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

你为什么不挠自己的痒痒呢？因为我们体验的感觉是我们自己行为的产物，与那些由外部因素的行为产生的感觉截然不同。由我们自己产生的感觉被称为“传入”，是我们日常经验的一个共同特征。重要的是，同样的感觉如果是传入的，可能会有完全不同的意义--当穿过森林时，静止的树木似乎向你冲来，区分这种表面上的动作和老虎跳出的真实动作可能是生死攸关的问题。因此，识别传入感觉并做出相应的反应是我们大脑最重要的功能之一。然而，有一种传入感觉是一种特别的挑战，因为它完全是现代生活的产物。对人造光的接触打破了环境光强度和一天中的时间之间原本不可侵犯的关系。以前总是发出白天信号的事件(光的出现)现在可以反映我们自己的行为(重新传入)。我们可能希望大脑能够区分出旭日东升和电灯开关，但因为后者完全是人为的，所以它不能。另一个问题是人造光促进的活动--唤醒和锻炼以前都与光：暗循环联系在一起，并加强了对白天的感觉。大脑仍然将它们视为时间线索，但现在它们的时机往往是我们自己选择的函数。这些新传入的感觉冲击着我们内在的生物(生理)时钟，后者提供了对外部时间的内在反映。有人提出，我们自己选择光照时间和相关活动的能力解释了为什么人类的首选睡眠时间(时型)存在如此大的差异。“Larks”(早睡早起)和“owls”(熬夜)会表现出截然不同的偏好。将这种不同的偏爱睡眠时间与统一的朝九晚五的工作/学校作息时间相匹配，会扰乱生物节奏，最明显的表现就是所谓的“社交时差”，即猫头鹰在工作日睡眠不足，周末睡懒觉。这种被打乱的节奏损害了学校/工作表现，并导致了广泛而棘手的公共卫生问题，包括情绪障碍和肥胖症。因此，迫切需要了解再传入是如何影响生物钟的，以及我们可以对此做些什么。在实验室动物身上解决这个问题，我们可以实现对实验条件的高度控制，并揭示机制，这是这项努力的一个重要因素。不幸的是，常见的实验动物(小鼠和大鼠)不能概括再传入的重要方面，因为它们是夜间活动的。它们通常避开光线，在夜间表现出兴奋和活动。我们已经建立了一种新的实验室啮齿动物，4-条纹小鼠，它有很强的白天活动。在为这项提案做准备时，我们已经展示了这些动物可以被训练来开关它们的灯，并利用这种自由来表达熟悉的偏好--白天选择明亮的光线，晚上选择黑暗睡觉。这一突破为研究自选光线对实验动物的影响提供了第一个机会。我们将使用4条纹小鼠来确定自己选择的光线对日常休息/活动节奏的影响，以及这种影响在模拟的“工作”(当它们在早上被叫醒时)和“自由”(当它们可以选择自己的唤醒时间)的日子中的表现。我们将通过研究大脑中容纳生物钟的部分，并观察它们如何改变休息/活动中的节奏，来确定唤醒和锻炼是如何影响节奏的。我们将最终尝试在面对再传入时支持良好生物节律的策略。

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.