Visual restoration after decades of blindness is now becoming possible by means of retinal and cortical prostheses, as well as emerging stem cell and gene therapeutic approaches. After restoring visual perception, however, a key question remains. Are there optimal means and methods for retraining the visual cortex to process visual inputs, and for learning or relearning to “see”? Up to this point, it has been largely assumed that if the sensory loss is visual, then the rehabilitation focus should also be primarily visual. However, the other senses play a key role in visual rehabilitation due to the plastic repurposing of visual cortex during blindness by audition and somatosensation, and also to the reintegration of restored vision with the other senses. I will present multisensory neuroimaging results, cortical thickness changes, as well as behavioral outcomes for patients with Retinitis Pigmentosa (RP), which causes blindness by destroying photoreceptors in the retina. These patients have had their vision partially restored by the implantation of a retinal prosthesis, which electrically stimulates still viable retinal ganglion cells in the eye. Our multisensory and structural neuroimaging and behavioral results suggest a new, holistic concept of visual rehabilitation that leverages rather than neglects audition, somatosensation, and other sensory modalities.

Photoreceptor loss is the primary cause behind vision impairment and blindness in diseases such as retinitis pigmentosa and age-related macular degeneration. However, the death of rods and cones allows retinoids to permeate the inner retina, causing retinal ganglion cells to become spontaneously hyperactive, severely reducing the signal-to-noise ratio, and creating interference in the communication between the surviving retina and the brain. Treatments aimed at blocking or reducing hyperactivity improve vision initiated from surviving photoreceptors and could enhance the signal fidelity generated by vision restoration methodologies.

In this talk, I will focus on recent work that has uncovered the diversity of intrinsically photosensitive retinal ganglion cells (ipRGCs). These are a unique type of retinal ganglion cell that contains the photopigment melanopsin. ipRGCs are the retinal neurons responsible for driving non-imaging forming behaviors and reflexes, such as circadian entrainment and pupil constriction, amongst many others. My lab has recently focused on uncovering the diversity of ipRGCs, their distribution throughout the mammalian retina, and their axon projections in the brain.

To maintain a stable and clear image of the world, our eyes reflexively follow the direction in which a visual scene is moving. Such gaze stabilization mechanisms reduce image blur as we move in the environment. In non-primate mammals, this behavior is initiated by ON-type direction-selective ganglion cells (ON-DSGCs), which detect the direction of image motion and transmit signals to brainstem nuclei that drive compensatory eye movements. However, ON-DSGCs have not yet been functionally identified in primates, raising the possibility that the visual inputs that drive this behavior instead arise in the cortex. In this talk, I will present molecular, morphological and functional evidence for identification of an ON-DSGC in macaque retina. The presence of ON-DSGCs highlights the need to examine the contribution of subcortical retinal mechanisms to normal and aberrant gaze stabilization in the developing and mature visual system. More generally, our findings demonstrate the power of a multimodal approach to study sparsely represented primate RGC types.

The rising and setting of the sun is accompanied by changes in both the irradiance and the spectral distribution of the sky. Since the discovery of intrinsically photosensitive retinal ganglion cells (ipRGCs) 20 years ago, considerable progress has been made in understanding melanopsin's contributions to encoding irradiance. Much less is known about the cone inputs to ipRGCs and how they could encode changes in the color of the sky. I will summarize our recent connectomic investigation into the cone-opponent inputs to primate ipRGCs and the implications of this work on our understanding of circadian photoentrainment and the evolution of color vision.

Since the discovery of the intrinsically photosensitive retinal ganglion cells (ipRGCs) – just two decades ago – substantial work has been carried out trying to understand their functioning. In this seminar, I’ll focus on pupillometry studies that have provided key clues about ipRGC behavior. Specifically, the interaction between the intrinsic response, rods, and cones will be discussed.

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.

Research in our lab focuses on the circuit mechanisms underlying sensory computation. We use the mouse retina as a model system because it allows us to stimulate the circuit precisely with its natural input, patterns of light, and record its natural output, the spike trains of retinal ganglion cells. We harness the power of genetic manipulations and detailed information about cell types to uncover new circuits and discover their role in visual processing. Our methods include electrophysiology, computational modeling, and circuit tracing using a variety of imaging techniques.

