Projection Targeting with Phototagging to Study the Structure and Function of Retinal Ganglion Cells.

Unlabelled: Visual information from the retina is sent to diverse targets throughout the brain by different retinal ganglion cells (RGCs). Much of our knowledge about the different RGC types and how they are routed to these brain targets is based on mice, largely due to the extensive library of genetically modified mouse lines. To alleviate the need for using genetically modified animal models for studying retinal projections, we developed a high-throughput approach called that combines retrograde viral labeling, optogenetic identification, functional characterization using multi-electrode arrays, and morphological analysis.

Decomposition of retinal ganglion cell electrical images for cell type and functional inference.

Identifying neuronal cell types and their biophysical properties based on their extracellular electrical features is a major challenge for experimental neuroscience and for the development of high-resolution brain-machine interfaces. One example is identification of retinal ganglion cell (RGC) types and their visual response properties, which is fundamental for developing future electronic implants that can restore vision.The electrical image (EI) of a RGC, or the mean spatio-temporal voltage footprint of its recorded spikes on a high-density electrode array, contains substantial information about its anatomical, morphological, and functional properties.

Functional organization and natural scene responses across mouse visual cortical areas revealed with encoding manifolds.

A challenge in sensory neuroscience is understanding how populations of neurons operate in concert to represent diverse stimuli. To meet this challenge, we have created "encoding manifolds" that reveal the overall responses of brain areas to diverse stimuli with the resolution of individual neurons and their response dynamics. Here we use encoding manifold to compare the population-level encoding of primary visual cortex (VISp) with five higher visual areas (VISam, VISal, VISpm, VISlm, and VISrl).

DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity.

Precision pharmacology aims to manipulate specific cellular interactions within complex tissues. In this pursuit, we introduce DART.2 (drug acutely restricted by tethering), a second-generation cell-specific pharmacology technology.

Local synaptic inhibition mediates cerebellar granule cell pattern separation and enables learned sensorimotor associations.

The cerebellar cortex has a key role in generating predictive sensorimotor associations. To do so, the granule cell layer is thought to establish unique sensorimotor representations for learning. However, how this is achieved and how granule cell population responses contribute to behavior have remained unclear.

Population encoding of stimulus features along the visual hierarchy.

The retina and primary visual cortex (V1) both exhibit diverse neural populations sensitive to diverse visual features. Yet it remains unclear how neural populations in each area partition stimulus space to span these features. One possibility is that neural populations are organized into discrete groups of neurons, with each group signaling a particular constellation of features.

GABAergic Inhibition Controls Receptive Field Size, Sensitivity, and Contrast Preference of Direction Selective Retinal Ganglion Cells Near the Threshold of Vision.

Information about motion is encoded by direction-selective retinal ganglion cells (DSGCs). These cells reliably transmit this information across a broad range of light levels, spanning moonlight to sunlight. Previous work indicates that adaptation to low light levels causes heterogeneous changes to the direction tuning of ON-OFF (oo)DSGCs and suggests that superior-preferring ON-OFF DSGCs (s-DSGCs) are biased toward detecting stimuli rather than precisely signaling direction.

Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss. This cell loss greatly diminishes vision, with most patients becoming legally blind. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention.

Decomposition of retinal ganglion cell electrical images for cell type and functional inference.

Objective: Identifying neuronal cell types and their biophysical properties based on their extracellular electrical features is a major challenge for experimental neuroscience and for the development of high-resolution brain-machine interfaces. One example is identification of retinal ganglion cell (RGC) types and their visual response properties, which is fundamental for developing future electronic implants that can restore vision.

Approach: The electrical image (EI) of a RGC, or the mean spatio-temporal voltage footprint of its recorded spikes on a high-density electrode array, contains substantial information about its anatomical, morphological, and functional properties.

Population encoding of stimulus features along the visual hierarchy.

The retina and primary visual cortex (V1) both exhibit diverse neural populations sensitive to diverse visual features. Yet it remains unclear how neural populations in each area partition stimulus space to span these features. One possibility is that neural populations are organized into discrete groups of neurons, with each group signaling a particular constellation of features.

Efficient coding, channel capacity, and the emergence of retinal mosaics.

Among the most striking features of retinal organization is the grouping of its output neurons, the retinal ganglion cells (RGCs), into a diversity of functional types. Each of these types exhibits a mosaic-like organization of receptive fields (RFs) that tiles the retina and visual space. Previous work has shown that many features of RGC organization, including the existence of ON and OFF cell types, the structure of spatial RFs, and their relative arrangement, can be predicted on the basis of efficient coding theory.

