Visual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF α-ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF α-cells are systematically smaller than ON α-cells. Analysis of natural scenes suggests that these asymmetries are optimal for visual encoding. To test the generality of ON/OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from the cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between RF properties, some of which were opposite to the findings of previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON/OFF asymmetries are pathway specific. SIGNIFICANCE STATEMENT Circuits that process sensory input frequently process increments separately from decrements, so-called ON and OFF responses. Theoretical studies indicate that this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show that their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways.

Understanding the function of modulatory inter neuron networks is a major challenge, because such networks typically operate over long spatial scales and involve many neurons of different types. Here, we use an indirect electrical imaging method to reveal the function of a spatially extended, recurrent retinal circuit composed of two cell types. This recurrent circuit produces peripheral response suppression of early visual signals in the primate magnocellular visual pathway. We identify a type of polyaxonal amacrine cell physiologically via its distinctive electrical signature, revealed by electrical coupling with ON parasol retinal ganglion cells recorded using a large-scale multi-electrode array. Coupling causes the amacrine cells to fire spikes that propagate radially over long distances, producing GABA-ergic inhibition of other ON parasol cells recorded near the amacrine cell axonal projections. We propose and test a model for the function of this amacrine cell type, in which the extra-classical receptive field of ON parasol cells is formed by reciprocal inhibition from other ON parasol cells in the periphery, via the electrically coupled amacrine cell network.

This study combines for the first time two major approaches to understanding the function and structure of neural circuits: large-scale multielectrode recordings, and confocal imaging of labeled neurons. To achieve this end, we develop a novel approach to the central problem of anatomically identifying recorded cells, based on the electrical image: the spatiotemporal pattern of voltage deflections induced by spikes on a large-scale, high-density multielectrode array. Recordings were performed from identified ganglion cell types in the macaque retina. Anatomical images of cells in the same preparation were obtained using virally transfected fluorescent labeling or by immunolabeling after fixation. The electrical image was then used to locate recorded cell somas, axon initial segments, and axon trajectories, and these signatures were used to identify recorded cells. Comparison of anatomical and physiological measurements permitted visualization and physiological characterization of numerically dominant ganglion cell types with high efficiency in a single preparation.

Peter H. Li,1,* GregD. Field,1,2 Martin Greschner,1,3 Daniel Ahn,1 Deborah E. Gunning,4 KeithMathieson,4 Alexander Sher,5 Alan M. Litke,5 and E.J. Chichilnisky1,6 1Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA 2Zilkha Neurogenetic Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA 3Department of Neuroscience, Carl von Ossietzky University, Oldenburg 26129, Germany 4Institute of Photonics, University of Strathclyde, Glasgow G4 0NW, UK 5Santa Cruz Institute for Particle Physics, University of California, Santa Cruz, CA 95064, USA 6Department of Neurosurgery, School of Medicine, Stanford University, Palo Alto, CA 94305, USA *Correspondence: peter.hawley.li@gmail.com http://dx.doi.org/10.1016/j.neuron.2013.10.043

The propagation of visual signals from individual cone photoreceptors through parallel neural circuits was examined in the primate retina. Targeted stimulation of individual cones was combined with simultaneous recording from multiple retinal ganglion cells of identified types. The visual signal initiated by an individual cone produced strong responses with different kinetics in three of the four numerically dominant ganglion cell types. The magnitude and kinetics of light responses in each ganglion cell varied nonlinearly with stimulus strength but in a manner that was independent of the cone of origin after accounting for the overall input strength of each cone. Based on this property of independence, the receptive field profile of an individual ganglion cell could be well estimated from responses to stimulation of each cone individually. Together, these findings provide a quantitative account of how elementary visual inputs form the ganglion cell receptive field.

Josef Turecek,1 Genevieve S. Yuen,2 Victor Z. Han,3 Xiao-Hui Zeng,3 K. Ulrich Bayer,4 and John P. Welsh3,5,* 1Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA 2Department of Psychiatry, New York Presbyterian Hospital-Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, USA 3Center for Integrative Brain Research, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, WA 98155, USA 4Department of Pharmacology, University of Colorado-Denver School of Medicine, 12800 E. 19th Avenue, Aurora, CO 80045, USA 5Department of Pediatrics, University of Washington, 1959 N.E. Pacific Street, Seattle, WA 98195, USA *Correspondence: john.welsh@seattlechildrens.org http://dx.doi.org/10.1016/j.neuron.2014.01.024

Amacrine cells are the most diverse and least understood cell class in the retina. Polyaxonal amacrine cells (PACs) are a unique subset identified by multiple long axonal processes. To explore their functional properties, populations of PACs were identified by their distinctive radially propagating spikes in large-scale high-density multielectrode recordings of isolated macaque retina. One group of PACs exhibited stereotyped functional properties and receptive field mosaic organization similar to that of parasol ganglion cells. These PACs had receptive fields coincident with their dendritic fields, but much larger axonal fields, and slow radial spike propagation. They also exhibited ON-OFF light responses, transient response kinetics, sparse and coordinated firing during image transitions, receptive fields with antagonistic surrounds and fine spatial structure, nonlinear spatial summation, and strong homotypic neighbor electrical coupling. These findings reveal the functional organization and collective visual signaling by a distinctive, high-density amacrine cell population.