My research uses electrophysiological techniques to evaluate normal retinal function, dysfunction caused by blinding retinal diseases and the restoration of function using a variety of therapeutic strategies. We can use our understanding or normal retinal function and disease-related changes to construct optimal therapeutic strategies and evaluate how they ameliorate the effects of disease. Retinitis pigmentosa (RP) is a family of blinding eye diseases caused by photoreceptor degeneration. The absence of the cells that for this primary signal leads to blindness. My interest in RP involves the evaluation of therapies to restore vision: replacing degenerated photoreceptors either with: (1) new stem or other embryonic cells, manipulated to become photoreceptors or (2) prosthetics devices that replace the photoreceptor signal with an electronic signal to light. Glaucoma is caused by increased intraocular pressure and leads to ganglion cell death, which eliminates the link between the retinal output and central visual processing. We are parsing out of the effects of increased intraocular pressure and aging on ganglion cells. Congenital Stationary Night Blindness (CSNB) is a family of diseases in which signaling is eliminated between rod photoreceptors and their postsynaptic targets, rod bipolar cells. This deafferents the retinal circuit that is responsible for vision under dim lighting. My interest in CSNB involves understanding the basic interplay between excitation and inhibition in the retinal circuit and its normal development. Because of the targeted nature of this disease, we are hopeful that a gene therapy approach can be developed to restore night vision. My work utilizes rodent disease models whose mutations mimic those found in human patients. While molecular manipulation of rodents is a fairly common approach, we have recently developed a mutant NIH miniature swine model of a common form of autosomal dominant RP (Pro23His rhodopsin mutation) in collaboration with the National Swine Resource Research Center at University of Missouri. More genetically modified mini-swine models are in the pipeline to examine other retinal diseases.

Statistics of natural scenes are not uniform - their structure varies dramatically from ground to sky. It remains unknown whether these non-uniformities are reflected in the large-scale organization of the early visual system and what benefits such adaptations would confer. By deploying an efficient coding argument, we predict that changes in the structure of receptive fields across visual space increase the efficiency of sensory coding. To test this experimentally, developed a simple, novel imaging system that is indispensable for studies at this scale. In agreement with our predictions, we could show that receptive fields of retinal ganglion cells change their shape along the dorsoventral axis, with a marked surround asymmetry at the visual horizon. Our work demonstrates that, according to principles of efficient coding, the panoramic structure of natural scenes is exploited by the retina across space and cell-types.

Vision begins in the eye, and what the “retina tells the brain” is a major interest in visual neuroscience. To deduce what the retina encodes (“tells”), computational models are essential. The most important models in the retina currently aim to understand the responses of the retinal output neurons – the ganglion cells. Typically, these models make simplifying assumptions about the neurons in the retinal network upstream of ganglion cells. One important assumption is linear spatial integration. In this talk, I first define what it means for a neuron to be spatially linear or nonlinear and how we can experimentally measure these phenomena. Next, I introduce the neurons upstream to retinal ganglion cells, with focus on bipolar cells, which are the connecting elements between the photoreceptors (input to the retinal network) and the ganglion cells (output). This pivotal position makes bipolar cells an interesting target to study the assumption of linear spatial integration, yet due to their location buried in the middle of the retina it is challenging to measure their neural activity. Here, I present bipolar cell data where I ask whether the spatial linearity holds under artificial and natural visual stimuli. Through diverse analyses and computational models, I show that bipolar cells are more complex than previously thought and that they can already act as nonlinear processing elements at the level of their somatic membrane potential. Furthermore, through pharmacology and current measurements, I illustrate that the observed spatial nonlinearity arises at the excitatory inputs to bipolar cells. In the final part of my talk, I address the functional relevance of the nonlinearities in bipolar cells through combined recordings of bipolar and ganglion cells and I show that the nonlinearities in bipolar cells provide high spatial sensitivity to downstream ganglion cells. Overall, I demonstrate that simple linear assumptions do not always apply and more complex models are needed to describe what the retina “tells” the brain.

