ABSTRACT During the past 2-3 decades important work has been done to resolve the mechanisms of light and dark adaptation as well as disease in the mammalian rod and cone photoreceptors using mouse as a model system. However, the mouse is a nocturnal animal that lacks the macula, a specialized central region in primate retina that provides high-acuity color vision critical for human everyday survival. Consequently, mechanisms of human daytime vision or diseases that disrupt photoreceptors in the macula, such as Age-Related Macular Degeneration (AMD), are challenging to study in mice. For example, there is no effective treatment for the dry form of AMD, the most common cause of blindness among the elderly. Thus, there is a critical need to better understand the biology of the photoreceptors in the human macula in health and disease. This is particularly true of cone photoreceptors compared to rods that have been more extensively studied. Recent studies have established both light-independent and light-dependent pigment regeneration pathways within the mouse retina isolated from the pigment epithelium (RPE). These pathways regenerate pigment via Müller cells in cone-specific pathways (light-independent and -dependent intraretinal visual cycles) or in the photoreceptor cells themselves by a cell-autonomous regeneration mechanism. However, nothing is known about these mechanisms in the human macula or fovea. The goal of this proposal is to determine the contribution of the RPE-independent pigment regeneration pathways to the ability of cones to dark adapt quickly and maintain sensitivity in bright light specifically in the human macula. Our central hypothesis is that the canonical visual cycle that operates via the RPE is too slow to maintain vision in bright light or mediate dark adaptation during rapidly changing levels of illumination in the human macula. The work is organized into two specific aims. These are to determine the contribution of the light-independent intraretinal visual cycle (Aim I) and photic pigment regeneration pathways (Aim II) to dark adaptation and maintenance of light sensitivity of human macular cones. The experiments will employ ex vivo electroretinography and single cell suction electrode recordings. These techniques are well suited for assessing the role of visual cycles and cell-autonomous pigment regeneration pathways in dark adaptation and maintenance of light sensitivity, respectively. We will leverage our experience and collaborations with Eye Banks that we have established during the past three years to develop donor criteria and protocols to record light-evoked responses of macular cones from organ or research donor human eyes 1 – 5 hours postmortem. Results of these studies will determine the contribution of different visual cycle pathways to human vision mediated by the cones across geographical regions of the retina, including the fovea. This information will provide a basis for studies to elucidate pathogenesis ...