A Retinal Circuit Generating a Dynamic Predictive Code for Oriented Features

Sensory systems must reduce the transmission of redundant information to function efficiently. One strategy is to continuously adjust the sensitivity of neurons to suppress responses to common features of the input while enhancing responses to new ones. Here we image the excitatory synaptic inputs and outputs of retinal ganglion cells to understand how such dynamic predictive coding is implemented in the analysis of spatial patterns. Synapses of bipolar cells become tuned to orientation through presynaptic inhibition, generating lateral antagonism in the orientation domain. Individual ganglion cells receive excitatory synapses tuned to different orientations, but feedforward inhibition generates a high-pass filter that only transmits the initial activation of these inputs, removing redundancy. These results demonstrate how a dynamic predictive code can be implemented by circuit motifs common to many parts of the brain.

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title: Laminar differences in the orientation selectivity of geniculate afferents in mouse primary visual cortex
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title: Active dendritic integration as a mechanism for robust and precise grid cell firing
abstract: Understanding how active dendrites are exploited for behaviorally relevant computations is a fundamental challenge in neuroscience. Grid cells in medial entorhinal cortex are an attractive model system for addressing this question, as the computation they perform is clear: they convert synaptic inputs into spatially modulated, periodic firing. Whether active dendrites contribute to the generation of the dual temporal and rate codes characteristic of grid cell output is unknown. We show that dendrites of medial entorhinal cortex neurons are highly excitable and exhibit a supralinear input–output function in vitro, while in vivo recordings reveal membrane potential signatures consistent with recruitment of active dendritic conductances. By incorporating these nonlinear dynamics into grid cell models, we show that they can sharpen the precision of the temporal code and enhance the robustness of the rate code, thereby supporting a stable, accurate representation of space under varying environmental conditions. Our results suggest that active dendrites may therefore constitute a key cellular mechanism for ensuring reliable spatial navigation.

title: Parametric Functional Maps of Visual Inputs to the Tectum
abstract: How features of the visual scene are encoded in the population activity of retinal ganglion cells (RGCs) targeting specific regions of the brain is not well understood. To address this, we have used a genetically encoded reporter of presynaptic function (SyGCaMP3) to record visually evoked activity in the population of RGC axons innervating the zebrafish tectum. Using unbiased voxel-wise analysis of SyGCaMP3 signals, we identify three subtypes of direction-selective and two subtypes of orientation-selective retinal input. Composite parametric functional maps generated across many larvae show laminar segregation of direction- and orientation-selective responses and unexpected retinotopic biases in the distribution of functional subtypes. These findings provide a systematic description of the form, organization, and dimensionality of visual inputs to the brain and will serve as a platform for understanding emergent properties in tectal circuits associated with visually driven behavior.

title: Divergence of visual channels in the inner retina
abstract: Bipolar cells form parallel channels that carry visual signals from the outer to the inner retina. Each type of bipolar cell is thought to carry a distinct visual message to select types of amacrine cells and ganglion cells. However, the number of ganglion cell types exceeds that of the bipolar cells providing their input, suggesting that bipolar cell signals diversify on transmission to ganglion cells. We explored in the salamander retina how signals from individual bipolar cells feed into multiple ganglion cells and found that each bipolar cell was able to evoke distinct responses among ganglion cells, differing in kinetics, adaptation and rectification properties. This signal divergence resulted primarily from interactions with amacrine cells that allowed each bipolar cell to send distinct signals to its target ganglion cells. Our findings indicate that individual bipolar cell–ganglion cell connections have distinct transfer functions. This expands the number of visual channels in the inner retina and enhances the computational power and feature selectivity of early visual processing.

title: Rapid mapping of visual receptive fields by filtered back projection: application to multi-neuronal electrophysiology and imaging
abstract: To understand vision, we must measure the spatio‐temporal receptive field of neurons in the visual system. We describe how the filtered back projection can be used to map the receptive fields of many neurons simultaneously, within a few minutes. This method can also reveal complex features of visual receptive fields such as the tuning of orientation selective neurons and the contributions from separate ON and OFF components. We demonstrate that the filtered back projection is suited to mapping receptive fields from populations of neurons recorded with imaging or electrophysiology and should therefore prove useful for investigations of visual processing throughout the visual pathway.

