Probing and predicting ganglion cell responses to smooth electrical stimulation in healthy and blind mouse retina

ABSTRACTRetinal implants are used to replace lost photoreceptors in blind patients suffering from retinopathies such as retinitis pigmentosa. Patients wearing implants regain some rudimentary visual function. However, it is severely limited compared to normal vision because non-physiological stimulation strategies fail to selectively activate different retinal pathways at sufficient spatial and temporal resolution. The development of improved stimulation strategies is rendered difficult by the large space of potential stimuli. Here we systematically explore a subspace of potential stimuli by electrically stimulating healthy and blind mouse retina in epiretinal configuration using smooth Gaussian white noise delivered by a high-density CMOS-based microelectrode array. We identify linear filters of retinal ganglion cells (RGCs) by fitting a linear-nonlinear-Poisson (LNP) model. Our stimulus evokes fast, reliable, and spatially confined spiking responses in RGC which are accurately predicted by the LNP model. Furthermore, we find diverse shapes of linear filters in the linear stage of the model, suggesting diverse preferred electrical stimuli of RGCs. Our smooth electrical stimulus could provide a starting point of a model-guided search for improved stimuli for retinal prosthetics.

Download Full-text

Subretinal electrical stimulation reveals intact network activity in the blind mouse retina

Journal of Neurophysiology ◽

10.1152/jn.01095.2015 ◽

2016 ◽

Vol 116 (4) ◽

pp. 1684-1693 ◽

Cited By ~ 15

Author(s):

Henrike Stutzki ◽

Florian Helmhold ◽

Max Eickenscheidt ◽

Günther Zeck

Keyword(s):

Microelectrode Array ◽

Vision Loss ◽

Ex Vivo ◽

Network Activity ◽

Mouse Retina ◽

Retinal Circuitry ◽

Vision Restoration ◽

Restoration Strategies ◽

Electrical Stimuli ◽

Stimulation Of

Retinal degeneration ( rd) leads to progressive photoreceptor cell death, resulting in vision loss. Stimulation of the inner-retinal neurons by neuroprosthetic implants is one of the clinically approved vision-restoration strategies, providing basic visual percepts to blind patients. However, little is understood as to what degree the degenerating retinal circuitry and the resulting aberrant hyperactivity may prevent the stimulation of physiological electrical activity. Therefore, we electrically stimulated ex vivo retinas from wild-type ( wt; C57BL/6J) and blind ( rd10 and rd1) mice using an implantable subretinal microchip and simultaneously recorded and analyzed the retinal ganglion cell (RGC) output with a flexible microelectrode array. We found that subretinal anodal stimulation of the rd10 retina and wt retina evoked similar spatiotemporal RGC-spiking patterns. In both retinas, electrically stimulated ON and a small percentage of OFF RGC responses were detected. The spatial selectivity of the retinal network to electrical stimuli reveals an intact underlying network with a median receptive-field center of 350 μm in both retinas. An antagonistic surround is activated by stimulation with large electrode fields. However, in rd10 and to a higher percentage, in rd1 retinas, rhythmic and spatially unconfined RGC patterns were evoked by anodal or by cathodal electrical stimuli. Our findings demonstrate that the surviving retinal circuitry in photoreceptor-degenerated retinas is preserved in a way allowing for the stimulation of temporally diverse and spatially confined RGC activity. Future vision restoration strategies can build on these results but need to avoid evoking the easily inducible rhythmic activity in some retinal circuits.

Download Full-text

Bipolar cell pathways for color vision in non-primate dichromats

Visual Neuroscience ◽

10.1017/s0952523810000271 ◽

2010 ◽

Vol 28 (1) ◽

pp. 51-60 ◽

Cited By ~ 26

Author(s):

CHRISTIAN PULLER ◽

SILKE HAVERKAMP

Keyword(s):

Color Vision ◽

Bipolar Cell ◽

Ganglion Cells ◽

Color Discrimination ◽

Model Systems ◽

Retinal Ganglion ◽

Retinal Pathways ◽

Retinal Information Processing ◽

Cone Opsins ◽

Retinal Information

AbstractColor vision in mammals is based on the expression of at least two cone opsins that are sensitive to different wavelengths of light. Furthermore, retinal pathways conveying color-opponent signals are required for color discrimination. Most of the primates are trichromats, and “color-coded channels” of their retinas are unveiled to a large extent. In contrast, knowledge of cone-selective pathways in nonprimate dichromats is only slowly emerging, although retinas of dichromats like mice or rats are extensively studied as model systems for retinal information processing. Here, we review recent progress of research on color-coded pathways in nonprimate dichromats to identify differences or similarities between di- and trichromatic mammals. In addition, we applied immunohistochemical methods and confocal microscopy to retinas of different species and present data on their neuronal properties, which are expected to contribute to color vision. Basic neuronal features such as the “blue cone bipolar cell” exist in every species investigated so far. Moreover, there is increasing evidence for chromatic OFF channels in dichromats and retinal ganglion cells that relay color-opponent signals to the brain. In conclusion, di- and trichromats share similar retinal pathways for color transmission and processing.

