Regulation of mammalian circadian rhythms by meal timing

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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