Classification of neurons, long viewed as a fairly boring enterprise, has emerged as a major bottleneck in analysis of neural circuits. High throughput single cell RNA-seq has provided a new way to improve the situation. We initially applied this method to mouse retina, showing that its five neuronal classes (photoreceptors, three groups of interneurons, and retinal ganglion cells) can be divided into 130 discrete types. We then applied the method to other species including human, macaque, zebrafish and chick. With the atlases in hand, we are now using them to address questions about how retinal cell types diversify, how they differ in their responses to injury and disease, and the extent to which cell classes and types are conserved among vertebrates.

Neuronal computations are matched to optimally encode the sensory information that is available and relevant for the animal. However, the physical distribution of sensory information is often shaped by the animal’s own behavior. One prominent example is the encoding of optic flow fields that are generated during self-motion of the animal and will therefore depend on the type of locomotion. How evolution has matched computational resources to the behavioral constraints of an animal is not known. Here we use in vivo two photon imaging to record from a population of >3.500 local-direction selective cells. Our data show that the local direction-selective T4/T5 neurons in Drosophila form a population code that is matched to represent optic flow fields generated during translational and rotational self-motion of the fly. This coding principle for optic flow is reminiscent to the population code of local direction-selective ganglion cells in the mouse retina, where four direction-selective ganglion cells encode four different axes of self-motion encountered during walking (Sabbah et al., 2017). However, in flies we find six different subtypes of T4 and T5 cells that, at the population level, represent six axes of self-motion of the fly. The four uniformly tuned T4/T5 subtypes described previously represent a local snapshot (Maisak et al. 2013). The encoding of six types of optic flow in the fly as compared to four types of optic flow in mice might be matched to the high degrees of freedom encountered during flight. Thus, a population code for optic flow appears to be a general coding principle of visual systems, resulting from convergent evolution, but matching the individual ethological constraints of the animal.

The mammalian retina is considered an autonomous neuronal tissue, yet there is evidence that it receives inputs from the brain in the form of retinopetal axons. A sub-population of these axons was suggested to belong to histaminergic neurons located in the tuberomammillarynucleus (TMN) of the hypothalamus. Using viral injections to the TMN, we identified these retinopetal axons and found that although few in number, they extensively branch to cover a large portion of the retina. Using Ca2+ imaging and electrophysiology, we show that histamine application increases spontaneous firing rates and alters the light responses of a significant portion of retinal ganglion cells (RGCs). Direct activation of the histaminergic axons also induced significant changes in RGCs activity. Since activity in the TMN was shown to correlate with arousal state, our data suggest the retinal code may change with the animal's behavioral state through the release of histamine from TMN histaminergic neurons.

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.

Intraneuronal accumulation of the microtubule associated protein Tau is largely recognized as an important toxic factor linked to neuronal cell death in Alzheimer’s disease and tauopathies. While there has been progress uncovering mechanisms leading to the formation of toxic Tau tangles, less is known about how intraneuronal Tau levels are regulated in health and disease. Here, I will discuss our recent work showing that the intracellular trafficking adaptor protein Numb is critical to control intraneuronal Tau levels. Inactivation of Numb in retinal ganglion cells increases monomeric and oligomeric Tau levels and leads to axonal blebbing in optic nerves, followed by significant neuronal cell loss in old mice. Interestingly, overexpression of the long isoform of Numb (Numb-72) decreases intracellular Tau levels by promoting exocytosis of monomeric Tau. In TauP301S and triple transgenic AD mouse models, expression of Numb-72 in RGCs reduces the number of axonal blebs and prevents neurodegeneration. Finally, inactivation of Numb in TauP301S mice accelerates neurodegeneration in both the retina and spinal cord and leads to precocious paralysis. Taken together, these results uncover Numb as a essential regulator of Tau homeostasis in neurons and as a potential therapeutic agent for AD and tauopathies.

Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) are vision disorders caused by loss of rod and cone photoreceptors, but downstream retinal neurons also show physiological and morphological changes, resulting in the emergence of hyperactivity and rhythmic firing in many retinal ganglion cells (RGC). We recently discovered that retinoic acid (RA) is a key signal that triggers hyperactivity and that blockers of RA unmask light responses in RGCs that would otherwise be obscured. Recent work is revealing where in the retina circuit RA initiates functional changes. Moreover, interfering with the RA signaling pathway with drug or gene therapy can improve spatial vision in a mouse model of RP, providing a new strategy for enhancing low vision in human RP and AMD.

The ability to encode the direction of image motion is fundamental to our sense of vision. Direction selectivity along the four cardinal directions is thought to originate in direction-selective ganglion cells (DSGCs), due to directionally-tuned GABAergic suppression by starburst cells. Here, by utilizing two-photon glutamate imaging to measure synaptic release, we reveal that direction selectivity along all four directions arises earlier than expected, at bipolar cell outputs. Thus, DSGCs receive directionally-aligned glutamatergic inputs from bipolar cell boutons. We further show that this bouton-specific tuning relies on cholinergic excitation and GABAergic inhibition from starburst cells. In this way, starburst cells are able to refine directional tuning in the excitatory visual pathway by modulating the activity of DSGC dendrites and their axonal inputs using two different neurotransmitters.

Animals are able to perceive self-motion and navigate in their environment using optic flow information. They often perform visually guided stabilization behaviors like the optokinetic (OKR) or optomotor response (OMR) in order to maintain their eye and body position relative to the moving surround. But how does the animal manage to perform appropriate behavioral response and how are processing tasks divided between the various non-cortical visual brain areas? Experiments have shown that the zebrafish pretectum, which is homologous to the mammalian accessory optic system, is involved in the OKR and OMR. The optic tectum (superior colliculus in mammals) is involved in processing of small stimuli, e.g. during prey capture. We have previously shown that many pretectal neurons respond selectively to rotational or translational motion. These neurons are likely detectors for specific optic flow patterns and mediate behavioral choices of the animal based on optic flow information. We investigate the motion feature extraction of brain structures that receive input from retinal ganglion cells to identify the visual computations that underlie behavioral decisions during prey capture, OKR, OMR and other visually mediate behaviors. Our study of receptive fields shows that receptive field sizes in pretectum (large) and tectum (small) are very different and that pretectal responses are diverse and anatomically organized. Since calcium indicators are slow and receptive fields for motion stimuli are difficult to measure, we also develop novel stimuli and statistical methods to infer the neuronal computations of visual brain areas.

Proper alignment of the circadian system the environmental light/dark cycle is central to human health and well-being, and occurs exclusively via light input from the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). I will discuss our lab’s recent work uncovering a new inhibitory signaling pathway from the eye to the brain that dampens the sensitivity of our circadian and pupil systems to light.

How does a circuit of neurons process sensory information? And how are transformations of neural signals altered by changes in synaptic strength? We investigate these questions in the context of the visual system and the lateral line of fish. A distinguishing feature of our approach is the imaging of activity across populations of synapses – the fundamental elements of signal transfer within all brain circuits. A guiding hypothesis is that the plasticity of neurotransmission plays a major part in controlling the input-output relation of sensory circuits, regulating the tuning and sensitivity of neurons to allow adaptation or sensitization to particular features of the input. Sensory systems continuously adjust their input-output relation according to the recent history of the stimulus. A common alteration is a decrease in the gain of the response to a constant feature of the input, termed adaptation. For instance, in the retina, many of the ganglion cells (RGCs) providing the output produce their strongest responses just after the temporal contrast of the stimulus increases, but the response declines if this input is maintained. The advantage of adaptation is that it prevents saturation of the response to strong stimuli and allows for continued signaling of future increases in stimulus strength. But adaptation comes at a cost: a reduced sensitivity to a future decrease in stimulus strength. The retina compensates for this loss of information through an intriguing strategy: while some RGCs adapt following a strong stimulus, a second population gradually becomes sensitized. We found that the underlying circuit mechanisms involve two opposing forms of synaptic plasticity in bipolar cells: synaptic depression causes adaptation and facilitation causes sensitization. Facilitation is in turn caused by depression in inhibitory synapses providing negative feedback. These opposing forms of plasticity can cause simultaneous increases and decreases in contrast-sensitivity of different RGCs, which suggests a general framework for understanding the function of sensory circuits: plasticity of both excitatory and inhibitory synapses control dynamic changes in tuning and gain.

