Computational Modeling of Vertebrate Phototransduction

Project Overview

Dr. Hamer's research program is a joint theoretical and experimental approach toward elucidation of vertebrate photoreceptor function. The overall goal of the research is the development of biochemically motivated models of phototransduction that ultimately provide a comprehensive account of the critical features of vertebrate rod and cone responses under both dark-adapted (DA) and light-adapted (LA) conditions. Development of such a model will advance our understanding of the role photoreceptors play in shaping the overall temporal properties and sensitivity at higher centers in the visual system. In addition, the models can provide powerful tools for evaluating new candidate mechanisms of phototransduction. Moreover, they allow one to test, noninvasively, putative mechanisms of retinal diseases affecting photoreceptor function, and to identify specific receptoral immaturities in developing visual systems.

Research Program

The research is focusing on key unresolved issues in phototransduction:

• Photoreceptor activation under both DA and LA conditions. Analysis of the activation steps in the biochemical (G-protein) transduction cascade, the relative rates of the component reactions, and the range of linearity of these reactions.
• Inactivation of the photoresponse. Analysis of the dominant recovery processes in the biochemical sequence, their relative rate constants, and their relation to nonlinear feedback mechanisms in the cell.
• Reproducibility of the rod single-photon response. Analysis of the biochemical mechanisms that permit rods to reliably signal the absorption of single photons of light. Given the intrinsic variability of all biochemical reactions, elucidation of the mechanisms underlying this ability of rods has eluded photoreceptor phyiologists for a quarter of a century. A new model we developed appears to have solved the mystery.
• Light-adaptation. Analysis of several feedback mechanisms that influence the recovery of the photoresponse in rods and cones, and that underlie their ability to adjust sensitivity and speed of response according to ambient light conditions.
• Towards a unified model of rod phototransduction. We are working to develop a comprehensive model of vertebrate rod phototransduction that is able to account for rod responses over the full gamut of their response repertoire, from single-photon responses to highly light-adapted responses. To date, no single model has been able to do this with a single set of parameters.
• Rod-cone differences. Much more is known about rod structure and function. The work focuses on identification of, and modeling of the mechanisms that confer cones with their faster response speed, their faster recovery from LA, and their larger range of nonlinear gain control under LA conditions.

Computational Modeling

To ensure maximum accuracy and physiological relevance, candidate models are constrained by the current estimates of relevant biochemical pathways and parameters within the biochemical cascade, and are quantitatively optimized to fit electrophysiological responses of individual photoreceptors. The quality of each candidate model is then evaluated by the quality of the fit to key sets of physiological data, and by the breadth of data accounted for by the model. The biochemical models are implemented as explicit differential equations in Matlab/Simulink and optimized using the Mathworks Optimization Toolbox.

Participating Scientists

Russell D. Hamer, Ph.D. has developed several detailed biochemical models that have provided a good account of a broad range of empirical data from vertebrate rods and cones. His background is in experimental and theoretical psychophysics, as well as in state-of-the art visual evoked potential recordings, specializing in analyses of human temporal processing, contrast sensitivity, spatial vision, and human cortical visual development.

Spero C. Nicholas, M.S. is collaborating on the investigation of the mechanisms underlying reproducibility of vertebrate rod single-photon responses. He is primarily involved in the development and implementation of computational models of the vertebrate phototransduction cascade, and the numerical optimization of these models to account for a wide array of physiological data. He has written extensive code for the reduction and analysis of single-cell recordings, including the creation of a GUI-based virtual-laboratory enviroment enabling the interactive exploration of model variations under a variety of stimulus paradigms.

Collaborations

The Hamer lab has an ongoing collaboration with Daniel Tranchina, Ph.D.^† at The Courant Institute of Mathematical Sciences, and The Department of Biology, NYU. Dr. Tranchina has a strong background in both single-cell electrophysiology and mathematical modeling of neural mechanisms, including modeling of vertebrate phototransduction.

Dr. Hamer also collaborates with Juan I. Korenbrot, Ph.D. at the Department of Physiology at University of California at San Francisco. Dr. Korenbrot was, and continues to be, one of the pioneers of vertebrate photoreceptor physiology and phototransduction research. His large body of work, spanning more than three decades, includes research into the mechanisms of light-adaptation, studies of calcium homeostasis in rods and cones as well as dynamic calcium changes in response to light, and mechanisms underlying rod-cone differences.

We have also been fortunate to establish a productive collaboration with Trevor D. Lamb, Ph.D.^† at the John Curtin School of Medical Research in Canberra, Australia. Dr. Lamb has been a central figure in photoreceptor physiology and modeling of phototransduction for three decades. His work has been seminal in many arenas in photoreceptor electrophysiology -- from development of important new recording techniques (e.g, the suction electrode for recording photoresponses from individual photoreceptor outer segments), to establishing the defining responses properties of rods and cones from many species, under a full range of stimulus conditions from single photon levels to highly light-adapted conditions. Moreover, he is one of the few researchers in any field whose work links the mechanisms of the system across all levels, from the molecular (biochemical basis of phototransduction), to the cellular (electrophysiological properties of rods and cones), to the organic (electroretinographic analysis of photoreceptor function), to the organismic (psychophysics, behavior).

Paul A. Liebman, M.D.^† is a profesor of Biochemistry & Bipohysics at the University of Pennsylvania School of Medicine, Philadelphia, PA. For more than four decades, Dr. Liebman's ground breaking research has focussed on the biochemical/biophysical mechanisms underlying vertebrate rod and cone photoreceptor function.

^†Co-authors on Hamer et al. (2003).

Current Research

Prior Research

• Normal & Abnormal Visual Development
• Normal Adult Vision
• Stiles-Crawford Effect
• Cutaneous Sensitivity & Vibrotaction

Contact Information

Russell D. Hamer, Ph.D.
Smith-Kettlewell Eye Research Institute
2318 Fillmore Street
San Francisco, CA 94115

415 345-2056 (office)
415 345-8455 (FAX)
russ@ski.org