Abstract
Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka '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, Retinoic acid induced-1 (Rai1), 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 Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output.
Highlights
In addition to its evident importance for vision, light is essential for multiple physiological functions
While probing the circadian timing system, we discovered that the suppression of locomotor activity by light was importantly increased in Retinoic acid induced-1 (Rai1)+/- mice
Results from the LD12:12 and LL experiments revealed that genotype did not alter the effects of sustained light exposure on total time-spent-awake, whereas the LD1:1 experiment provided evidence that the acute suppressing effects of light on time-spentwake time were stronger in Rai1+/- mice, as was the case for locomotor activity and thetadominated wakefulness (TDW)
Summary
In addition to its evident importance for vision, light is essential for multiple physiological functions. Light information encoded in the retina and received by the suprachiasmatic nuclei (SCN), which harbor the master circadian pacemaker, can reset circadian rhythm phase of overt behaviors such as sleep and locomotor activity (Brainard and Hanifin, 2005) Apart from these circadian effects, light directly impacts physiology, behavior, and cognition, including the well-known light suppression of the circadian hormone melatonin, as well as the maybe less well known light-induced increases in body temperature, cortisol, heart rate, alertness, performance, and mood (Badia et al, 1991; Cajochen et al, 1992, Cajochen et al, 2000; Leproult et al, 2001; Lewy et al, 1980; Scheer et al, 2004; Stephenson et al, 2012). The aim of the current study was to take advantage of an SMS mouse model to elucidate which of the pathways encoding light information were underlying some of the behavioral and physiological characteristics of the disease
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