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. (Figure presented.)
The Blue Light-Responsive Lateral Pathway of the Retinohypothalamic Tract Promotes Endocannabinoid-Driven Modulation of Orexin Neurons
Forte N.;Imperatore R.;
2025-01-01
Abstract
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. (Figure presented.)I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
