Local and global interneuron function in the retina

Brain regions consist of intricate neuronal circuits with diverse interneuron types. In order to gain mechanistic insights into brain function, it is essential to understand the computational purpose of the different types of interneurons. How does a single interneuron type shape the input-output transformation of a given brain region? Here I investigated how different interneuron types of the retina contribute to retinal computations. I developed approaches to systematically and quantitatively investigate the function of retinal interneurons by combining precise circuit perturbations with a system-wide read-out of activity. I studied the functional roles of a locally acting interneuron type, starburst amacrine cells, and of a globally acting type, horizontal cells. In Chapter 1, I show how a defined genetic perturbation in starburst amacrine cells, the mutation of the FRMD7 gene, leads to specific effects in the direction-selective output channels of the retina. Our findings provide a link between a specific neuronal computation and a human disease, and present an entry point for understanding the molecular pathways responsible for generating neuronal circuit asymmetries. Chapter 2 addresses how mutated FRMD7 in starburst cells and the genetic ablation of starburst cells affect the computation of visual motion in the retina and in primary visual cortex. Chapter 3 addresses how horizontal cells mediate rod depolarization under bright daylight conditions. In Chapter 4, I combined the precise, yet retina-wide, perturbation of horizontal cells with a system-level readout of the retinal output. I uncovered that horizontal cells can differentially shape the response dynamics of individual retinal output channels. Our combined experimental and theoretical work shows how the inhibitory feedback at the first visual synapse shapes functional diversity in the retina

Screening Transgenic Mouse Models of Human Eye Diseases with CMOS High-Density Microelectrode Arrays

ISSN:1662-453XISSN:1662-454

How Diverse Retinal Functions Arise from Feedback at the First Visual Synapse

International audienceMany brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region? We addressed this question in the mouse retina by chemogenetically perturbing horizontal cells, an interneuron type providing feedback at the first visual synapse, while monitoring the light-driven spiking activity in thousands of ganglion cells, the retinal output neurons. We uncovered six reversible perturbation-induced effects in the response dynamics and response range of ganglion cells. The effects were enhancing or suppressive, occurred in different response epochs, and depended on the ganglion cell type. A computational model of the retinal circuitry reproduced all perturbation-induced effects and led us to assign specific functions to horizontal cells with respect to different ganglion cell types. Our combined experimental and theoretical work reveals how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region

Rods in daylight act as relay cells for cone-driven horizontal cell mediated surround inhibition

Vertebrate vision relies on two types of photoreceptors, rods and cones, which signal increments in light intensity with graded hyperpolarizations. Rods operate in the lower range of light intensities while cones operate at brighter intensities. The receptive fields of both photoreceptors exhibit antagonistic center-surround organization. Here we show that at bright light levels, mouse rods act as relay cells for cone-driven horizontal cell-mediated surround inhibition. In response to large, bright stimuli that activate their surrounds, rods depolarize. Rod depolarization increases with stimulus size, and its action spectrum matches that of cones. Rod responses at high light levels are abolished in mice with nonfunctional cones and when horizontal cells are reversibly inactivated. Rod depolarization is conveyed to the inner retina via postsynaptic circuit elements, namely the rod bipolar cells. Our results show that the retinal circuitry repurposes rods, when they are not directly sensing light, to relay cone-driven surround inhibition.status: publishe

Causal evidence for retina-dependent and -independent visual motion computations in mouse cortex

How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex

Rods in daylight act as relay cells for cone-driven horizontal cell–mediated surround inhibition

Vertebrate vision relies on two types of photoreceptors, rods and cones, which signal increments in light intensity with graded hyperpolarizations. Rods operate in the lower range of light intensities while cones operate at brighter intensities. The receptive fields of both photoreceptors exhibit antagonistic center-surround organization. Here we show that at bright light levels, mouse rods act as relay cells for cone-driven horizontal cell-mediated surround inhibition. In response to large, bright stimuli that activate their surrounds, rods depolarize. Rod depolarization increases with stimulus size, and its action spectrum matches that of cones. Rod responses at high light levels are abolished in mice with nonfunctional cones and when horizontal cells are reversibly inactivated. Rod depolarization is conveyed to the inner retina via postsynaptic circuit elements, namely the rod bipolar cells. Our results show that the retinal circuitry repurposes rods, when they are not directly sensing light, to relay cone-driven surround inhibitio