The analogue and digital clock: Role and mechanisms of analogue signalling in the brain's master circadian clock and its outputs.

昼夜节律（约24小时）遍及我们生理和行为的许多方面。例如，我们的身体在新陈代谢、认知、心血管输出、荷尔蒙分泌、觉醒和睡眠-觉醒周期中显示出每天的变化或节奏。现代24小时社会生活方式导致的这些节律紊乱（如慢性时差或倒班工作）可能会对一些严重疾病产生广泛影响，如精神健康、代谢综合征、心血管疾病、睡眠障碍和癌症。在包括人类在内的哺乳动物中，昼夜节律是由大脑中的主昼夜节律钟（称为视交叉上核（SCN））通过所谓的核心时钟基因/蛋白质（分子时钟）的有节奏和同步的活动来协调的。长期以来，人们一直认为，为了协调我们体内的昼夜节律，SCN神经元释放一种称为动作电位（APs：一种全有或全无的数字代码）的电信号，其频率在白天增加，在夜间下降。然而，我们现在知道至少有两种类型的SCN神经元，那些包含分子时钟的（时钟神经元）和那些不包含分子时钟的（非时钟神经元）。我们还知道，白天放电活动的数字峰值实际上主要是非时钟神经元的活动。值得注意的是，在一天的大部分时间里，时钟神经元变得如此兴奋（过度兴奋），以至于它们停止产生ap，取而代之的是，它们开始发出连续波的信号，即“模拟”代码。由于这种模拟代码是时钟神经元的电输出，我们认为它对SCN的整体功能和昼夜节律计时至关重要。遗憾的是，到目前为止，与数字信号不同，模拟信号在SCN功能中的作用仍然未知。在这项工作中，我们将使用神经科学研究中以前无法使用的最先进的工具，通过检查时钟和非时钟神经元之间的关键联系，来研究模拟信号在SCN中的重要性。我们还将研究时钟神经元在模拟编码中开始交流时发出的信号，并研究它如何与非时钟数字信号合作，向大脑和身体广播昼夜节律。这项工作将在我们理解分子钟和SCN神经元活动之间的功能关系方面弥合一个关键的神经生理学知识缺口。这一结果将使我们对昼夜节律如何在SCN中产生和传递，以及如何向其大脑目标发出信号的认识发生重大变化。这将使我们掌握必要的知识，知道如何在时差、倒班、疾病和衰老等干扰下修复“坏掉的时钟”。

Circadian (~24h) rhythms pervade many aspects of our physiology and behaviour. For example, our body shows daily variation or rhythms in metabolism, cognition, cardiovascular output, hormonal production, arousal, and the sleep-wake cycle. Disruption of these rhythms as a result of our modern 24h society lifestyles (e.g. chronic jet-lag or shift-work) can have wide implications for some serious illnesses, such as mental health, metabolic syndrome, cardiovascular disease, sleep disorders, and cancer. In mammals, including humans, circadian rhythms are orchestrated by a master circadian clock within the brain, called the suprachiasmatic nucleus (SCN), through the rhythmic and synchronised activity of the so-called core clock genes/proteins (the molecular clock). It was long believed that in order to coordinate circadian rhythms in our body, SCN neurons discharge a type of electrical signal called action potentials (APs: an all or nothing digital code), whose frequency increases during the day and falls at night. However, we now know that there are at least two types of SCN neurons, those that contain the molecular clock (clock neurons), and those that do not (non-clock neurons). We also know that the digital peak of firing activity during the day is, in fact, mostly the activity of non-clock neurons. Remarkably, throughout most of the day, clock neurons become so excited (hyperexcited) that they stop generating APs, and instead, they start signalling with a continuous wave, the "analogue" code. Since this analogue code is the electrical output of clock neurons, we argue here that it must be critical for the overall functioning of the SCN and circadian timekeeping. Sadly, as yet, unlike its digital counterpart, the role of analogue signalling in SCN function remains unknown. In this proposed work, we will use state-of-the-art tools previously unavailable in neuroscience research, to investigate the importance of analogue signalling in the SCN, by examining the crucial link between the clock and non-clock neurons. We will also examine the signal that is emitted by clock neurons when they start communicating in the analogue code, and investigate how this cooperates with the non-clock digital signal to broadcast circadian timing to the brain and body. This work will bridge a critical neurophysiological knowledge-gap in our understanding of the functional relationship between the molecular clock and SCN neuronal activity. The results will provide a step change in our knowledge of how circadian rhythms are generated and communicated in the SCN, and signalled to its brain targets. This will arm us with the necessary knowledge of how to fix a "broken clock" following disruptions, as during jet-lag, shift work, disease and ageing.