Orexin-A Intensifies Mouse Pupillary Light Response by Modulating Intrinsically Photosensitive Retinal Ganglion Cells

• Published in: The Journal of neuroscience Vol. 41; no. 12; pp. 2566 - 2580
• Main Authors: Zhou, Wei, Wang, Li-Qin, Shao, Yu-Qi, Han, Xu, Yu, Chen-Xi, Yuan, Fei, Wang, Xin, Weng, Shi-Jun, Zhong, Yong-Mei, Yang, Xiong-Li
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 24.03.2021
• Subjects: Constrictions; Depolarization; Excitability; Firing rate; Hybridization; Ion channels; Membrane potential; Orexins; Photosensitivity; Potassium; Potassium channels; Potassium channels (inwardly-rectifying); Pupil size; Retina; Retinal ganglion cells; Visual perception; melanopsin; intrinsic excitability; intrinsically photosensitive retinal ganglion cell; orexin; light response; pupillary light response
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0217-20.2021

We show for the first time that the neuropeptide orexin modulates pupillary light response, a non-image-forming visual function, in mice of either sex. Intravitreal injection of the orexin receptor (OXR) antagonist TCS1102 and orexin-A reduced and enhanced pupillary constriction in response to light, respectively. Orexin-A activated OX Rs on M2-type intrinsically photosensitive retinal ganglion cells (M2 cells), and caused membrane depolarization of these cells by modulating inward rectifier potassium channels and nonselective cation channels, thus resulting in an increase in intrinsic excitability. The increased intrinsic excitability could account for the orexin-A-evoked increase in spontaneous discharges and light-induced spiking rates of M2 cells, leading to an intensification of pupillary constriction. Orexin-A did not alter the light response of M1 cells, which could be because of no or weak expression of OX Rs on them, as revealed by RNAscope hybridization. In sum, orexin-A is likely to decrease the pupil size of mice by influencing M2 cells, thereby improving visual performance in awake mice via enhancing the focal depth of the eye's refractive system. This study reveals the role of the neuropeptide orexin in mouse pupillary light response, a non-image-forming visual function. Intravitreal orexin-A administration intensifies light-induced pupillary constriction via increasing the excitability of M2 intrinsically photosensitive retinal ganglion cells by activating the orexin receptor subtype OX R. Modulation of inward rectifier potassium channels and nonselective cation channels were both involved in the ionic mechanisms underlying such intensification. Orexin could improve visual performance in awake mice by reducing the pupil size and thereby enhancing the focal depth of the eye's refractive system.