Chronotype and circadian reafference: the impact of free will on the mammalian circadian clock

时间类型和昼夜节律重新影响：自由意志对哺乳动物生物钟的影响

• 批准号: BB/V011111/1
• 负责人: Robert Lucas
• 金额: $ 82.83万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV011111%2F1
• 关键词: Chronotype; circadian; reafference; impact; free

Why can't you tickle yourself? Because we experience sensations that are a product of our own actions as quite distinct from those that arise from the action of external agents. Sensations produced by ourselves are termed 'reafferent' and are a common feature of our everyday experience. Importantly, the same sensation can have a quite different meaning if it is reafferent - when running through a forest stationary trees appear to rush towards you, distinguishing this apparent motion from the real motion of a tiger jumping out could be a matter of life and death. As a result, recognising reafferent sensations and responding accordingly is one of our brain's most important functions. However, there is a class of reafferent sensation which presents a particular challenge because it is entirely a product of modern-day life. Access to artificial light has disrupted the previously inviolable relationship between ambient light intensity and time of day. An event (the appearance of light), that previously always signalled daytime, can now instead reflect our own actions (be reafferent). We might wish that the brain was able to distinguish the rising sun from the light switch, but because the latter is an entirely artificial situation it cannot. An additional problem is the activities which artificial light facilitates - both arousal and exercise were previously tied to the light:dark cycle and reinforced that sense of daytime. The brain still takes them as time cues, but now their timing is often a function of our own choices. These newly reafferent sensations impinge upon our internal biological (circadian) clock which provides an internal reflection of external time. It has been suggested that our ability to self-select the timing of light exposure and associated activities explains why there is so much variation in preferred sleep time ('chronotype') among humans. 'Larks' (early to bed, early to rise) and 'owls' (stay up late) can show very different preferences. Fitting such divergent preferred sleep times to a uniform 9-5 work/school routine disrupts biological rhythms, the most obvious manifestation of which is so called 'social jetlag' in which owls are sleep deprived during the week and sleep in at weekends. Such disrupted rhythms impair school/work performance and contribute to widespread and intractable public health problems including mood disorders and obesity. There is thus an urgent need to understand how reafference impacts biological clocks and what we may be able to do about it. Addressing this question in laboratory animals, in which we can achieve high control over experimental conditions and uncover mechanisms, is an important element of this endeavour. Unfortunately, common lab animals (mice and rats) do not recapitulate important aspects of reafference because they are nocturnal. They typically avoid light, and display arousal and activity during their night-time. We have established a new laboratory rodent, the 4-striped mouse, which is strongly day active. In preparation for this proposal, we have shown that these animals can be trained to switch their lights on and off, and use this freedom to express familiar preferences - choosing bright light during the day and darkness to sleep at night. This breakthrough provides the first opportunity to study the impact of self-selected light in lab animals. We will use the 4-striped mice to determine how daily rhythms in rest/activity are impacted by access to self-selected light and how this appears on simulated 'work' (when they are woken in the morning) and 'free' (when they can choose their own wakeup time) days. We will establish how arousal and exercise impact rhythms by studying the part of the brain that houses the clock and by looking at how they alter rhythms in rest/activity. We will finally trial strategies for supporting good biological rhythms in the face of reafference.

你为什么不能发痒？因为我们经历的感觉是我们自己行动的产物，与外部代理人的作用完全不同。我们自己产生的感觉被称为“重申”，是我们日常体验的共同特征。重要的是，如果重申的话，同样的感觉可能具有完全不同的含义 - 当穿过森林固定的树木时，似乎朝着您冲向您，将这种明显的运动与虎头跳出的真实动作区分开来可能是生死攸关的问题。结果，认识到重申的感觉并相应地做出反应是我们大脑最重要的功能之一。但是，有一类重申的感觉提出了一个特定的挑战，因为它完全是现代生活的产物。访问人造光已破坏了环境光强度与一天中的时间之间的先前不可侵犯的关系。事件（光的外观）以前始终发出白天的信号，现在可以反映我们自己的行为（重申）。我们可能希望大脑能够将升起的太阳与光开关区分开，但是因为后者是完全人为的情况，所以它不能。另一个问题是人造光促进的活动 - 以前唤醒和运动都与光周期相关：黑暗循环并加强了白天的感觉。大脑仍然将它们作为时间提示，但是现在他们的时机通常是我们自己选择的函数。这些新的重申感觉影响了我们的内部生物学（昼夜节律）时钟，后者提供了外部时间的内部反射。有人建议，我们自我选择光暴露时间和相关活动的能力解释了为什么人类首选的睡眠时间（'Chronotype'）有如此多的变化。 “百灵鸟”（早到床，早起）和“猫头鹰”（熬夜）可以表现出非常不同的偏好。将这种不同的偏爱睡眠时间适应统一的9-5工作/学校常规，这会破坏生物节奏，最明显的表现就是所谓的“社交喷气拉格”，其中猫头鹰在一周内被剥夺了睡眠，并在周末睡觉。这种干扰的节奏会损害学校/工作表现，并导致广泛而棘手的公共卫生问题，包括情绪障碍和肥胖症。因此，迫切需要了解重申生物时钟的影响以及我们对此可能有什么能力。在实验动物中解决这个问题，在该问题中，我们可以对实验条件进行高度控制和发现机制，这是这项努力的重要因素。不幸的是，普通实验室动物（小鼠和大鼠）没有概括重新依从性的重要方面，因为它们是夜间的。他们通常避免使用光，并在夜间表现出唤醒和活动。我们已经建立了一种新的实验室啮齿动物，这是4条式的小鼠，这是强烈的日子。为了准备该提案，我们表明可以训练这些动物以打开和关闭灯光，并利用这种自由来表达熟悉的偏好 - 白天选择明亮的光线，而黑暗在晚上睡觉。这一突破为研究实验室动物的自我选择光的影响提供了第一个机会。我们将使用4条条纹的小鼠来确定休息/活动中的每日节奏如何受到自我选择的光的访问以及模拟的“工作”（早上唤醒时）和“免费”（当他们可以选择自己的唤醒时间）几天的影响。我们将通过研究容纳时钟的大脑部分以及查看它们如何改变休息/活动的节奏来确定唤醒和运动如何影响节奏。最终，我们将试图在面对重申的情况下支持良好的生物节奏。