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

跨物种的日常活动在很大程度上受到地球自转造成的24小时变化的影响。为了确保对这种太阳日环境的最佳适应，内部计时器已经进化出来，生物钟在睡眠中创造出24小时的节奏：醒来和其他身体过程。然而，生物体的节律也表现出更短的范围，在2-6小时的范围内--称为极端节律--例如，驱动活动、摄食和激素的节律。这似乎也适用于人类，他们在婴儿早期表现出强烈的极端进食节奏，他们通常将每天的食物摄入量解析为3-4个相当等距离分布的主餐。重要的是，在啮齿动物身上已经表明，即使在实际摄食被阻止的情况下，仍会发生超长距离的喂食尝试。 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控制的，即极端振荡器，它与生物钟一起调节我们的睡眠、醒来和食物摄入的日常模式。通过这里提出的研究，我们想要澄清进食时间是否真的由我们实验室最近发现的这种新的节奏过程决定，我们将其命名为超多巴胺能振荡器或二人组。 通过使用允许对大脑回路进行精细解剖的遗传啮齿动物模型和工具，我们将测试这两个人是否驱动啮齿动物的摄食周期，并反过来检查是否有节奏的摄食本身可以通过改变节奏速度来改变这两个人。我们还将研究二人组是否以及如何影响与新陈代谢和喂养控制相关的激素的节律。 同样众所周知的是，如果食物获取被暂时限制为一天一餐，包括哺乳动物在内的生物体开始预测每天提供的食物，导致在获得食物之前1-2小时增强觉醒和运动。因为这种食物预期活动(FAA)的出现不需要外部时间提示，所以有人提出，内部计时系统产生这种餐前唤醒，并将其命名为食物携带振荡器(FEO)。尽管进行了密集的研究工作，但FEO的身份和位置至今仍难以捉摸。 我们提议的进餐时间研究将使我们能够检验这两个人是否需要餐前唤醒，从而代表FEO。我们的研究旨在阐明进食时间的潜在机制，这些机制可能有助于促进社会同步，从而使群居物种(包括人类)处于适应优势。重要的是，对决定我们暂时饮食习惯的基本了解可能会为治疗精神疾病提供新的途径，特别是经常与不规律的进餐时间相关的饮食障碍。考虑到这两个人和精神疾病有一个共同的联系元素，那就是多巴胺系统，这一命题似乎特别合理。

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.