The Blue Light-Responsive Lateral Pathway of the Retinohypothalamic Tract Promotes Endocannabinoid-Driven Modulation of Orexin Neurons

: Circadian light influences brain functions in mammals. Photic non-image-forming stimuli are transduced into electrochemical signals by photosensitive retinal ganglion cells containing melanopsin, a selective blue light-responsive photopigment. The hypothalamus receives light-related information via the retinohypothalamic tract (RHT). Here, we demonstrate that, in the mouse, a lateral branch of the RHT (l-RHT) projects monosynaptically to orexin-A (OX-A) neurons in the perifornical hypothalamic area (PFH). Intravitreal injection of the anterograde tracer cholera toxin-β (CTβ) filled most of the vesicular glutamate transporter (VGluT1)/cannabinoid receptor 1 (CB1R)-positive retinal-derived inputs projecting to the OX-A neurons. Monocular injection of Fluo4-Dextran, a fluorimetric sensor of calcium mobilization, yielded fast labeling of these inputs 10 min after eye exposure to blue light, concomitantly with the enhancement of hypothalamic 2-arachidonoylglycerol (2-AG) levels, and inhibition of OX-A neuronal firing, an effect prevented by in vivo administration of the CB1R antagonist AM251. Our findings provide anatomical and functional evidence of a selective retino-hypothalamic network responsive to blue light, whose control should be suitable for therapies to counteract sleep disorders, seasonal affective disorder, or even conditions like narcolepsy or anxiety.