Human vision starts when photoreceptors collect and respond to light. Normal photoreceptor function and structure are essential for normal vision, yet techniques to assess these in vivo are limited. Current optical and electrophysiological approaches have limited spatial resolution and sensitivity, and target only specific functional processes. New optical modalities that are rapid, specific, and non-invasive hold the promise of greatly expanding our capability to monitor more accurately and completely photoreceptor function and structure. We will use adaptive optics (AO) and spectral-domain optical coherence tomography (SD-OCT) to non-invasively image the human retina at the cellular scale. We will study the waveguide properties of photoreceptors, the interaction of fundus structure with wavefront sensing, and the phototransduction process. The specific aims are to: (1.) Evaluate the anatomical origins and functional implications of optical waveguiding by photoreceptors in central and peripheral retina. This will be achieved in a hypothesis driven study using SD-OCT. (2.) Develop a quantitative optical model of the human fundus as a thick reflector that accounts for the impact of fundus structure on accuracy and precision of wavefront sensing. SD-OCT will be used to test the hypothesis that axial elongation and variation with pupil position of the fundus reflection leads to wavefront measurement errors if not controlled. (3.) Evaluate the potential of AO and SD-OCT as non-invasive, optical methods for measuring functional mechanisms of phototransduction by measuring light-evoked changes in the scattering properties of photoreceptors. The long term goal of this research is to establish advanced optical techniques for non-invasive probing of cellular function and structure in the human retina. These techniques will be used to study photoreceptors in vivo, and once established will promise improvements in early detection and treatment monitoring for diseases that impact these cells.