title: A Synaptic Mechanism for Retinal Adaptation to Luminance and Contrast
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title: Encoding of Luminance and Contrast by Linear and Nonlinear Synapses in the Retina
abstract: Understanding how neural circuits transmit information is technically challenging because the neural code is contained in the activity of large numbers of neurons and synapses. Here, we use genetically encoded reporters to image synaptic transmission across a population of sensory neurons—bipolar cells in the retina of live zebrafish. We demonstrate that the luminance sensitivities of these synapses varies over 104 with a log-normal distribution. About half the synapses made by ON and OFF cells alter their polarity of transmission as a function of luminance to generate a triphasic tuning curve with distinct maxima and minima. These nonlinear synapses signal temporal contrast with greater sensitivity than linear ones. Triphasic tuning curves increase the dynamic range over which bipolar cells signal light and improve the efficiency with which luminance information is transmitted. The most efficient synapses signaled luminance using just 1 synaptic vesicle per second per distinguishable gray level.

title: Bipolar cell–photoreceptor connectivity in the zebrafish (Danio rerio) retina
abstract: Bipolar cells convey luminance, spatial, and color information from photoreceptors to amacrine and ganglion cells. We studied the photoreceptor connectivity of 321 bipolar cells in the adult zebrafish retina. 1,1′‐Dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate (DiI) was inserted into whole‐mounted transgenic zebrafish retinas to label bipolar cells. The photoreceptors that connect to these DiI‐labeled cells were identified by transgenic fluorescence or their positions relative to the fluorescent cones, as cones are arranged in a highly ordered mosaic: rows of alternating blue‐ (B) and ultraviolet‐sensitive (UV) single cones alternate with rows of red‐ (R) and green‐sensitive (G) double cones. Rod terminals intersperse among cone terminals. As many as 18 connectivity subtypes were observed, 9 of which—G, GBUV, RG, RGB, RGBUV, RGRod, RGBRod, RGBUVRod, and RRod bipolar cells—accounted for 96% of the population. Based on their axon terminal stratification, these bipolar cells could be further subdivided into ON, OFF, and ON–OFF cells. The dendritic spread size, soma depth and size, and photoreceptor connections of the 308 bipolar cells within the nine common connectivity subtypes were determined, and their dendritic tree morphologies and axonal stratification patterns compared. We found that bipolar cells with the same axonal stratification patterns could have heterogeneous photoreceptor connectivity whereas bipolar cells with the same dendritic tree morphology usually had the same photoreceptor connectivity, although their axons might stratify on different levels.  2012.

title: Neural Mechanisms Generating Orientation Selectivity in the Retina
abstract: The orientation of visual stimuli is a salient feature of visual scenes. In vertebrates, the first neural processing steps generating orientation selectivity take place in the retina. Here, we dissect an orientation-selective circuit in the larval zebrafish retina and describe its underlying synaptic, cellular, and molecular mechanisms. We genetically identify a class of amacrine cells (ACs) with elongated dendritic arbors that show orientation tuning. Both selective optogenetic ablation of ACs marked by the cell-adhesion molecule Teneurin-3 (Tenm3) and pharmacological interference with their function demonstrate that these cells are critical components for orientation selectivity in retinal ganglion cells (RGCs) by being a source of tuned GABAergic inhibition. Moreover, our morphological analyses reveal that Tenm3+ ACs and orientation-selective RGCs co-stratify their dendrites in the inner plexiform layer, and that Tenm3+ ACs require Tenm3 to acquire their correct dendritic stratification. Finally, we show that orientation tuning is present also among bipolar cell presynaptic terminals. Our results define a neural circuit underlying orientation selectivity in the vertebrate retina and characterize cellular and molecular requirements for its assembly.

