Seminars

The science of the retina has reached an interesting stage of completion. There exists now a consensus standard model of this neural system - at least in the minds of many researchers - that serves as a baseline against which to evaluate new claims. The standard model links phenomena from molecular biophysics, cell biology, neuroanatomy, synaptic physiology, circuit function, and visual psychophysics. It is further supported by a normative theory explaining what the purpose is of processing visual information this way. Most new reports of retinal phenomena fit squarely within the standard model, and major revisions seem increasingly unlikely. Given that our understanding of other brain circuits with comparable complexity is much more rudimentary, it is worth considering an example of what success looks like. In this talk I will summarize what I think are the ingredients that led to this mature understanding of the retina. Equally important, a number of practices and concepts that are currently en vogue in neuroscience were not needed or indeed counterproductive. I look forward to debating how these lessons might extend to other areas of brain research.

The visual system of the brain is highly parallel in its architecture. This is clearly evident in the outputs of the retina, which arise from neurons called ganglion cells. Work in our lab has shown that mammalian retinas contain more than a dozen distinct types of ganglion cells. Each type appears to filter the retinal image in a unique way and to relay this processed signal to a specific set of targets in the brain. My students and I are working to understand the meaning of this parallel organization through electrophysiological and anatomical studies. We record from light-responsive ganglion cells in vitro using the whole-cell patch method. This allows us to correlate directly the visual response properties, intrinsic electrical behavior, synaptic pharmacology, dendritic morphology and axonal projections of single neurons. Other methods used in the lab include neuroanatomical tracing techniques, single-unit recording and immunohistochemistry. We seek to specify the total number of ganglion cell types, the distinguishing characteristics of each type, and the intraretinal mechanisms (structural, electrical, and synaptic) that shape their stimulus selectivities. Recent work in the lab has identified a bizarre new ganglion cell type that is also a photoreceptor, capable of responding to light even when it is synaptically uncoupled from conventional (rod and cone) photoreceptors. These ganglion cells appear to play a key role in resetting the biological clock. It is just this sort of link, between a specific cell type and a well-defined behavioral or perceptual function, that we seek to establish for the full range of ganglion cell types. My research concerns the structural and functional organization of retinal ganglion cells, the output cells of the retina whose axons make up the optic nerve. Ganglion cells exhibit great diversity both in their morphology and in their responses to light stimuli. On this basis, they are divisible into a large number of types (>15). Each ganglion-cell type appears to send its outputs to a specific set of central visual nuclei. This suggests that ganglion cell heterogeneity has evolved to provide each visual center in the brain with pre-processed representations of the visual scene tailored to its specific functional requirements. Though the outline of this story has been appreciated for some time, it has received little systematic exploration. My laboratory is addressing in parallel three sets of related questions: 1) How many types of ganglion cells are there in a typical mammalian retina and what are their structural and functional characteristics? 2) What combination of synaptic networks and intrinsic membrane properties are responsible for the characteristic light responses of individual types? 3) What do the functional specializations of individual classes contribute to perceptual function or to visually mediated behavior? To pursue these questions, we label retinal ganglion cells by retrograde transport from the brain; analyze in vitro their light responses, intrinsic membrane properties and synaptic pharmacology using the whole-cell patch clamp method; and reveal their morphology with intracellular dyes. Recently, we have discovered a novel ganglion cell in rat retina that is intrinsically photosensitive. These ganglion cells exhibit robust light responses even when all influences from classical photoreceptors (rods and cones) are blocked, either by applying pharmacological agents or by dissociating the ganglion cell from the retina. These photosensitive ganglion cells seem likely to serve as photoreceptors for the photic synchronization of circadian rhythms, the mechanism that allows us to overcome jet lag. They project to the circadian pacemaker of the brain, the suprachiasmatic nucleus of the hypothalamus. Their temporal kinetics, threshold, dynamic range, and spectral tuning all match known properties of the synchronization or "entrainment" mechanism. These photosensitive ganglion cells innervate various other brain targets, such as the midbrain pupillary control center, and apparently contribute to a host of behavioral responses to ambient lighting conditions. These findings help to explain why circadian and pupillary light responses persist in mammals, including humans, with profound disruption of rod and cone function. Ongoing experiments are designed to elucidate the phototransduction mechanism, including the identity of the photopigment and the nature of downstream signaling pathways. In other studies, we seek to provide a more detailed characterization of the photic responsiveness and both morphological and functional evidence concerning possible interactions with conventional rod- and cone-driven retinal circuits. These studies are of potential value in understanding and designing appropriate therapies for jet lag, the negative consequences of shift work, and seasonal affective disorder.

