Retinal innervation tunes circuits that drive nonphotic entrainment to food

Daily changes in light and food availability are major time-cues influencing circadian timing(1). Little is known, however, about the circuits integrating these time-cues to drive a coherent circadian output(1–3). Here, we investigated whether retinal inputs modulate the entrainment to non-photic cues, such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN), which houses the central circadian pacemaker, and the intergeniculate leaflet (IGL) through intrinsically-photosensitive retinal ganglion cells (ipRGCs)(4). Adult mice lacking ipRGCs since early-postnatal stages displayed impaired entrainment to time-restricted feeding, whereas ablating ipRGCs at later stages had no effect. Early-postnatal ipRGC innervation influences neuropeptide Y (NPY)-expressing IGL neurons, guiding the functional IGL(NPY)-SCN circuit assembly. Moreover, silencing the IGL(NPY) neurons in adult animals mimicked the deficits induced by early-postnatal ipRGC ablation, and acute inhibition of IGL(NPY) terminals in the SCN decreased food-anticipatory activity. Thus, early-postnatal ipRGC innervation tunes the IGL(NPY)-SCN circuit to allow entrainment to time-restricted feeding.