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

不同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。为了确保最佳适应这种太阳日环境的内部计时器，生物钟已经进化，它在睡眠中创造了24小时的节奏：唤醒和其他身体过程。然而，生物体也在更短的尺度上表现出节律，在2- 6小时的范围内-称为超日节律-例如驱动活动，进食和激素。这似乎也适用于人类，他们在婴儿早期表现出强烈的超昼夜喂养节律，并且将他们的每日食物摄入量通常分解为3-4个相当等距分布的主餐。重要的是，在啮齿类动物中已经显示，即使实际的食物摄入被阻止，超日摄食尝试仍然会发生 因此，我们假设，进餐的开始不仅仅是空腹的结果，而是由第二个大脑时钟控制的，超昼夜振荡器，与昼夜节律钟一起调节我们的睡眠，清醒和食物摄入的日常模式。通过这里提出的研究，我们想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的节律过程决定的，我们将其命名为超日多巴胺振荡器或DUO。 通过采用遗传啮齿动物模型和工具，允许精细解剖大脑回路，我们将测试DUO是否驱动啮齿动物的摄食周期，并反过来检查节律性摄食本身是否可以通过改变其节律速度来改变DUO。我们还将研究DUO是否以及如何影响与代谢和摄食控制相关的激素节律。 还众所周知的是，如果食物获取暂时限于每天一餐，则包括哺乳动物在内的生物体开始预期食物的每日呈现，导致在食物获取之前1-2小时唤醒和运动增强。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产生这种餐前唤醒，并将其称为食物可消化振荡器（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。 我们提出的关于进餐时间的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用餐时间的机制，这可能有助于促进社会同步，以使包括人类在内的群居物种具有适应性优势。重要的是，从根本上了解是什么决定了我们的时间饮食习惯，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用餐时间有关的饮食失调。考虑到DUO和精神疾病有一个共同的联系因素，即多巴胺系统，这个命题似乎特别合理。

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.