To restore vision, we must understand how information is processed in the retina and what circuit mechanisms shape the retinal output. One such mechanism is the interaction between converging excitatory and inhibitory signals, which plays a central role in regulating key properties of a neuronal output across most neural circuits. The nature of this interaction can be diverse based on 1) site of action and 2) temporal dynamics and determines how a neuron integrates the excitatory and inhibitory inputs (synaptic integration) to produce a response. This is exemplified in the retina where inhibitory interneurons can act postsynaptically on the dendrites of ganglion cells or presynaptically on bipolar cell terminals. Moreover, synaptic inhibition can exhibit a variety of temporal relationships (motifs) with excitation in the retina such as feedforward, feedback and crossover inhibition. An emerging theme of recent work in non-primate retina has been the surprisingly complex functions performed by ganglion cells, which rely heavily on inhibition and the mechanisms of synaptic integration. However, several fundamental questions remain unaddressed. How does synaptic integration regulate the output of key retinal circuits that dominate our visual perception? For instance, the primate fovea accounts for ~50% of the retinal output and yet we know nothing about the functional properties of excitatory and inhibitory inputs and how ganglion cells integrate these inputs. Secondly, what is the relative contribution of synaptic inhibition acting on pre vs postsynaptic neurons in shaping visual signals? The long-term goal of this project is to understand how retinal circuits use different modes of synaptic integration to drive distinct functions and visually guided behavior. The current objective is to identify what mode of synaptic integration shapes responses across distinct ganglion cell types and how it depends on the site of action. My central hypothesis is that there are different motifs by which excitatory and inhibitory inputs interact and the relation between the motifs and ganglion cell function is of direct relevance to behavior.
In Aim 1, we will determine the properties of excitatory and inhibitory inputs, how they interact in time and their impact on output of diverse ganglion cell types in primate fovea. Moreover, we will determine if the functional properties change with retinal location underlying the retinal basis of known differences in visual perception across visual field.
In Aim 2, we will dissect the role of presynaptic inhibition in ganglion cell function in distinct retinal circuits using transgenic approaches in mouse retina that will selectively eliminate inhibitory receptors in specific bipolar cell types. A common theme of both Aims will be to map the anatomical correlate of synaptic inhibition and excitation in the above retinal circuits using a combination of light and electron microscopy techniques. This will help construct a structure-function framework for how synaptic integration shapes retinal output. The approach is innovative because we will determine ganglion cell function in the fovea, which has so far been largely obscure. Moreover, we will be able to isolate the role of presynaptic inhibition using transgenic manipulation in mouse retina. The proposed works is significant because it will provide a structure-function framework for understanding how synaptic integration refines GC function in key retinal circuits and thus bridge the gap between anatomy, function and behavior. Knowledge about function at the level of individual circuits will be crucial to understanding the retinal substrates for diverse visual behavior and for identifying targets in retinal diseases for therapeutic interventions.
This project is relevant to public health because treating retinal disease requires an understanding of how visual information is processed in the mature retina and especially in the fovea that mediates most of our central vision. The results from the proposed research are expected to have a two-fold positive impact: (1) further understanding of circuit processing in the mature retina will facilitate the development of prosthetic devices that perform more similarly to the retina, and (2) will provide key insights into central vision given the importance of the fovea for normal high-acuity vision, the debilitating effects of diseases that target the fovea (such as macular degeneration), and the lack of information about how neural pathways in the fovea operate.
