A time to every purpose: SCN cell-specific control of daily physiological timing

几乎所有的身体机能都受到大脑中占主导地位的生物钟——视交叉上核（SCN）的影响。SCN提供的时间信息有助于优化我们的内部生理机能，以预测24小时内的预期需求。由于需求高峰的时间因不同的行为或生理过程（例如睡眠、心血管和胃肠）而异，因此需要对生理的特定方面进行单独定时，以确保健康和福祉。这种内部协调暂时中断的影响对任何经历过时差反应的人来说都很熟悉。不幸的是，现在很清楚，对我们内部计时机制的长期破坏与许多严重的健康后果有关，包括癌症和代谢疾病的风险增加。因此，在这里，我们试图了解SCN时钟协调大脑和身体其他部分活动的生物学机制，以及这种机制在环境变化中是如何受到干扰的。特别是，我们将确定SCN时钟差异控制生理学的许多不同方面的能力是否源于“时钟细胞”的多个子集的存在，每个子集都具有独特的特性。为了支持这一观点，众所周知，时钟细胞产生各种不同的神经化学信使和/或向大脑的不同区域发送信号。我们自己最近的工作表明，时钟细胞的功能特性也是多种多样的，不同的时钟细胞群在一天中的不同时间变得电活性。同样，我们也已经确定，视网膜提供了使SCN时钟与外部世界同步所需的主要信号，我们和其他人现在已经确定了不同组的时钟细胞，它们对光照条件的变化表现出不同的反应。到目前为止，要回答SCN如何协调生理这一基本问题的主要障碍是无法直接将特定时钟细胞亚群的功能特性与生理的特定方面联系起来。病毒和基因靶向的最新进展使这一目标得以实现。我们将采用这些尖端的方法，使我们能够选择性地识别和监测与特定大脑区域通信和/或产生特定化学信使的时钟细胞群的活动。因此，我们将能够确定向整个大脑的关键调节中心提供的定时信号的性质，以及这些信号如何受到光环境中短期或长期变化的影响。然后，我们将使用类似的方法在全面的生理和行为监测期间专门操纵这些细胞群的活动，使我们能够明确地将特定组的SCN细胞的活动与特定的身体功能（如代谢率，摄食行为，心率等）联系起来。这个项目将使我们对内部时钟如何影响身体其他部分的理解取得重大进展。此外，通过确定各种SCN细胞群的活动如何受到光环境变化的影响，这项工作还将为轮班工作或跨越时区导致的生理破坏的机制基础提供新的见解。最后，我们希望这项工作能够发现利用光选择性调节具有特定生理作用的特定SCN细胞群活性的新方法。这样的策略对于社会上许多内部时钟与社会强加的时间表不一致的人来说，可能会有实质性的实际好处。

Almost every bodily function is influenced by a dominant biological clock within the brain, the suprachiasmatic nucleus (SCN). The timing information provided by the SCN serves to optimise our internal physiology in anticipation of expected demands across the 24h day. Since the timing of peak demand varies between different behavioural or physiological processes (e.g. sleep, cardiovascular and gastrointestinal), particular aspects of physiology need to be individually timed to ensure health and well-being. The impact of temporary disruptions to this internal coordination will be familiar to anyone who has experienced jet-lag. Unfortunately, it is now clear that longer-term disruptions to our internal timing mechanism are associated with a number of serious health consequences including increased risk of cancer and metabolic disease. Accordingly, here we seek to understand the biological mechanisms by which the SCN clock coordinates activity across the rest of brain and body, and how this is disturbed during shifts in the environment. In particular, we will determine whether the ability of the SCN clock to differentially control so many different aspects of physiology stems from the presence of multiple subsets of 'clock cells', each with unique properties. In support of this view, it is well known that clock cells produce a variety of different neurochemical messengers and/or send signals to different regions of the brain. Our own recent work indicates that the functional properties of clock cells are also diverse, with different groups of clock cells becoming electrically active at different times of day. Similarly, it is well established that the major signal required for synchronising the SCN clock to the external world is supplied by the retina, and we and others have now identified various groups of clock cells that exhibit distinct responses to changes in lighting conditions. Until now a major impediment to answering this fundamental question as to how the SCN orchestrates physiology has been an inability to directly connect the functional properties of particular subgroups of clock cells to specific aspects of physiology. Recent advances in viral and genetic targeting now make this goal achievable. We will employ these cutting-edge approaches to allow us to selectively identify and monitor the activity of groups of clock cells communicating to specific brain regions and/or producing particular chemical messengers. We will thus be able to determine the nature of the timing signals supplied to key regulatory centres across the brain and how these are influenced by short or longer term changes in the light environment. We will then use similar approaches to specifically manipulate the activities of the these cell groups during comprehensive physiological and behavioural monitoring, allowing us to unequivocally link the activity of particular groups of SCN cells to specific body functions (such as metabolic rate, feeding behaviour, heart rate, etc).This project will produce a crucial advance in our understanding of how our internal clock influences the rest of the body. Moreover, by determining how the activities of various groups of SCN cells are influenced by changes in light environment, this work will also provide new insight into the mechanistic basis of the physiological disruptions that occur as a result of shift work or crossing time zones. Finally, we expect this work to uncover new ways of using light to selectively adjust the activities of specific SCN cell groups with particular physiological roles. Such strategies that could be of substantial practical benefit to the wide sections of society whose internal clocks are misaligned with their societally imposed schedules.