Entrainment of circadian rhythms by food: neurobiological mechanisms

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Most living organisms, from cyanobacteria to humans, are ruled by genetically based ‘circadian’ (~24h) clocks that generate daily rhythms of behaviour, physiology and biochemistry. To ensure that organisms do the right thing at the right time of day, circadian clocks are synchronized (‘entrained’) to local environmental time by sensitivity to time cues, most importantly light-dark (LD) cycles and mealtimes. In mammals, LD cycles act through a pathway from the retina to a master brain clock, the suprachiasmatic nucleus, which in turn regulates the timing of secondary clocks in other brain regions and body tissues. Food intake can directly entrain these secondary clocks, enabling animals to modify their daily rhythms if food availability is restricted to certain times of day. Some of these secondary clocks control behaviour, and generate daily rhythms of food seeking activity that anticipate a regular daily meal, a form of learning by clock entrainment. The location of these clocks, and the feeding-related stimuli that entrain them, remain to be determined. We and others have found that animals can anticipate the daily availability of other strong rewards. We are pursuing a hypothesis that circadian clocks mediating food anticipatory rhythms are located in the brain’s reward system, and are entrained by the reward neurotransmitter dopamine. We will test this hypothesis by manipulating and measuring dopamine signalling and circadian clock gene cycling in the reward system of lab rats and mice, and measuring effects on daily rhythms of behaviour and clock genes in various brain and body tissues. In parallel work, we will determine what feeding-related stimuli are responsible for entraining a circadian clock in the olfactory bulb to daily meals, to assess a hypothesis that these stimuli may be brain region and tissue specific. We will also examine the role of genes that are important for brain plasticity (which underpin learning and memory), using genetic knockout mouse models. Finally, we will examine how light and mealtimes can be manipulated to accelerate adaptation of circadian rhythms to new time zones or work schedules. We believe that this work may provide fundamental insights into how memory is organized (is time of day represented and stored in memory?) and into how social patterns of drug taking (strong rewards) may induce compulsive drug seeking by entraining circadian clocks that regulate motivated behaviour. Our approach is to first understand how this system works to control adaptive behaviour in search of natural rewards (food).