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

模拟和数字时钟：模拟信号在大脑主生物钟及其输出中的作用和机制。

• 批准号: BB/S01764X/2
• 负责人: Mino Belle
• 金额: $ 33.67万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS01764X%2F2
• 关键词: analogue; digital; clock; Role; mechanisms

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.

昼夜节律（~ 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、激素产生、觉醒和睡眠-觉醒周期方面表现出每日变化或节律。由于我们现代24小时社会生活方式（例如慢性时差或轮班工作）而导致的这些节奏的中断可能对一些严重疾病产生广泛影响，例如心理健康，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，昼夜节律由大脑内的主昼夜节律钟（称为视交叉上核（SCN））通过所谓的核心时钟基因/蛋白（分子时钟）的节律和同步活动来协调。长期以来，人们一直认为，为了协调我们体内的昼夜节律，SCN神经元会释放一种称为动作电位（AP：一种全有或全无的数字代码）的电信号，其频率在白天增加，晚上福尔斯下降。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，白天的数字放电活动高峰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，相反，它们开始用连续波发出信号，“模拟”代码。由于这种模拟代码是时钟神经元的电输出，我们在这里认为，它必须是关键的SCN和昼夜节律计时的整体功能。遗憾的是，与数字信号不同，模拟信号在SCN功能中的作用仍然未知。 在这项拟议的工作中，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SCN中模拟信号的重要性。我们还将研究时钟神经元开始以模拟代码进行通信时发出的信号，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。这项工作将弥合一个关键的神经生理学知识的差距，在我们的分子时钟和SCN神经元活动之间的功能关系的理解。这些结果将为我们了解昼夜节律如何在SCN中产生和传达并向其大脑目标发出信号提供一个步骤。这将使我们掌握必要的知识，知道如何在时差反应、轮班工作、疾病和衰老等中断后修复“坏钟”。