"Feeding time" for the brain: a matter of clocks

Circadian clocks are autonomous time-keeping mechanisms that allow living organisms to predict and adapt to environmental rhythms of light, temperature and food availability. At the molecular level, circadian clocks use clock and clock-controlled genes to generate rhythmicity and distribute temporal signals. In mammals, synchronization of the master circadian clock located in the suprachiasmatic nuclei of the hypothalamus is accomplished mainly by light stimuli. Meal time, that can be experimentally modulated by temporal restricted feeding, is a potent synchronizer for peripheral oscillators with no clear synchronizing influence on the suprachiasmatic clock. Furthermore, food-restricted animals are able to predict meal time, as revealed by anticipatory bouts of locomotor activity, body temperature and plasma corticosterone. These food anticipatory rhythms have long been thought to be under the control of a food-entrainable clock (FEC). Analysis of clock mutant mice has highlighted the relevance of some, but not all of the clock genes for food-entrainable clockwork. Mutations of Clock or Per1 do not impair expression of food anticipatory components, suggesting that these clock genes are not essential for food-entrainable oscillations. By contrast, mice mutant for Npas2 or deficient for Cry1 and Cry2 show more or less altered responses to restricted feeding conditions. Moreover, a lack of food anticipation is specifically associated with a mutation of Per2, demonstrating the critical involvement of this gene in the anticipation of meal time. The actual location of the FEC is not yet clearly defined. Nevertheless, current knowledge of the putative brain regions involved in food-entrainable oscillations is discussed. We also describe several neurochemical pathways, including orexinergic and noradrenergic, likely to participate in conveying inputs to and outputs from the FEC to control anticipatory processes.