Download Full-text

Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact

eLife ◽

10.7554/elife.34241 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 13

Author(s):

Thomas A Ray ◽

Suva Roy ◽

Christopher Kozlowski ◽

Jingjing Wang ◽

Jon Cafaro ◽

...

Keyword(s):

Synapse Formation ◽

Ganglion Cells ◽

Plexiform Layer ◽

Surface Protein ◽

Amacrine Cells ◽

Direction Selectivity ◽

Mouse Retina ◽

Inner Plexiform Layer ◽

Starburst Amacrine Cells ◽

Developing Neurons

A common strategy by which developing neurons locate their synaptic partners is through projections to circuit-specific neuropil sublayers. Once established, sublayers serve as a substrate for selective synapse formation, but how sublayers arise during neurodevelopment remains unknown. Here, we identify the earliest events that initiate formation of the direction-selective circuit in the inner plexiform layer of mouse retina. We demonstrate that radially migrating newborn starburst amacrine cells establish homotypic contacts on arrival at the inner retina. These contacts, mediated by the cell-surface protein MEGF10, trigger neuropil innervation resulting in generation of two sublayers comprising starburst-cell dendrites. This dendritic scaffold then recruits projections from circuit partners. Abolishing MEGF10-mediated contacts profoundly delays and ultimately disrupts sublayer formation, leading to broader direction tuning and weaker direction-selectivity in retinal ganglion cells. Our findings reveal a mechanism by which differentiating neurons transition from migratory to mature morphology, and highlight this mechanism’s importance in forming circuit-specific sublayers.

Download Full-text

Transient Responses of Rabbit Retinal Ganglion Cells to Photic and Electrical Stimuli

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100026044 ◽

1976 ◽

Vol 3 (1) ◽

pp. 73-79 ◽

Cited By ~ 7

Author(s):

S. Molotchnikoff

Keyword(s):

Receptive Field ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Electrical Activation ◽

Retinal Ganglion ◽

Transient Responses ◽

Long Latency ◽

Latency Response ◽

Electrical Stimuli ◽

Inhibitory Period

SUMMARY:The relationships between the center and the surround of the receptive field of the rabbit retinal ganglion cell were investigated. This was done by coupling localized light spots and electrical activation of the retina and by analyzing the time of the excitatory and inhibitory periods. The responsiveness to the electrical transretinal pulse revealed a) that ON stimulation in OFF-center cells and OFF stimulation in ON-center cells, elicited a primary period of inhibition with a short latency; b) the long latency response of surround stimulation was not preceded by an inhibitory period unless the center was simultaneously stimulated in the same direction; c) a transient response to a stationary spot of light is followed by a period of inhibition. These results are discussed in relation to the known cellular retinal networks.

Download Full-text

The anemia of the newborn induces erythropoietin expression in the developing mouse retina

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00108.2010 ◽

2010 ◽

Vol 299 (1) ◽

pp. R111-R118 ◽

Cited By ~ 5

Author(s):

N. Scheerer ◽

N. Dünker ◽

S. Imagawa ◽

M. Yamamoto ◽

N. Suzuki ◽

...

Keyword(s):

Transforming Growth Factor ◽

Fluorescent Protein ◽

Ganglion Cells ◽

Retinal Development ◽

Transforming Growth Factor Β ◽

Neuroprotective Activity ◽

Mouse Retina ◽

Mrna Levels ◽

Neuroprotective Effects

The hematopoietic hormone erythropoietin (Epo), regularly produced by the kidneys and the liver, is also expressed in neuronal tissue, where it has been found to mediate paracrine neuroprotective effects. In most studies exploring the rescue effects of Epo, apoptosis was exogenously induced by different cell death stimuli. Herein, we set out to study the expression and function of Epo in physiologically occurring apoptosis in a model of retinal development. We made use of an organotypic retinal wholemount culture system that resembles the physiological in vivo situation with cell connections still retained. Epo mRNA expression in the retina, liver, and kidney showed a significant increase during early development, coinciding with the anemia of the newborn. In the retina of Epo-green fluorescent protein transgenic mice, Epo-expressing cells were identified and found to be distributed in the retinal ganglion cell layer. Treatment of retinal wholemount cultures with recombinant Epo resulted in a significant decrease of apoptotic ganglion cells as well as photoreceptor cells throughout retinal development. Moreover, transforming growth factor-β-induced apoptosis was completely antagonized by Epo when both factors were simultaneously applied. Investigations on the signaling pathway revealed a decrease in Bax mRNA levels in Epo-treated retinal cells. We conclude that Epo exerts wide and prolonged neuroprotective activity in physiologically occurring apoptosis and thus contributes to proper retinal development.

Download Full-text

Intrinsically Self-renewing Neuroprogenitors From the A/J Mouse Spiral Ganglion as Virtually Unlimited Source of Mature Auditory Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.599152 ◽

2020 ◽

Vol 14 ◽

Author(s):

Francis Rousset ◽

Vivianne B. C. Kokje ◽

Rebecca Sipione ◽

Dominik Schmidbauer ◽

German Nacher-Soler ◽

...

