Entrainment of circadian rhythms by food: neurobiological mechanisms

大多数生物体，从蓝藻到人类，都是由基于遗传的“昼夜节律”（约24小时）时钟控制的，这些时钟产生日常的行为，生理和生物化学节律。为了确保生物体在一天中正确的时间做正确的事情，生物钟通过对时间线索的敏感性（最重要的是光暗（LD）周期和进餐时间）与当地环境时间同步（“夹带”）。在哺乳动物中，LD周期通过从视网膜到主大脑时钟（视交叉上核）的通路起作用，该通路进而调节其他大脑区域和身体组织中的次级时钟的时间。食物的摄入可以直接驱动这些二级生物钟，如果食物的供应被限制在一天中的某些时间，动物就可以改变它们的日常节奏。其中一些辅助时钟控制行为，并产生每天寻找食物的活动节奏，预期每天有规律的饮食，这是一种通过时钟诱导的学习形式。这些生物钟的位置，以及与喂食相关的刺激，仍然有待确定。我们和其他人已经发现，动物可以预测其他强奖励的日常可用性。我们正在研究一个假设，即调节食物预期节律的生物钟位于大脑的奖励系统中，并受到奖励神经递质多巴胺的影响。我们将通过操纵和测量实验室大鼠和小鼠奖励系统中的多巴胺信号和生物钟基因循环来测试这一假设，并测量对各种大脑和身体组织中行为和生物钟基因的日常节律的影响。在平行的工作中，我们将确定哪些与喂养相关的刺激负责将嗅球中的昼夜节律钟带入日常膳食，以评估这些刺激可能是大脑区域和组织特异性的假设。我们还将使用基因敲除小鼠模型来研究对大脑可塑性（支持学习和记忆）重要的基因的作用。最后，我们将研究如何控制光线和用餐时间，以加速昼夜节律对新时区或工作时间表的适应。我们相信，这项工作可能会为记忆是如何组织的（一天中的时间是在记忆中表示和存储的吗？）以及吸毒的社会模式（强烈的奖励）如何通过控制调节动机行为的生物钟来诱导强迫性药物寻求。我们的方法是首先了解这个系统如何控制寻找自然奖励（食物）的适应行为。

Most living organisms, from cyanobacteria to humans, are ruled by genetically based ‘circadian’ (~24h) clocks that generate daily rhythms of behaviour, physiology and biochemistry. To ensure that organisms do the right thing at the right time of day, circadian clocks are synchronized (‘entrained’) to local environmental time by sensitivity to time cues, most importantly light-dark (LD) cycles and mealtimes. In mammals, LD cycles act through a pathway from the retina to a master brain clock, the suprachiasmatic nucleus, which in turn regulates the timing of secondary clocks in other brain regions and body tissues. Food intake can directly entrain these secondary clocks, enabling animals to modify their daily rhythms if food availability is restricted to certain times of day. Some of these secondary clocks control behaviour, and generate daily rhythms of food seeking activity that anticipate a regular daily meal, a form of learning by clock entrainment. The location of these clocks, and the feeding-related stimuli that entrain them, remain to be determined. We and others have found that animals can anticipate the daily availability of other strong rewards. We are pursuing a hypothesis that circadian clocks mediating food anticipatory rhythms are located in the brain’s reward system, and are entrained by the reward neurotransmitter dopamine. We will test this hypothesis by manipulating and measuring dopamine signalling and circadian clock gene cycling in the reward system of lab rats and mice, and measuring effects on daily rhythms of behaviour and clock genes in various brain and body tissues. In parallel work, we will determine what feeding-related stimuli are responsible for entraining a circadian clock in the olfactory bulb to daily meals, to assess a hypothesis that these stimuli may be brain region and tissue specific. We will also examine the role of genes that are important for brain plasticity (which underpin learning and memory), using genetic knockout mouse models. Finally, we will examine how light and mealtimes can be manipulated to accelerate adaptation of circadian rhythms to new time zones or work schedules. We believe that this work may provide fundamental insights into how memory is organized (is time of day represented and stored in memory?) and into how social patterns of drug taking (strong rewards) may induce compulsive drug seeking by entraining circadian clocks that regulate motivated behaviour. Our approach is to first understand how this system works to control adaptive behaviour in search of natural rewards (food).