title: Three forms of spatial temporal feedforward inhibition are common to different ganglion cell types in rabbit retina.
abstract: There exist more than 30 different morphological amacrine cell types, but there may be fewer physiological types. Here we studied the amacrine cell outputs by measuring the temporal and spatial properties of feedforward inhibition to four different types of ganglion cells. These ganglion cells, each with concentric receptive field organization, appear to receive a different relative contribution of the same three forms of feed-forward inhibition, namely: local glycinergic, local sustained GABAergic, and broad transient GABAergic inhibition. Two of these inhibitory components, local glycinergic inhibition and local sustained GABAergic inhibition were localized to narrow regions confined to the dendritic fields of the ganglion cells. The third, a broad transient GABAergic inhibition, was driven from regions peripheral to the dendritic area. Each inhibitory component is also correlated with characteristic kinetics expressed in all ganglion cells: broad transient GABAergic inhibition had the shortest latency, local glycinergic inhibition had an intermediate latency, and local sustained GABAergic inhibition had the longest latency. We suggest each of these three inhibitory components represents the output from a distinct class of amacrine cell, mediates a specific visual function, and each forms a basic functional component for the four ganglion cell types. Similar subunits likely exist in the circuits of other ganglion cell types as well.

title: Inhibitory Interneurons in the Retina: Types, Circuitry, and Function.
abstract: Visual signals in the vertebrate retina are shaped by feedback and feedforward inhibition in two synaptic layers. In one, horizontal cells establish fundamental center-surround receptive-field properties via morphologically and physiologically complex synapses with photoreceptors and bipolar cells. In the other, a panoply of amacrine cells imbue ganglion cell responses with spatiotemporally complex information about the visual world. Here, I review current ideas about horizontal cell signaling, considering the evidence for and against the leading, competing theories. I also discuss recent work that has begun to make sense of the remarkable morphological and physiological diversity of amacrine cells. These latter efforts have been aided tremendously by increasingly complete connectivity maps of inner retinal circuitry and new genetic tools that enable study of individual, sparsely expressed amacrine cell types.

title: How Inhibition Shapes Cortical Activity
abstract: Cortical processing reflects the interplay of synaptic excitation and synaptic inhibition. Rapidly accumulating evidence is highlighting the crucial role of inhibition in shaping spontaneous and sensory-evoked cortical activity and thus underscores how a better knowledge of inhibitory circuits is necessary for our understanding of cortical function. We discuss current views of how inhibition regulates the function of cortical neurons and point to a number of important open questions.

title: Input normalization by global feedforward inhibition expands cortical dynamic range
abstract: The cortex is sensitive to weak stimuli, but responds to stronger inputs without saturating. The mechanisms that enable this wide range of operation are not fully understood. We found that the amplitude of excitatory synaptic currents necessary to fire rodent pyramidal cells, the threshold excitatory current, increased with stimulus strength. Consequently, the relative contribution of individual afferents in firing a neuron was inversely proportional to the total number of active afferents. Feedforward inhibition, acting homogeneously across pyramidal cells, ensured that threshold excitatory currents increased with stimulus strength. In contrast, heterogeneities in the distribution of excitatory currents in the neuronal population determined the specific set of pyramidal cells recruited. Together, these mechanisms expand the range of afferent input strengths that neuronal populations can represent.

title: Inhibitory Gating of Input Comparison in the CA1 Microcircuit
abstract: Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.

title: Synaptic Rectification Controls Nonlinear Spatial Integration of Natural Visual Inputs
abstract: A central goal in the study of any sensory system is to predict neural responses to complex inputs, especially those encountered during natural stimulation. Nowhere is the transformation from stimulus to response better understood than the vertebrate retina. Nevertheless, descriptions of retinal computation are largely based on stimulation using artificial visual stimuli, and it is unclear how these descriptions map onto the encoding of natural stimuli. We demonstrate that nonlinear spatial integration, a common feature of retinal ganglion cell (RGC) processing, shapes neural responses to natural visual stimuli in primate Off parasol RGCs, whereas On parasol RGCs exhibit surprisingly linear spatial integration. Despite this asymmetry, both cell types show strong nonlinear integration when presented with artificial stimuli. We show that nonlinear integration of natural stimuli is a consequence of rectified excitatory synaptic input and that accounting for nonlinear spatial integration substantially improves models that predict RGC responses to natural images.