Organisms sense light for purposes that range from recognizing objects to synchronizing activity with environmental cycles. What mechanisms serve these diverse tasks? This seminar will examine the specializations of two cell types. First are the foveal cone photoreceptors. These neurons are used by primates to see far greater detail than other mammals, which lack them. How do the biophysical properties of foveal cones support high-acuity vision? Second are the melanopsin retinal ganglion cells, which are conserved among mammals and essential for processes that include regulation of the circadian clock, sleep, and hormone levels. How do these neurons encode light, and is encoding customized for animals of different niches? In pursuing these questions, a broad goal is to learn how various levels of biological organization are shaped to behavioural needs.

The development of neural circuits is profoundly impacted by both spontaneous and sensory experience. This is perhaps most well studied in the visual system, where disruption of early spontaneous activity called retinal waves prior to eye opening and visual deprivation after eye opening leads to alterations in the response properties and connectivity in several visual centers in the brain. We address this question in the retina, which comprises multiple circuits that encode different features of the visual scene, culminating in over 40 different types of retinal ganglion cells. Direction-selective ganglion cells respond strongly to an image moving in the preferred direction and weakly to an image moving in the opposite, or null, direction. Moreover, as recently described (Sabbah et al, 2017) the preferred directions of direction selective ganglion cells cluster along four directions that align along two optic flow axes, causing variation of the relative orientation of preferred directions along the retinal surface. I will provide recent progress in the lab that addresses the role of visual experience and spontaneous retinal waves in the establishment of direction selective tuning and direction selectivity maps in the retina.

Popular notions of how the retina encodes visual stimuli typically focus on the center-surround receptive fields of retinal ganglion cells, the output neurons of the retina. In this view, the receptive field acts as a linear filter on the visual stimulus, highlighting spatial contrast and providing efficient representations of natural images. Yet, we also know that many ganglion cells respond vigorously to fine spatial gratings that should not activate the linear filter of the receptive field. Thus, ganglion cells may integrate visual signals nonlinearly across space. In this talk, I will discuss how these (and other) nonlinearities relate to the encoding of natural visual stimuli in the retina. Based on electrophysiological recordings of ganglion and bipolar cells from mouse and salamander retina, I will present methods for assessing nonlinear processing in different cell types and examine their importance and potential function under natural stimulation.

Understanding how neural circuits in the brain compute information not only requires determining how individual inhibitory and excitatory elements of circuits are wired together, but also a detailed knowledge of their functional interactions. Recent advances in optogenetic techniques and mouse genetics now offer ways to specifically probe the functional properties of neural circuits with unprecedented specificity. Perhaps one of the most heavily interrogated circuits in the mouse brain is one in the retina that is involved in coding direction (reviewed by Mauss et al., 2017; Vaney et al., 2012). In this circuit, direction is encoded by specialized direction-selective (DS) ganglion cells (DSGCs), which respond robustly to objects moving in a ‘preferred’ direction but not in the opposite or ‘null’ direction (Barlow and Levick, 1965). We now know this computation relies on the coordination of three transmitter systems: glutamate, GABA and acetylcholine (ACh). In this talk, I will discuss the synaptic mechanisms that produce the spatiotemporal patterns of inhibition and excitation that are crucial for shaping directional selectivity. Special emphasis will be placed on the role of ACh, as it is unclear whether it is mediated by synaptic or non-synaptic mechanisms, which is in fact a central issue in the CNS. Barlow, H.B., and Levick, W.R. (1965). The mechanism of directionally selective units in rabbit's retina. J Physiol 178, 477-504. Mauss, A.S., Vlasits, A., Borst, A., and Feller, M. (2017). Visual Circuits for Direction Selectivity. Annu Rev Neurosci 40, 211-230. Vaney, D.I., Sivyer, B., and Taylor, W.R. (2012). Direction selectivity in the retina: symmetry and asymmetry in structure and function. Nat Rev Neurosci 13, 194-208