Dissecting the mechanistic basis of meal timing and food anticipation: a role for the DUO

剖析进餐时间和食物预期的机制基础：DUO 的作用

• 批准号: RGPIN-2020-06610
• 负责人: Storch, KaiFlorian
• 金额: $ 2.91万
• 依托单位: McGill 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=718400
• 关键词: Dissecting; mechanistic; basis; meal; timing

Daily activities across species are to a great deal influenced by the 24hr changes imposed by the earth rotation. To insure optimal adaptation to this solar day environment an internal timer, the circadian clock has evolved, which creates 24hr rhythms in sleep:wake and other bodily processes. However, organisms also exhibit rhythms at a much shorter scale, in the 2-6hr range -called ultradian rhythms- that drive activity, feeding, and hormones for instance. This seems also true for humans, who exhibit strong ultradian feeding rhythms in early infancy and who parse their daily food intake typically into 3-4 quite equidistantly spread main meals. Importantly, it has been shown in rodents that ultradian feeding attempts will still occur even when actual food intake is prevented We therefore hypothesize that meal initiation is not merely a consequence of an empty stomach but instead controlled by a second brain clock, the ultradian oscillator, that together with the circadian clock regulates our daily patterns in sleep, wake, and food intake. With the research proposed here, we want to elucidate if meal timing is indeed determined by this novel rhythmic process our lab recently uncovered and which we named the ultradian dopaminergic oscillator' or DUO. By employing genetic rodent models and tools that allow for the fine dissection of brain circuits we will test if the DUO drives feeding cycles in rodents and conversely examine if rhythmic feeding per se can alter the DUO, by changing its rhythmic speed. We will also examine if and how the DUO affects rhythms in hormones that are relevant for metabolic and feeding control. It is also well known that if food access is temporally restricted to one meal a day, organism including mammals start to anticipate the daily presentation of food leading to heighten arousal and locomotion 1-2 hrs prior to food access. Because emergence of this food-anticipatory activity (FAA) does not require an external time cue it was proposed that an internal timing system produces this pre-prandial arousal and dubbed it the food-entrainable oscillator (FEO). Despite intensive research efforts, the identity and location of the FEO has remained elusive to this date. Our proposed research on meal timing will allow us to examine if the DUO is required for pre-prandial arousal and thus represents the FEO. Together our studies are aimed to shed light on the mechanisms underlying meal timing which may serve to facilitate social synchrony in order to place gregarious species, which includes humans, at an adaptive advantage. Importantly, a fundamental understanding of what determines our temporal eating habits may provide new avenues for the treatment of psychiatric conditions and here specifically eating disorders which are frequently associated with irregular meal timing. This proposition seems particularly plausible considering that the DUO and psychiatric conditions have a common linkage element, which is the dopamine system.

不同物种的日常活动在很大程度上受到地球自转带来的 24 小时变化的影响。为了确保最佳地适应这种太阳日环境，内部计时器、生物钟已经进化，它在睡眠、觉醒和其他身体过程中创造了 24 小时的节律。然而，生物体也表现出更短的节律，在 2-6 小时范围内，称为超电节律，例如驱动活动、摄食和激素。对于人类来说似乎也是如此，人类在婴儿早期表现出强烈的超日喂养节律，并且通常将每日食物摄入量分解为 3-4 份相当等距分布的主餐。重要的是，啮齿类动物的研究表明，即使实际食物摄入被阻止，超电喂养尝试仍然会发生 因此，我们假设进餐不仅仅是空腹的结果，而是由第二个大脑时钟（超电振荡器）控制，它与生物钟一起调节我们睡眠、醒来和食物摄入的日常模式。通过这里提出的研究，我们想要阐明进餐时间是否确实是由我们实验室最近发现的这种新颖的节律过程决定的，我们将其命名为“超电多巴胺能振荡器”或“DUO”。 通过使用遗传啮齿动物模型和工具来精细解剖大脑回路，我们将测试 DUO 是否驱动啮齿动物的进食周期，并反过来检查有节奏的进食本身是否可以通过改变其节奏速度来改变 DUO。我们还将研究 DUO 是否以及如何影响与代谢和喂养控制相关的激素节律。 还众所周知，如果食物获取暂时限制为每天一顿饭，则包括哺乳动物在内的有机体开始预期食物的每日呈现，从而导致在食物获取前1-2小时增强唤醒和运动。由于这种食物预期活动（FAA）的出现不需要外部时间提示，因此有人提出内部计时系统会产生这种餐前唤醒，并将其称为食物夹带振荡器（FEO）。尽管进行了大量的研究工作，但迄今为止，FEO 的身份和位置仍然难以捉摸。 我们提出的进餐时间研究将使我们能够检查 DUO 是否是餐前唤醒所必需的，从而代表 FEO。我们的研究旨在揭示进餐时间的潜在机制，这可能有助于促进社会同步，从而使包括人类在内的群居物种处于适应性优势。重要的是，对决定我们暂时饮食习惯的因素的基本了解可能会为治疗精神疾病，特别是通常与不规则进餐时间相关的饮食失调提供新途径。考虑到 DUO 和精神疾病有一个共同的联系元素，即多巴胺系统，这个命题似乎特别合理。