Toward a computer model that predicts the outcome of eye diseases

June 22, 2018, Institute of Molecular and Clinical Ophthalmology Basel (IOB)
Top view of horizontal cells: Retinal horizontal cells express a chemogenetic channel after systemic AAV infection. Cell bodies of horizontal cells are labeled in red; chemogenetic channels are labeled in yellow. Strong expression of the chemogenetic channel in the entire horizontal cell network allowed us to reversibly and efficiently perturb the activity of all horizontal cells throughout the retina, which had not been possible before. The image was obtained using a confocal microscope. Credit: Institute of Molecular and Clinical Ophthalmology Basel (IOB)

The eye hosts a powerful biological computer, the retina. Understanding how the retina transforms images from the outside world into signals that the brain can interpret would not only result in insights into brain computations, but could also be useful for medicine. As machine learning and artificial intelligence advance, eye diseases will soon be described in terms of the perturbations of computations performed by the retina. Do we have enough knowledge of retinal circuits to understand how a perturbation will affect the computations the retina performs? An international team of scientists has addressed this question in a set of experiments combining genetics, viral and molecular tools, high-density microelectrode arrays, and computer models. The work shows that their newly developed model of the retina can predict with high precision the outcome of a defined perturbation. The work is an important step towards a computer model of the retina that can predict the outcome of retinal diseases.

Vision starts in the , where photoreceptor cells capture the light that falls on the eye and transduce it into neuronal activity. Ganglion cells, the output neurons of the retina, then send the visual signals to the brain. However, the retina is much more than just a camera and a cable: Between photoreceptors and , the retina contains intricate neuronal circuits, which are assembled from many different neuronal cell types. These circuits process the incoming signals in a complex way and extract important features of the visual scene. At the output level of the retina, the computations of the retinal circuits result in ~30 different neuronal representations of the visual scene: these are then transmitted in parallel to the brain. Thus, the retina acts like a powerful computing device, shaping visual representation in a profound way.

To understand the mechanisms of vision and to predict the outcomes of visual diseases, it is essential to understand how the ~30 retinal output channels represent the visual world, and how their different functional properties arise from the architecture of the retinal . To address this question, a team of scientists from the Friedrich Miescher Institute (FMI), the Institute of Molecular and Clinical Ophthalmology Basel (IOB), ETH Zurich, and the Ecole Normale Supérieure perturbed a specific retinal circuit element while studying how this perturbation changes the functional properties of the different retinal output channels.

Antonia Drinnenberg, a former graduate student from Botond Roska's group, and lead author of the paper, developed a method to control the activity of . Horizontal cells are a retinal circuit element that provides feedback inhibition at the first visual synapse between photoreceptors and bipolar cells. The method, which involved a specific set of viruses, transgenic mice, and engineered ligand-gated ion channels, allowed her to switch the feedback at the first visual synapse on and off. To measure the effects of this perturbation in the retinal output, she used high density microelectrode arrays developed in Andreas Hierlemann's group and recorded the electrical signals of hundreds of ganglion cells simultaneously. Surprisingly, the perturbation caused a large set of different changes in the output of the retina. "We were astonished by the variety of effects that we observed due to the perturbation of a single, well-defined circuit element," says Drinnenberg. "At first, we suspected that technical issues might underlie this variety." However, after measuring the signals in thousands of ganglion cells and in defined retinal output channels, it became clear that the variety in the horizontal cell contributions that were measured must arise from the specific architecture of the retinal circuitry.

How can a single element of the retinal circuitry lead to such a variety of effects? Felix Franke, co-first author of the paper, and Rava A. da Silveira, a senior author, built a computer model of the retina. The model simulated the different pathways that the signal can take through the retina, and enabled the team to investigate if our current understanding of the retinal circuitry could account for the effects they observed during the experiments. While studying the behavior of the model, the researchers found that the model could reproduce the entire set of changes that they had measured experimentally. In addition, the team found that the model made five further predictions about the role of horizontal , which they had previously not seen in the data. "We were surprised to see that the model went further than what we had in mind at the time we built it," says Franke. "All additional predictions turned out to be correct when we conducted additional experiments to test them."

"One way to test our understanding of the retina is to perturb one of its elements, measure all the outputs, and see if our 'understanding', which is a model, can predict the observed changes," explains da Silveira. "The next step is to use the to predict the outcome of eye diseases," adds Roska.

Explore further: Computations of visual motion in the brain

More information: Antonia Drinnenberg et al. How Diverse Retinal Functions Arise from Feedback at the First Visual Synapse, Neuron (2018). DOI: 10.1016/j.neuron.2018.06.001

Related Stories

Computations of visual motion in the brain

May 22, 2017
Botond Roska and his group at the FMI have elucidated how the retina and the visual cortex work together in visual motion perception. They found that cortical cells, which respond preferentially to backward image motion, ...

Microglia protect sensory cells needed for vision after retinal detachment

June 18, 2018
A research team at Massachusetts Eye and Ear has shown that microglia, the primary immune cells of the brain and retina, play a protective role in response to retinal detachment. Retinal detachment and subsequent degeneration ...

New insights into how the retina processes orientation

February 26, 2018
In a study published in Nature Communications, Northwestern Medicine scientists detail the discovery of two types of cells in the retina that determine horizontal or vertical orientation, and demonstrated for the first time ...

Researchers shed light on how our eyes process visual cues

June 7, 2017
The mystery of how human eyes compute the direction of moving light has been made clearer by scientists at The University of Queensland.

Early retina cell changes in glaucoma identified

February 11, 2015
Glaucoma, the second leading cause of blindness, usually stems from elevated eye pressure, which in turn damages and destroys specialized neurons in the eye known as retinal ganglion cells. To better understand these cellular ...

Transcriptional barcoding of retinal cells identifies disease target cells

January 23, 2012
(Medical Xpress) -- By developing a large scale gene expression map for retinal cell types, FMI Neurobiologists have been able to identify the cells in the retina, where the genes causing retinal diseases specifically act. ...

Recommended for you

Scientists combine technologies to view the retina in unprecedented detail

November 14, 2018
By combining two imaging modalities—adaptive optics and angiography—investigators at the National Eye Institute (NEI) can see live neurons, epithelial cells, and blood vessels deep in the eye's light-sensing retina. Resolving ...

Eyepatch with dissolvable needles used to treat eye disease

November 12, 2018
A team of researchers affiliated with several institutions in Singapore has developed an eyepatch with dissolvable needles for use in treating eye diseases. In their paper published in the journal Nature Communications, the ...

Calcifications in the eye increase risk for progression to advanced AMD by more than six times

November 8, 2018
Calcified nodules in the retina are associated with progression to late stages of age-related macular degeneration (AMD). Experts from Queen's University Belfast, working in partnership with the University of Alabama of Birmingham ...

Traditional glaucoma test can miss severity of disease

November 8, 2018
The most common tests for glaucoma can underestimate the severity of the condition by not detecting the presence of central vision loss, according to a new Columbia University study.

New contact lens to treat eye injuries

November 5, 2018
A new therapeutic contact lens that acts as a bandage for eye surface injuries being developed by QUT researchers could soon fast track the healing of previously difficult to treat corneal wounds.

New study offers hope for patients suffering from a rare form of blindness

November 1, 2018
A new form of therapy may halt or even reverse a form of progressive vision loss that, until now, has inevitably led to blindness. This hyper-targeted approach offers hope to individuals living with spinocerebellar ataxia ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.