“Call me a marine vision scientist. Some years ago - never mind how long precisely - having little or no money in my purse, and nothing particular to interest me on shore, I thought I would sail about a little and see what animals see in the watery part of the world. It is a way I have of dividing off the spectrum, and regulating circular polarisation.” Sometimes I wish I had just set out to harpoon a white whale as it would have been easier than studying stomatopod (mantis shrimp) vision. Nowhere near as much fun of course and certainly less dangerous so in this presentation I track the history of discovery and confusion that stomatopods deliver in trying to understand what the do actually see. The talk unashamedly borrows from that of Mike Bok a few weeks ago (April 13th 2021 “The Blurry Beginnings: etc” talk) as an introduction to the system (do go look at his talk again, it is beautiful!) and goes both backwards and forwards in time, trying to provide an explanation for the design of this visual system. The journey is again one of retinal anatomy and physiology, neuroanatomy, electrophysiology, behaviour and body ornaments but this time focusses more on polarisation vision (Mike covered the colour stuff well). There is a comparative section looking at the cephalopods too and by the end, I hope you will understand where we are at with trying to understand this extraordinary way of seeing the world and why we ‘pod-people’ wave our arms around so much when asked to explain; what do stomatopods see? Maybe, to butcher another quote: “mantis shrimp have been rendered visually beautiful for vision’s sake.”

I am working on the vertebrate retina, with a main focus on the mouse and bird retina. Currently my work is focused on three major topics: Functional and molecular analysis of electrical synapses in the retina Circuitry and functional role of retinal interneurons: horizontal cells Circuitry for light-dependent magnetoreception in the bird retina Electrical synapses Electrical synapses (gap junctions) permit fast transmission of electrical signals and passage of metabolites by means of channels, which directly connect the cytoplasm of adjoining cells. A functional gap junction channel consists of two hemichannels (one provided by each of the cells), each comprised of a set of six protein subunits, termed connexins. These building blocks exist in a variety of different subtypes, and the connexin composition determines permeability and gating properties of a gap junction channel, thereby enabling electrical synapses to meet a diversity of physiological requirements. In the retina, various connexins are expressed in different cell types. We study the cellular distribution of different connexins as well as the modulation induced by transmitter action or change of ambient light levels, which leads to altered electrical coupling properties. We are also interested in exploiting them as therapeutic avenue for retinal degeneration diseases. Horizontal cells Horizontal cells receive excitatory input from photoreceptors and provide feedback inhibition to photoreceptors and feedforward inhibition to bipolar cells. Because of strong electrical coupling horizontal cells integrate the photoreceptor input over a wide area and are thought to contribute to the antagonistic organization of bipolar cell and ganglion cell receptive fields and to tune the photoreceptor–bipolar cell synapse with respect to the ambient light conditions. However, the extent to which this influence shapes retinal output is unclear, and we aim to elucidate the functional importance of horizontal cells for retinal signal processing by studying various transgenic mouse models. Retinal circuitry for light-dependent magnetoreception in the bird We are studying which neuronal cell types and pathways in the bird retina are involved in the processing of magnetic signals. Likely, magnetic information is detected in cryptochrome-expressing photoreceptors and leaves the retina through ganglion cell axons that project via the thalamofugal pathway to Cluster N, a part of the visual wulst essential for the avian magnetic compass. Thus, we aim to elucidate the synaptic connections and retinal signaling pathways from putatively magnetosensitive photoreceptors to thalamus-projecting ganglion cells in migratory birds using neuroanatomical and electrophysiological techniques.

Axons in the optic nerve are arranged in bundles and conducting action potential with resistance related to their membrane. Optic nerve axons do not form absolutely independent conductive channels. They are directly coupled by gap junctions formed in majority by neuronal Cx45. Coupling of axons, except known transpassing functions, allows to reduce axonal membrane resistance of optic nerve and accelerates transduction of visual signal. This novel finding have substantial implications for understanding of the pathogenesis of various optic neuropathies and identifies a new potential target for a therapeutic approach.