Two types of melanopsin retinal ganglion cell differentially innervate the hypothalamic suprachiasmatic nucleus and the olivary pretectal nucleus

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Abstract
Melanopsin‐expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) innervate the hypothalamic suprachiasmatic nucleus (SCN) and the olivary pretectal nucleus (OPN), providing irradiance information for entrainment of circadian rhythms and for stimulating the pupillary light reflex. In this study, mice were used in which the melanopsin gene was replaced with the tau‐lacZ gene. Heterozygous (tau‐lacZ+/–) mice express both melanopsin and β‐galactosidase. In tau‐lacZ+/– mice, only ∼50% of melanopsin ipRGCs contain β‐galactosidase, and these cells are specifically labeled with a C‐terminus melanopsin antibody. Retrograde tracer injection into the SCN labels β‐galactosidase‐expressing ipRGCs (termed M1) that comprise ∼80% of the SCN‐projecting ipRGCs. M1 ipRGCs and an additional set of ipRGCs (termed M2) are labeled with a melanopsin antiserum targeted against the N‐terminus of the melanopsin protein; M2 ipRGCs do not contain detectable β‐galactosidase, and these cells make up the remainder of the SCN‐projecting RGCs. Tracer injection into the OPN labeled non‐melanopsin RGCs and both types of melanopsin ipRGC: 45% M1 and 55% M2. Infection of the iris with pseudorabies virus (PRV) results in retrograde transneuronal label of OPN projection neurons that innervate preganglionic parasympathetic neurons of the Edinger‐Westphal nucleus; PRV‐labeled cells were located almost exclusively within the terminal field of M1 ipRGCs in the periphery (shell) of the OPN. The OPN core receives retinal input, and we hypothesize that the OPN core receives input from the M2 ipRGCs. Two subtypes of melanopsin ipRGCs project differentially to the SCN and OPN; the functional significance of ipRGCs subtypes is currently unknown.