<i>Rai1</i> frees mice from the repression of active wake behaviors by light.

Abstract

Besides its role in vision, light impacts physiology and behavior through circadian and direct (<i>aka</i> 'masking') mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, <i>Retinoic acid induced-1</i> (<i>Rai1</i>), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate <i>Rai1</i> as a novel and central player in processing non-visual light information, from input to behavioral output.