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Progenitor Cells ◽

Ganglion Cells ◽

Spiral Ganglion ◽

Specific Cell ◽

Auditory Neurons ◽

Self Renewal ◽

Starting Point ◽

Ganglion Neurons

Nearly 460 million individuals are affected by sensorineural hearing loss (SNHL), one of the most common human sensory disorders. In mammals, hearing loss is permanent due to the lack of efficient regenerative capacity of the sensory epithelia and spiral ganglion neurons (SGN). Sphere-forming progenitor cells can be isolated from the mammalian inner ear and give rise to inner ear specific cell types in vitro. However, the self-renewing capacities of auditory progenitor cells from the sensory and neuronal compartment are limited to few passages, even after adding powerful growth factor cocktails. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit robust intrinsic self-renewal properties beyond 40 passages. At any passage or freezing–thawing cycle, phoenix spheres can be efficiently differentiated into mature spiral ganglion cells by withdrawing growth factors. The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.

Download Full-text

The Interplay between Retinal Pathways of Cholesterol Output and Its Effects on Mouse Retina

Biomolecules ◽

10.3390/biom9120867 ◽

2019 ◽

Vol 9 (12) ◽

pp. 867 ◽

Cited By ~ 3

Author(s):

Alexey M. Petrov ◽

Artem A. Astafev ◽

Natalia Mast ◽

Aicha Saadane ◽

Nicole El-Darzi ◽

...

Keyword(s):

Energy Homeostasis ◽

Cytochromes P450 ◽

Cholesterol Biosynthesis ◽

Mouse Retina ◽

Minor Role ◽

Compensatory Mechanisms ◽

Cholesterol Levels ◽

Transmission Electron ◽

Retinal Pathways ◽

A Minor

In mammalian retina, cholesterol excess is mainly metabolized to oxysterols by cytochromes P450 27A1 (CYP27A1) and 46A1 (CYP46A1) or removed on lipoprotein particles containing apolipoprotein E (APOE). In contrast, esterification by sterol-O-acyltransferase 1 (SOAT) plays only a minor role in this process. Accordingly, retinal cholesterol levels are unchanged in Soat1−/− mice but are increased in Cyp27a1−/−Cyp46a1−/− and Apoe−/− mice. Herein, we characterized Cyp27a1−/−Cyp46a1−/−Soat1−/− and Cyp27a1−/−Cyp46a1−/−Apoe−/− mice. In the former, retinal cholesterol levels, anatomical gross structure, and vasculature were normal, yet the electroretinographic responses were impaired. Conversely, in Cyp27a1−/−Cyp46a1−/−Apoe−/− mice, retinal cholesterol levels were increased while anatomical structure and vasculature were unaffected with only male mice showing a decrease in electroretinographic responses. Sterol profiling, qRT-PCR, proteomics, and transmission electron microscopy mapped potential compensatory mechanisms in the Cyp27a1−/−Cyp46a1−/−Soat1−/− and Cyp27a1−/−Cyp46a1−/−Apoe−/− retina. These included decreased cholesterol biosynthesis along with enhanced formation of intra- and extracellular vesicles, possibly a reserve mechanism for lowering retinal cholesterol. In addition, there was altered abundance of proteins in Cyp27a1−/−Cyp46a1−/−Soat1−/− mice that can affect photoreceptor function, survival, and retinal energy homeostasis (glucose and fatty acid metabolism). Therefore, the levels of retinal cholesterol do not seem to predict retinal abnormalities, and it is rather the network of compensatory mechanisms that appears to determine retinal phenotype.

Download Full-text

Inverse molecular design using machine learning: Generative models for matter engineering

Science ◽

10.1126/science.aat2663 ◽

2018 ◽

Vol 361 (6400) ◽

pp. 360-365 ◽

Cited By ~ 297

Author(s):

Benjamin Sanchez-Lengeling ◽

Alán Aspuru-Guzik

Keyword(s):

Machine Learning ◽

Technological Progress ◽

Rational Design ◽

Molecular Design ◽

Generative Models ◽

New Materials ◽

Large Space ◽

Starting Point ◽

Rapid Pace ◽

Synthetic Routes

The discovery of new materials can bring enormous societal and technological progress. In this context, exploring completely the large space of potential materials is computationally intractable. Here, we review methods for achieving inverse design, which aims to discover tailored materials from the starting point of a particular desired functionality. Recent advances from the rapidly growing field of artificial intelligence, mostly from the subfield of machine learning, have resulted in a fertile exchange of ideas, where approaches to inverse molecular design are being proposed and employed at a rapid pace. Among these, deep generative models have been applied to numerous classes of materials: rational design of prospective drugs, synthetic routes to organic compounds, and optimization of photovoltaics and redox flow batteries, as well as a variety of other solid-state materials.

Download Full-text