Project Summary Rod-mediated vision transitions seamlessly to cone-mediated vision as light levels rise through the mesopic visual range. Despite the fact that mesopic vision is the major mode of vision for people who spend most of their time indoors under artificial lighting, there is a glaring lack of knowledge of how rod and cone photoresponses shape the temporal, spatial, and spectral sensitivities of mesopic vision. For decades it has been accepted that rods subserve vision in dim scenes, detecting only slow variations in light levels (contrast), and cones subserve vision in bright scenes when contrast changes rapidly. Our recently published results show that at indoor (mesopic) light levels, rods drive the visual responses to fast — not slow — temporal variations. Our findings reveal, for the first time, that adaptation of both rod and cone-driven visual responses underlie the seamless transition between scotopic and photopic vision over the mesopic range, but we do not understand how this happens. Therefore, there is a critical need to understand the physiology and functional significance of rod responses at mesopic, indoor light levels. In this application our objectives are: (i) to determine the adaptation mechanisms that control the responses of rods to slow and fast light variations in mesopic lights, and (ii) to determine the behavioral significance of rod-driven visual responses to fast changing scenes in mesopic lights. Our model is that a hierarchical system of adaptation mechanisms is in place to differentially regulate rod sensitivity as lights rise through the mesopic range. To test this model we propose two related but independent aims that investigate the underlying cellular and perceptual mechanisms. These aims are to determine 1) how rods respond to slow and fast variations in mesopic lights, and 2) the behavioral significance of inner segment conductances to the adaptation of rod visual responses in mesopic lights. For the first aim we will combine the power of mouse genetics, electrophysiological recordings, quantitative modeling, and operant behavioral assays to determine how different phototransduction adaptation mechanisms, including background and bleaching adaptation, work together to differentially regulate the responses to slow and fast light variations and to overcome the crippling effects of response compression in mesopic illumination. For the second aim, we will use mice with rod-specific knockout of voltage-gated conductances that are typically activated at mesopic lights to probe the functional significance of inner segment conductances to rod-driven responses in mesopic lights. Our expected outcome is to provide evidence for mechanisms that the visual system uses to encode signal variations in mesopic lights (Advancement of Basic Knowledge). Knowledge of this mechanisms will open new strategies for understanding and treating retinal pathological conditions, with implications beyond this particular applicatio...