Regulation of mammalian circadian rhythms by meal timing

通过进餐时间调节哺乳动物的昼夜节律

• 批准号: RGPIN-2020-06666
• 负责人: Mistlberger, Ralph
• 金额: $ 4.74万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=718416
• 关键词: Regulation; mammalian; circadian; rhythms; meal

Mammalian behaviour and physiology exhibit daily rhythms generated by circadian clocks in the brain and throughout the body. A master clock in the brain (the suprachiasmatic nucleus, SCN) is synchronized (entrained) to local time by input from retinal photoreceptors. SCN outputs coordinate circadian clocks elsewhere in the body via neural, physiological and behavioural pathways. An important behavioural pathway is SCN control of the daily rhythm of food intake. Circadian clocks in most organs are reset by stimuli associated with feeding, including nutrients and metabolic hormones. Importantly, if food is limited to a particular time of day or night, food-entrained clocks shift to align with mealtime independently of the SCN pacemaker, which remains entrained to the light-dark (LD) cycle. In rats, mice and other species, this is associated with emergence of a circadian rhythm of food anticipatory activity, and realignment of physiological rhythms, ensuring that animals are prepared to look for and metabolize food when it is most likely to be found. By contrast with entrainment to LD, the cells and signals that mediate synchrony of behavioural rhythms to feeding schedules are not well understood. The proposed research aims to fill important knowledge gaps. Aims 1 and 2. The feeding-related stimuli that synchronize behaviour and brain clocks to mealtime are unknown. We will test hypotheses that metabolic signals from peripheral organs (e.g., gastric ghrelin, liver ketones, pancreatic insulin) are neccessary or sufficient to induce or shift behavioural rhythms and brain clocks in rats and mice. Behavioural rhythms will be measured using activity sensors. Brain clocks will be measured using bioluminescent clock gene imaging in transgenic mice. Aim 3. The role of mealtiming in adaptation of circadian rhythms to shifted LD cycles has received little attention. LD shifts simulating jet travel or shiftwork rotation cause desynchrony between clocks and the environment, and among clocks in the brain and body, which shift at different rates. We quantify shift rate of activity, feeding and clock gene rhythms in the brain and body of mice after LD shifts of 6-12h. We will then use scheduled feeding and fasting to attempt to accelerate LD reentrainment while minimizing internal desynchrony. Aim 4. Principles of circadian entrainment by light, food and other cues were established by controlled lab experiments. How these cues are integrated to control entrainment in the real world is a major knowledge gap. We will begin to address this by tracking activity rhythms of rats living in social groups in an outdoor, enclosed seminatural environment. The proposed research will yield insights into how mealtiming controls circadian clocks, affects adaptation of rhythms to LD shifts, and interacts with light in more natural, socially complex, outdoor environments. Outcomes are expected to inform future studies of circadian clock regulation by food and light in humans

哺乳动物的行为和生理表现出由大脑和整个身体的生物钟产生的每日节奏。大脑中的主时钟(视交叉上核，SCN)通过视网膜光感受器的输入与当地时间同步(携带)。SCN的输出通过神经、生理和行为通路协调身体其他部位的生物钟。一条重要的行为途径是SCN控制每日食物摄入的节律。大多数器官的生物钟被与摄食相关的刺激重新设置，包括营养和代谢激素。重要的是，如果食物被限制在白天或晚上的特定时间，食物携带的时钟会与进餐时间保持一致，而不受SCN起搏器的影响，SCN起搏器仍然处于光-暗(LD)循环。在大鼠、小鼠和其他物种中，这与食物预期活动的昼夜节律的出现和生理节律的重新排列有关，确保动物准备在最有可能找到食物的时候寻找和代谢食物。与携带到LD相反，调节行为节律与摄食时间表同步的细胞和信号并没有被很好地理解。这项拟议的研究旨在填补重要的知识空白。目标1和目标2。与进食有关的刺激使行为和大脑时钟与进餐时间同步尚不清楚。我们将测试来自外周器官(例如胃促生长素、肝酮、胰岛胰岛素)的代谢信号对于诱导或改变大鼠和小鼠的行为节律和大脑时钟是必要的或足够的。行为节律将使用活动传感器进行测量。在转基因小鼠中，将使用生物发光时钟基因成像来测量大脑时钟。目的3.进餐时间在昼夜节律适应变化的LD周期中的作用尚未引起注意。模拟喷气式飞机旅行或轮班轮换的LD移动会导致时钟与环境之间以及大脑和身体中的时钟之间的不同步，而这些时钟的移动速度不同。我们量化了LD移位6-12小时后小鼠大脑和身体的活动、摄食和时钟基因节律的移位率。然后，我们将使用计划喂食和禁食来尝试加速LD的重新夹带，同时最大限度地减少内部不同步。目的4.通过实验室对照实验，建立光、食物等线索的昼夜节律夹带原理。如何整合这些线索以控制现实世界中的夹带，这是一个重大的知识缺口。我们将通过跟踪生活在室外封闭半自然环境中的群居大鼠的活动节律来开始解决这个问题。这项拟议中的研究将深入了解用餐时间如何控制生物钟，影响节奏对LD班次的适应，以及在更自然、更复杂的社交户外环境中与光线相互作用。这一结果有望为未来关于食物和光对人体生物钟调节的研究提供信息。