title: Energy limitation as a selective pressure on the evolution of sensory systems
abstract: Evolution of animal morphology, physiology and behaviour is shaped by the selective pressures to which they are subject. Some selective pressures act to increase the benefits accrued whilst others act to reduce the costs incurred, affecting the cost/benefit ratio. Selective pressures therefore produce a trade-off between costs and benefits that ultimately influences the fitness of the whole organism. The nervous system has a unique position as the interface between morphology, physiology and behaviour; the final output of the nervous system is the behaviour of the animal, which is a product of both its morphology and physiology. The nervous system is under selective pressure to generate adaptive behaviour, but at the same time is subject to costs related to the amount of energy that it consumes. Characterising this trade-off between costs and benefits is essential to understanding the evolution of nervous systems, including our own. Within the nervous system, sensory systems are the most amenable to analysing costs and benefits, not only because their function can be more readily defined than that of many central brain regions and their benefits quantified in terms of their performance, but also because recent studies of sensory systems have begun to directly assess their energetic costs. Our review focuses on the visual system in particular, although the principles we discuss are equally applicable throughout the nervous system. Examples are taken from a wide range of sensory modalities in both vertebrates and invertebrates. We aim to place the studies we review into an evolutionary framework. We combine experimentally determined measures of energy consumption from whole retinas of rabbits and flies with intracellular measurements of energy consumption from single fly photoreceptors and recently constructed energy budgets for neural processing in rats to assess the contributions of various components to neuronal energy consumption. Taken together, these studies emphasize the high costs of maintaining neurons at rest and whilst signalling. A substantial proportion of neuronal energy consumption is related to the movements of ions across the neuronal cell membrane through ion channels, though other processes such as vesicle loading and transmitter recycling also consume energy. Many of the energetic costs within neurons are linked to 3Na+/2K+ ATPase activity, which consumes energy to pump Na+ and K+ ions across the cell membrane and is essential for the maintenance of the resting potential and its restoration following signalling. Furthermore, recent studies in fly photoreceptors show that energetic costs can be related, via basic biophysical relationships, to their function. These findings emphasize that neurons are subject to a law of diminishing returns that severely penalizes excess functional capacity with increased energetic costs. The high energetic costs associated with neural tissue favour energy efficient coding and wiring schemes, which have been found in numerous sensory systems. We discuss the role of these efficient schemes in reducing the costs of information processing. Assessing evidence from a wide range of vertebrate and invertebrate examples, we show that reducing energy expenditure can account for many of the morphological features of sensory systems and has played a key role in their evolution.

title: Network anatomy and in vivo physiology of visual cortical neurons
abstract: In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property—the preferred stimulus orientation—of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons’ local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.

title: Mechanisms of Orientation Selectivity in the Primary Visual Cortex.
abstract: The mechanisms underlying the emergence of orientation selectivity in the visual cortex have been, and continue to be, the subjects of intense scrutiny. Orientation selectivity reflects a dramatic change in the representation of the visual world: Whereas afferent thalamic neurons are generally orientation insensitive, neurons in the primary visual cortex (V1) are extremely sensitive to stimulus orientation. This profound change in the receptive field structure along the visual pathway has positioned V1 as a model system for studying the circuitry that underlies neural computations across the neocortex. The neocortex is characterized anatomically by the relative uniformity of its circuitry despite its role in processing distinct signals from region to region. A combination of physiological, anatomical, and theoretical studies has shed some light on the circuitry components necessary for generating orientation selectivity in V1. This targeted effort has led to critical insights, as well as controversies, concerning how neural circuits in the neocortex perform computations.

