Emergence of retinal ganglion cell response diversity from synaptic interactions in the inner retina - a combined approach of two-photon population imaging and computational modeling

• Applicant: Professor Dr. Philipp Berens, since 6/2016
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260009071

To process information, neurons integrate synaptic inputs from a multitude of presynaptic partners. In the retina, each retinal ganglion cell (RGC) extracts one of ~20 parallel representations from the visual scene and sends it to the brain. To arrive at its unique response pattern, it integrates synaptic inputs from specific types of bipolar (BC) and amacrine cells (AC). This happens in the retinal switchboard, the inner plexiform layer. Although this highly structured sheet of tissue is anatomically well-characterized, the functional connections and the integration rules within each BC/AC/RGC microcircuit are largely unknown. We will combine optical recordings taken at three consecutive levels (presynaptic bipolar cell terminals, postsynaptic RGC dendrites/somata) and computational models to establish how synaptic connectivity in the inner retina gives rise to RGC response specificity. As a first step, we will generate a complete functional fingerprint of BC output channels. Previously, we have differentiated 8 functionally distinct BC types in the mouse retina. However, 12 types have been identified anatomically. To identify a functional signature for each anatomical type, we will use two-photon imaging to record light-driven calcium changes in the synaptic terminals of individual BCs in response to a standardized battery of stimuli and clustering techniques. Using this data and existing data on more than 10,000 optical recordings taken from RGC somata, we will map the functional connections between BC and RGC types using Bayesian inference in linear-nonlinear-cascade models with flexible non-linearities chosen based on our experimental data. The approach will be restricted to anatomically plausible connections and will allow inferring functional inputs from ACs onto RGCs as well. We will focus initially on three specific RGC circuits before expanding the approach to the remainder of RGCs. Finally, we will determine how different RGC types integrate BC and AC synaptic inputs along the length of their dendrites. To this end, we will record light evoked calcium signals at different dendritic segments of selected RGC types and combine these measurements with patch clamp recordings from the soma and pharmacological manipulation. Combining this data with biophysical models based on morphological reconstructions of selected RGC types, will allows to disentangle the contributions of presynaptic input, morphology and active dendritic computation for creating RGC response specificity. This project will aid our understanding of how the response building blocks provided by the different BC types are combined by each RGC type to yield the observed diversity in the retinal output. Our results will offer a unique view on a set of neural computations from the functional level to the circuit level of implementation. In addition, they can serve as a starting point for a better understanding of the synaptic basis underlying retinal degenerative diseases.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Thomas Baden, until 5/2016