Extended Data Fig. 8: Putative model for the circuit that drives circadian food-anticipatory activity.

Time-restricted access to food constitutes a strong environmental cue that causes the alignment of the circadian system to feeding schedules, driving food-anticipatory activity that precedes the expected meal. The current view in the field is that a widespread system—composed of elements referred to as food-entrainable oscillators (FEOs)—controls the physiological and behavioural responses to TRF. Among the candidates for FEOs are areas of the hypothalamus (such as the paraventricular nucleus, ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus and arcuate nucleus), thalamic areas (such as the paraventricular thalamus and the IGL), the brainstem (including the dorsal raphe nucleus and parabrachial nucleus), other brain regions (such as the dorsal striatum, infralimbic cortex, nucleus accumbens and cerebellum) as well as peripheral targets (such as the gastrointestinal system). In this Article, we have delineated a brain circuit (IGL^NPY–SCN) that is critical for driving food-anticipatory activity in adult mice. The functional assembly of this circuit requires innervation by retinal ipRGCs to the SCN during a critical window. The proposed model suggests crosstalk between an FEO (or FEOs) and the IGL, in which IGL neurons act as a node of connection between the FEOs and the central pacemaker in the SCN. Under TRF, inhibitory signals from IGL^NPY neurons modulate the SCN function, causing reduced firing activity, and therefore allowing signals from the FEO (or FEOs) to drive robust food-anticipatory activity. The IGL could also be part of the FEO (or FEOs), as previously suggested⁷. IGL^NPY neurons send projections to several brain regions and, therefore, a role of any of these non-SCN projections in modulating food-anticipatory activity should not be excluded. How feeding-related stimuli modulate the FEO (or FEOs) and possibly the IGL are unknown. Different humoral signals, such as ghrelin and insulin, are strong candidates for modulating the FEO (or FEOs) and IGL.