title: Recruitment of an inhibitory hippocampal network after bursting in a single granule cell
abstract: The hippocampal CA3 area, an associational network implicated in memory function, receives monosynaptic excitatory as well as disynaptic inhibitory input through the mossy-fiber axons of the dentate granule cells. Synapses made by mossy fibers exhibit low release probability, resulting in high failure rates at resting discharge frequencies of 0.1 Hz. In recordings from functionally connected pairs of neurons, burst firing of a granule cell increased the probability of glutamate release onto both CA3 pyramidal cells and inhibitory interneurons, such that subsequent low-frequency stimulation evoked biphasic excitatory/inhibitory responses in a CA3 pyramidal cell, an effect lasting for minutes. Analysis of the unitary connections in the circuit revealed that granule cell bursting caused powerful activation of an inhibitory network, thereby transiently suppressing excitatory input to CA3 pyramidal cells. This phenomenon reflects the high incidence of spike-to-spike transmission at granule cell to interneuron synapses, the numerically much greater targeting by mossy fibers of inhibitory interneurons versus principal cells, and the extensively divergent output of interneurons targeting CA3 pyramidal cells. Thus, mossy-fiber input to CA3 pyramidal cells appears to function in three distinct modes: a resting mode, in which synaptic transmission is ineffectual because of high failure rates; a bursting mode, in which excitation predominates; and a postbursting mode, in which inhibitory input to the CA3 pyramidal cells is greatly enhanced. A mechanism allowing the transient recruitment of inhibitory input may be important for controlling network activity in the highly interconnected CA3 pyramidal cell region.

title: Synaptic dynamics mediate sensitivity to motion independent of stimulus details
abstract: Humans and other animals generally perceive motion independently of the cues that define the moving object. To understand the underlying mechanisms of this generalization of stimulus attributes, we have examined the cellular properties of avian wide-field tectal neurons that are sensitive to a variety of moving stimuli but not to static stationary stimuli. This in vitro study showed phasic signal transfer at the retinotectal synapse and binary dendritic responses to synaptic inputs that interact in a mutually exclusive manner in the postsynaptic tectal neuron. A model of the tectal circuitry predicts that these two cellular properties mediate sensitivity to a wide range of dynamic spatiotemporal stimuli, including moving stimuli, but not to static stationary stimuli in a tectal neuron. The computation that is independent of stimulus detail is initiated by tectal neurons and is completed by rotundal neurons that integrate outputs from multiple tectal neurons in a directionally selective manner.

title: Towards a comprehensive catalog of zebrafish behavior 1.0 and beyond.
abstract: Zebrafish (Danio rerio) are rapidly gaining popularity in translational neuroscience and behavioral research. Physiological similarity to mammals, ease of genetic manipulations, sensitivity to pharmacological and genetic factors, robust behavior, low cost, and potential for high-throughput screening contribute to the growing utility of zebrafish models in this field. Understanding zebrafish behavioral phenotypes provides important insights into neural pathways, physiological biomarkers, and genetic underpinnings of normal and pathological brain function. Novel zebrafish paradigms continue to appear with an encouraging pace, thus necessitating a consistent terminology and improved understanding of the behavioral repertoire. What can zebrafish 'do', and how does their altered brain function translate into behavioral actions? To help address these questions, we have developed a detailed catalog of zebrafish behaviors (Zebrafish Behavior Catalog, ZBC) that covers both larval and adult models. Representing a beginning of creating a more comprehensive ethogram of zebrafish behavior, this effort will improve interpretation of published findings, foster cross-species behavioral modeling, and encourage new groups to apply zebrafish neurobehavioral paradigms in their research. In addition, this glossary creates a framework for developing a zebrafish neurobehavioral ontology, ultimately to become part of a unified animal neurobehavioral ontology, which collectively will contribute to better integration of biological data within and across species.

title: Neuroscience: Towards functional connectomics
abstract: To understand the brain, the thousands of synaptic connections made by each of billions of neurons should be mapped and related to neuronal function. First steps towards this formidable goal are now reported. See Articles p.177
 & p.183
 Connectivity forms the basis of functional computations performed by neural circuits, but it is notoriously difficult to follow the complex structural wiring between neurons to the function of individual cells. Now, using a combination of functional imaging and three-dimensional serial electron-microscopic reconstruction at an unprecedented scale, two groups present detailed representations of the connectivity of single cells in the mouse visual system. Davi Bock et al. in Clay Reid's lab investigate connectivity in the primary visual cortex, and find that inhibitory neurons receive input from excitatory cells with widely varying functions, consistent with predictions from recent physiological studies of the mouse cortex. Kevin Briggman, Moritz Helmstaedter and Winfried Denk show that direction-selective ganglion cells receive more synapses from a starburst amacrine cell dendrite if their preferred directions are opposites, suggesting that the directional sensitivity of retinal ganglion cells arises from the asymmetry in their wiring with amacrine cells.

