HARVARD COLLEGE, PRESIDENT & FELLOWS OF

The long-term goal of this research is a fundamental understanding of how the eye communicates with the brain. More immediately, the research serves to validate and improve a set of genetic tools for the study of neural circuits. The retina is a complex network of neurons in the back of the eye that converts a visual image into streams of action potentials that travel through the fibers of the optic nerve to the brain. The circuits of the retina begin with the photoreceptor cells that sense the light, pass through bipolar cells and other interneurons, and end with the ganglion cells that form the optic nerve. In all, the retina uses over 50 different types of neurons; the ganglion cells alone comprise about 20 different types. Each of these ganglion cell types extracts and reports a different aspect of the visual scene. A long-term goal of visual neuroscience is to understand what kind of visual processing occurs in each of these streams, and how those processes are implemented by the elaborate neural circuitry of the retina. New genetic methods are beginning to accelerate our understanding of neural systems. In particular, there has been great interest in finding genetic markers that distinguish the brain's many different neuron types. Experience has shown that availability of such a marker, in combination with new molecular and physiological approaches, can dramatically accelerate scientific progress on the structure and function of the corresponding neural circuits. Here we propose to apply these methods to assemble a complete catalog of the ganglion cell types in the mouse retina and to analyze their visual functions. The specific research goals are: (1) to find genes that are expressed specifically in one type of retinal ganglion cell; (2) to construct transgenic mice based on these genes in which all neurons of a given type are marked; (3) to exploit these lines for targeted studies of the structure and function of retinal pathways. For each type of retinal ganglion cell, we will determine the distribution of the neurons across the retina, how their dendritic fields cover visual space, and where in the brain their axons project. At the single-cell level we will examine the shape and location of the ganglion cell's dendritic tree within the retina to deduce its likely synaptic partners among retinal interneurons. To analyze visual function, we will determine what image features each ganglion cell type extracts from the visual scene. In addition, we will assess its involvement in ecologically important computations, such as the processing of image movement, and adaptation to the visual environment. This research will lead to a qualitatively new understanding of retinal function. It will inform our understanding of higher visual areas that draw all their input from the retina. Furthermore, the work will validate and gather experience with a set of genetic tools that can generalize to all brain circuits. PUBLIC HEALTH RELEVANCE: This project concerns basic research into the function of brain circuits. It will develop and test new genetic methods for visualizing types of nerve cells, and exploit these markers to understand how the circuits process information. In the long run, this will enhance our understanding of how the brain works, and how it fails in certain disorders.

Clarification of Codes