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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764089
• 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全身的生物钟产生的每日节律。大脑中的主时钟（视交叉上核，SCN）通过来自视网膜光感受器的输入与本地时间同步。SCN输出通过神经、生理和行为途径协调身体其他部位的生物钟。一个重要的行为途径是SCN控制食物摄入的每日节律。大多数器官的生物钟会被与进食相关的刺激重置，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，食物携带的时钟会独立于SCN起搏器而与进餐时间对齐，SCN起搏器仍然被携带到亮-暗（LD）周期。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调整有关，确保动物准备好在最有可能被发现的时候寻找和代谢食物。这项研究旨在填补重要的知识空白。目标1和2。与进食相关的刺激使行为和大脑时钟与进餐时间同步是未知的。我们将检验来自外周器官的代谢信号（例如，胃促生长素释放肽、肝酮、胰胰岛素）是必需的或足以诱导或改变大鼠和小鼠的行为节律和脑时钟。将使用活动传感器测量行为节律。将使用生物发光时钟基因成像在转基因小鼠中测量脑时钟。目标3.进餐时间的作用，在适应昼夜节律的转变LD周期很少受到关注。模拟喷气式飞机旅行或轮班工作旋转的LD移位会导致时钟与环境之间以及大脑和身体中以不同速率移位的时钟之间的延迟。我们量化了LD偏移6 - 12小时后小鼠大脑和身体中活动、进食和时钟基因节律的偏移率。然后，我们将使用预定的喂养和禁食，试图加速LD再夹带，同时最大限度地减少内部损耗。目标4。通过控制实验室实验建立了光、食物和其他线索的昼夜节律夹带原理。如何将这些线索整合到真实的世界中以控制夹带是一个主要的知识缺口。我们将开始通过跟踪生活在户外封闭的自然环境中的社会群体中的大鼠的活动节律来解决这个问题。拟议的研究将深入了解进餐时间如何控制生物钟，影响节奏对LD变化的适应，以及在更自然，社会复杂的户外环境中与光的相互作用。这些结果有望为未来关于食物和光线对人类生物钟调节的研究提供信息