Photoreceptors: molecules to cellular function

Visual processing begins in the photoreceptors, rods and cones, where incident light is converted into an electrical signal. This biochemical process called phototransduction is one of the most extensively studied G-protein signaling cascade in biology. Early work in rod photoreceptors has led the way in our understanding of G-protein signaling. Our lab is interested in understanding how photoreceptor signaling varies across types and across the visual field. What are the underlying mechanisms that give rise to this diversity? Early work has illustrated the differences in response properties between rods and cones and the molecular differences in the phototransduction cascade. We are interested in studying diversity of signaling in cone photoreceptors.

Our everyday visual experience – including your ability to read this text – is dominated by signaling in the fovea. The first step in our high definition foveal vision occurs in the cone photoreceptors that are tightly packed in a hexagonal lattice forming an array of fine pixels. Such an arrangement together with the unusual morphology of foveal cones and downstream retinal circuitry is key for the high spatial and chromatic resolution attributed to our foveal/central vision. Even though, the anatomical specializations of foveal cones have been known for almost a century, our knowledge about their functional specializations is almost lacking. Our lab is interested in understanding i) the functional properties of foveal cones and differences across retinal locations and ii) specialization of the phototransduction cascade in the fovea. Our recent work (Sinha et al. Cell 2017) provided the first insight into how foveal cones operate at a cellular level and to our surprise, we found that their functional responses to light are unique and quite distinct from cones in other locations in the retina. The goal is to build on this initial observation and characterize the functional specialization of foveal cones at an unprecedented resolution from single molecules to cellular function and then use this in vivo information as a baseline for testing cone function in human stem cell-derived retina.

Functional diversity of retinal neurons  

Vision involves the simultaneous processing of multiple aspects of the incident light, for example, the intensity, spectrum, and spatial location of photons. At the earliest stage of visual processing, each point in space is sampled by a handful of retinal neurons that must convey every aspect of the light stimuli necessary for a meaningful interpretation of the environment. One possible mechanism for processing multiple features involves parsing and processing information across separate channels. This begins at the level of photoreceptors (rods and cones) and is further enriched at the level of second-order neurons (bipolar cells > 10 types). Such parallel visual processing is best exemplified in the retinal output neurons (ganglion cells) which have recently been classified into >30 types each of which perform a defined neural computation eg. direction selectivity. Our lab is interested in studying distinct computations in mammalian retina and identifying novel ones in retinal specializations such as the fovea. This will be important for engineering of prosthetics that can better mimic the retina since vision restoration following retinal disease requires a deeper understanding of how the retina processes information

Synaptic and circuit mechanisms shaping retinal function 

An emerging theme from work on non-primate model systems is the complexity of retinal computations carried out by retinal output neurons called ganglion cells (Wei et al., 2011; Munch et al., 2009). Most of these computations rely on synaptic and circuit mechanisms (Jadzinsky and Baccus, 2013; Demb and Singer, 2015). Thus, a key question about our vision is whether such mechanisms provide a similar diversity of signaling properties in the retina. To understand how each retinal output neuron is specialized we need to have a deeper knowledge of i) the properties of the synaptic inputs and how they are integrated (synaptic integration) by the retinal output neuron to produce a meaningful response to a stimulus and ii) how they are connected within the circuit. While extensive work in non-primate retinas has illustrated the importance of synaptic integration in retinal computations such as direction selectivity, orientation selectivity and others (Jadzinsky and Baccus, 2013), our recent study illustrates how synaptic integration can differ markedly for a given neural circuit, such as the midget pathway, between foveal and peripheral retina (Sinha et al. 2017). This signifies the importance of studying the diversity of circuit and synaptic mechanisms across visual pathways and their anatomical organization in primate retina to better understand the structure and function of the human retina. Our research focuses on three of the following mechanisms that shape retinal output:

a) Synaptic integration: Integration of excitatory and inhibitory signals shapes neural responses in most sensory and cortical circuits. What are the properties of excitatory and inhibitory inputs across diverse types of retinal ganglion cells.

b) Presynaptic inhibition: Presynaptic inhibition plays a key role in regulating neurotransmitter release from the axon terminal and hence controlling the input-output properties of the synapse. But it has been difficult to isolate its contribution from postsynaptic inhibition in most neural circuits and study its impact on circuit output. We are using genetic strategies to selectively perturb presynaptic inhibition and determine how it shapes bipolar to ganglion cell signaling.

c) Circuit and synaptic organization of retina. Understanding vision requires unraveling the circuit-level organization of the mammalian retina. Achieving this goal requires a detailed knowledge of the anatomical/synaptic connections between retinal neurons . To determine detailed synaptic connectivity, we are collaborating to perform serial electron microscopic (EM) reconstructions of retinal sections.