title: Tol2: a versatile gene transfer vector in vertebrates
abstract: The medaka fish Tol2 element is an autonomous transposon that encodes a fully functional transposase. The transposase protein can catalyze transposition of a transposon construct that has 200 and 150 base pairs of DNA from the left and right ends of the Tol2 sequence, respectively. These sequences contain essential terminal inverted repeats and subterminal sequences. DNA inserts of fairly large sizes (as large as 11 kilobases) can be cloned between these sequences without reducing transpositional activity. The Tol2 transposon system has been shown to be active in all vertebrate cells tested thus far, including zebrafish, Xenopus, chicken, mouse, and human. In this review I describe and discuss how the Tol2 transposon is being applied to transgenic studies in these vertebrates, and possible future applications.

title: Synaptic Activity and Activity-Dependent Competition Regulates Axon Arbor Maturation, Growth Arrest, and Territory in the Retinotectal Projection
abstract: In the retinotectal projection, synapses guide retinal ganglion cell (RGC) axon arbor growth by promoting branch formation and by selectively stabilizing branches. To ask whether presynaptic function is required for this dual role of synapses, we have suppressed presynaptic function in single RGCs using targeted expression of tetanus toxin light-chain fused to enhanced green fluorescent protein (TeNT-Lc:EGFP). Time-lapse imaging of singly silenced axons as they arborize in the tectum of zebrafish larvae shows that presynaptic function is not required for stabilizing branches or for generating an arbor of appropriate complexity. However, synaptic activity does regulate two distinct aspects of arbor development. First, single silenced axons fail to arrest formation of highly dynamic but short-lived filopodia that are a feature of immature axons. Second, single silenced axons fail to arrest growth of established branches and so occupy significantly larger territories in the tectum than active axons. However, if activity-suppressed axons had neighbors that were also silent, axonal arbors appeared normal in size. A similar reversal in phenotype was observed when single TeNT-Lc:EGFP axons are grown in the presence of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]. Although expansion of arbor territory is prevented when neighbors are silent, formation of transient filopodia is not. These results suggest that synaptic activity by itself regulates filopodia formation regardless of activity in neighboring cells but that the ability to arrest growth and focusing of axonal arbors in the target is an activity-dependent, competitive process.

title: Optimized Gal4 genetics for permanent gene expression mapping in zebrafish
abstract: Combinatorial genetics for conditional transgene activation allows studying gene function with temporal and tissue specific control like the Gal4-UAS system, which has enabled sophisticated genetic studies in Drosophila. Recently this system was adapted for zebrafish and promising applications have been introduced. Here, we report a systematic optimization of zebrafish Gal4-UAS genetics by establishing an optimized Gal4-activator (KalTA4). We provide quantitative data for KalTA4-mediated transgene activation in dependence of UAS copy numbers to allow for studying dosage effects of transgene expression. Employing a Tol2 transposon-mediated KalTA4 enhancer trap screen biased for central nervous system expression, we present a collection of self-reporting red fluorescent KalTA4 activator strains. These strains reliably transactivate UAS-dependent transgenes and can be rendered homozygous. Furthermore, we have characterized the transactivation kinetics of tissue-specific KalTA4 activation, which led to the development of a self-maintaining effector strain “Kaloop.” This strain relates transient KalTA4 expression during embryogenesis via a KalTA4-mediated autoregulatory mechanism to live adult structures. We demonstrate its use by showing that the secondary octaval nucleus in the adult hindbrain is likely derived from egr2b-expressing cells in rhombomere 5 during stages of early embryogenesis. These data demonstrate prolonged and maintained expression by Kalooping, a technique that can be used for permanent spatiotemporal genetic fate mapping and targeted transgene expression in zebrafish.

title: The Psychophysics Toolbox.
abstract: The Psychophysics Toolbox is a software package that supports visual psychophysics. Its routines provide an interface between a high-level interpreted language (MATLAB on the Macintosh) and the video display hardware. A set of example programs is included with the Toolbox distribution.

