Besides the rod/cone pathway, a melanopsin-associated photoreception pathway is now known to exist in the retina. This pathway involves melanopsin-expressing retinal ganglion cells (mRGCs), a small subset of RGCs that are intrinsically photosensitive but also receive synaptic inputs from the rod/cone pathway. Unlike the non-mRGCs, which project predominantly to image-forming visual centers in the brain (the dorsal lateral geniculate nucleus and the superior colliculus), the mRGCs project primarily to non-image-forming (accessory) visual centers such as the suprachiasmatic nucleus and the intergeniculate leaflet (for circadian photoentrainment) as well as the olivary pretectal nucleus (for pupillary light reflex). Thus, there appears to be a functional segregation between non-mRGCs and mRGCs, with the mRGCs not only contributing to non-image-forming photoreception but also constituting the major conduit for all non-image-associated photic information to the brain. Besides the rod/cone system and the melanopsin system, there appears to be no other photoreception system in the eye that signal to the brain. The long-term objective of this proposal is to understand the light responses and the signaling by mRGCs in great detail. Aim 1 is to investigate the general physiological and biophysical properties of the light responses of mRGCs in detail. Aim 2 is to investigate light adaptation by mRGCs. Aim 3 is to investigate the conversion of the receptor potential into action potentials in the mRGCs, and the roles played by the various voltage-gated ion channels. Aim 4 is to understand the phototransduction mechanism in mRGCs and to identify the various proteins involved in this process. Both electrophysiology and mouse genetics will be used for study. These experiments will yield important information not only relevant to the basic understanding of this newly discovered melanopsin system, but also to disease states affecting light detection in the eye. PUBLIC HEALTH RELEVANCE: The studies proposed in this application will enhance our understanding of the newly discovered melanopsin-associated photoreception system in the retina. Any new information derived from these studies will also be highly relevant to disease states affecting light detection by the eye.