忆能力。

Biological rhythms are critical for good health and the optimal function of many physiological systems. The daily-circadian-regulation of body rhythms is controlled by a group of cells in the suprachiasmatic nucleus (SCN) of the hypothalamus. These cells employ a specific molecular machinery of so-called clock genes, which use a self-regulating feedback system to maintain an approximate 24-hour rhythm of activity. This central clock / whose activity is fine tuned by external cues such as light / regulates multiple physiological systems including endocrine, metabolic, cardiovascular, cognitive and behavioural outputs. The discovery that clock genes are also found in other areas of the brain and in many peripheral tissues challenges the concept of a single SCN pacemaker. Unlike the SCN however, the clock genes in these other areas do not necessarily express independent long-term rhythms and need the SCN to entrain and maintain their rhythms. This immediately demands that we address the question of how the SCN can control these slave oscillators. One obvious candidate as a controller of the clock genes outside the SCN is the glucocorticoid secreted by the adrenal cortex, which is secreted in a circadian rhythm. This rhythm is under the control of the SCN, and we have recently shown that signalling through this system depends on both its circadian rhythm and the pulse character of its secretion. Furthermore, we know that a critically important clock gene / period 1 (per 1) / has the molecular signature that allows it to be regulated by glucocorticoids. In this application therefore, we want to define how the SCN effects glucocorticoid secretory dynamics, and how changes in these dynamics alter the regulation of clock genes in areas of the brain vital for cognitive function and anxiety behaviour. We shall then go on to investigate how these changes in clock genes alter the efficiency of neurones to interact (synaptic plasticity) and how this in turn alters the memory abilities of conscious animals.