title: ScanImage: Flexible software for operating laser scanning microscopes
abstract: BackgroundLaser scanning microscopy is a powerful tool for analyzing the structure and function of biological specimens. Although numerous commercial laser scanning microscopes exist, some of the more interesting and challenging applications demand custom design. A major impediment to custom design is the difficulty of building custom data acquisition hardware and writing the complex software required to run the laser scanning microscope.ResultsWe describe a simple, software-based approach to operating a laser scanning microscope without the need for custom data acquisition hardware. Data acquisition and control of laser scanning are achieved through standard data acquisition boards. The entire burden of signal integration and image processing is placed on the CPU of the computer. We quantitate the effectiveness of our data acquisition and signal conditioning algorithm under a variety of conditions. We implement our approach in an open source software package (ScanImage) and describe its functionality.ConclusionsWe present ScanImage, software to run a flexible laser scanning microscope that allows easy custom design.

title: The Retinal Projectome Reveals Brain-Area-Specific Visual Representations Generated by Ganglion Cell Diversity
abstract: Visual information is transmitted to the vertebrate brain exclusively via the axons of retinal ganglion cells (RGCs). The functional diversity of RGCs generates multiple representations of the visual environment that are transmitted to several brain areas. However, in no vertebrate species has a complete wiring diagram of RGC axonal projections been constructed. We employed sparse genetic labeling and in vivo imaging of the larval zebrafish to generate a cellular-resolution map of projections from the retina to the brain.



Our data define 20 stereotyped axonal projection patterns, the majority of which innervate multiple brain areas. Morphometric analysis of pre- and postsynaptic RGC structure revealed more than 50 structural RGC types with unique combinations of dendritic and axonal morphologies, exceeding current estimates of RGC diversity in vertebrates. These single-cell projection mapping data indicate that specific projection patterns are nonuniformly specified in the retina to generate retinotopically biased visual maps throughout the brain. The retinal projectome also successfully predicted a functional subdivision of the pretectum.



Our data indicate that RGC projection patterns are precisely coordinated to generate brain-area-specific visual representations originating from RGCs with distinct dendritic morphologies and topographic distributions.

title: Whole-Brain Activity Maps Reveal Stereotyped, Distributed Networks for Visuomotor Behavior
abstract: Most behaviors, even simple innate reflexes, are mediated by circuits of neurons spanning areas throughout the brain. However, in most cases, the distribution and dynamics of firing patterns of these neurons during behavior are not known. We imaged activity, with cellular resolution, throughout the whole brains of zebrafish performing the optokinetic response. We found a sparse, broadly distributed network that has an elaborate but ordered pattern, with a bilaterally symmetrical organization. Activity patterns fell into distinct clusters reflecting sensory and motor processing. By correlating neuronal responses with an array of sensory and motor variables, we find that the network can be clearly divided into distinct functional modules. Comparing aligned data from multiple fish, we find that the spatiotemporal activity dynamics and functional organization are highly stereotyped across individuals. These experiments systematically reveal the functional architecture of neural circuits underlying a sensorimotor behavior in a vertebrate brain.

title: The First Stage of Cardinal Direction Selectivity Is Localized to the Dendrites of Retinal Ganglion Cells
abstract: Inferring the direction of image motion is a fundamental component of visual computation and essential for visually guided behavior. In the retina, the direction of image motion is computed in four cardinal directions, but it is not known at which circuit location along the flow of visual information the cardinal direction selectivity first appears. We recorded the concerted activity of the neuronal circuit elements of single direction-selective (DS) retinal ganglion cells at subcellular resolution by combining GCaMP3-functionalized transsynaptic viral tracing and two-photon imaging. While the visually evoked activity of the dendritic segments of the DS cells were direction selective, direction-selective activity was absent in the axon terminals of bipolar cells. Furthermore, the glutamate input to DS cells, recorded using a genetically encoded glutamate sensor, also lacked direction selectivity. Therefore, the first stage in which extraction of a cardinal motion direction occurs is the dendrites of DS cells.