Large-scale interrogation of retinal cell functions by 1-photon light-sheet microscopy.

Visual processing in the retina depends on the collective activity of large ensembles of neurons organized in different layers. Current techniques for measuring activity of layer-specific neural ensembles rely on expensive pulsed infrared lasers to drive 2-photon activation of calcium-dependent fluorescent reporters. We present a 1-photon light-sheet imaging system that can measure the activity in hundreds of neurons in the retina over a large field of view while presenting visual stimuli.

Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss and eventual blindness. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilized a mouse model of retinitis pigmentosa capable of artificial genetic rescue.

Scalable Variational Inference for Low-Rank Spatiotemporal Receptive Fields.

An important problem in systems neuroscience is to characterize how a neuron integrates sensory inputs across space and time. The linear receptive field provides a mathematical characterization of this weighting function and is commonly used to quantify neural response properties and classify cell types. However, estimating receptive fields is difficult in settings with limited data and correlated or high-dimensional stimuli.

Cones and cone pathways remain functional in advanced retinal degeneration.

Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of daylight vision and high-acuity perception, is the most debilitating feature of the disease. To understand better why cones degenerate and how cone vision might be restored, we have made the first single-cell recordings of light responses from degenerating cones and retinal interneurons after most rods have died and cones have lost their outer-segment disk membranes and synaptic pedicles. We show that degenerating cones have functional cyclic-nucleotide-gated channels and can continue to give light responses, apparently produced by opsin localized either to small areas of organized membrane near the ciliary axoneme or distributed throughout the inner segment.

Neuroscience: Visual restoration with optogenetics.

Treating photoreceptor degenerative diseases is an exciting application of optogenetic technologies. However, there are significant challenges, such as producing normal visual signaling as the retina rewires in response to photoreceptor death. However, a new study shows remarkable functional stability in retinal circuits that can be engaged by optogenetics following photoreceptor loss.

An optical approach for mapping functional connectivity at single-cell resolution in brain circuits.

In the current issue of , Spampinato et al. demonstrate a multiplexed system combining holographic photo-stimulation and functional imaging that may offer a generalizable approach for revealing how signals interact in complex neural circuits.

Robust cone-mediated signaling persists late into rod photoreceptor degeneration.

Rod photoreceptor degeneration causes deterioration in the morphology and physiology of cone photoreceptors along with changes in retinal circuits. These changes could diminish visual signaling at cone-mediated light levels, thereby limiting the efficacy of treatments such as gene therapy for rescuing normal, cone-mediated vision. However, the impact of progressive rod death on cone-mediated signaling remains unclear.

Scene statistics and noise determine the relative arrangement of receptive field mosaics.

Many sensory systems utilize parallel ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways consist of ensembles or grids of ON and OFF detectors spanning sensory space. Yet, encoding by opponent pathways raises a question: How should grids of ON and OFF detectors be arranged to optimally encode natural stimuli? We investigated this question using a model of the retina guided by efficient coding theory.

High-resolution light-field microscopy with patterned illumination.

Light-field fluorescence microscopy can record large-scale population activity of neurons expressing genetically-encoded fluorescent indicators within volumes of tissue. Conventional light-field microscopy (LFM) suffers from poor lateral resolution when using wide-field illumination. Here, we demonstrate a structured-illumination light-field microscopy (SI-LFM) modality that enhances spatial resolution over the imaging volume.

Properties of multivesicular release from mouse rod photoreceptors support transmission of single-photon responses.

Vision under starlight requires rod photoreceptors to transduce and transmit single-photon responses to the visual system. Small single-photon voltage changes must therefore cause detectable reductions in glutamate release. We found that rods achieve this by employing mechanisms that enhance release regularity and its sensitivity to small voltage changes.

Inter-mosaic coordination of retinal receptive fields.

The output of the retina is organized into many detector grids, called 'mosaics', that signal different features of visual scenes to the brain. Each mosaic comprises a single type of retinal ganglion cell (RGC), whose receptive fields tile visual space. Many mosaics arise as pairs, signalling increments (ON) and decrements (OFF), respectively, of a particular visual feature.

Ignoring correlated activity causes a failure of retinal population codes.

From starlight to sunlight, adaptation alters retinal output, changing both the signal and noise among populations of retinal ganglion cells (RGCs). Here we determine how these light level-dependent changes impact decoding of retinal output, testing the importance of accounting for RGC noise correlations to optimally read out retinal activity. We find that at moonlight conditions, correlated noise is greater and assuming independent noise severely diminishes decoding performance.