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

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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.