A fovea like representation of space in mouse visual cortex

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By IMPC

Published 30th October 2018

SfN 2018 Annual Meeting – research using mouse models

Guest post by Matthew W. Self – Netherlands Institute for Neuroscience, Amsterdam

The human retina has a small region called the ‘fovea’ in which all the cone photoreceptors are packed closely together. The fovea provides by far the highest spatial resolution of the retina and we use this region of the retina for all our daytime detailed vision (e.g. reading, recognizing faces). Humans and other primates move their eyes around 3 times per second to point their foveas at interesting locations in the visual world. We essentially build-up a detailed view of the world by ‘scanning’ it with our foveas.

Recently interest in mouse vision has exploded as scientists put to use the sophisticated genetic tools that are available in mice to try to understand vision. The kind of rapid eye-movement scanning found in primates is largely absent from mice. The mouse retina doesn’t have a fovea and is thought to be uniformly sensitive to light. The question then arises whether mice have any spatial biases in their vision – do they have a ‘hot-spot’ in which vision is more detailed, as we do?

We addressed this question by mapping the responses of the visual cortex of mice to visual images. We used a mouse genetic line in which a fluorescent calcium indicator (GCaMP) is present in all neurons in cortex. GCaMP increases in fluorescence when cells become active, allowing us to map out which parts of the brain respond to different regions of the visual world under a microscope. To measure the resolution of vision we measured the ‘population receptive field’ or pRF at different points in the brain. The size of the pRF tells us how accurate the representation of the visual world is; brain regions with large pRFs have only a coarse representation of space, whereas regions with small pRFs have a very detailed view. Surprisingly we found that mouse visual cortex contains a region in which the pRFs are 50% smaller than the rest of the brain. In this region brain cells respond to more closely packed parts of the visual world and can therefore build up a more detailed picture of the world. This region responded to visual stimuli placed directly in front of the mouse and slightly above it, suggesting that mice, like primates, also have a visual hot-spot that they could use to see the world in more detail. This result provides more support for the use of the mouse as a model of human vision.

SfN poster: Sunday 4th, 13:00 – 17:00; board no. CC9 219.18

15 novel genes related to retinal function have been found in research published by Dr. Melanie Samuel and colleagues in Cell Reports. The research reveals previously unknown retinal regulators which will help expand our understanding of the genetic landscape that regulates retinal function and uncover how genes are involved in vision loss and disease.

The retina processes visual information from the world around us and relays it to the brain. This sensory circuit is complex but highly ordered. It is comprised of distinct neural layers, and each layer has an array of different neuron types. These neurons are supported by a rich vascular system.

Vision defects globally affect around 253 million people. Such diseases can arise from disruptions to different parts of the visual circuit. For example, vascular changes can be a sign of diabetic neuropathy and defects in light-sensing photoreceptors can lead to retinitis pigmentosa. Yet many of the genes and mechanisms responsible for vision loss remain unknown.

This schematic outlines the complex circuitry in the retina. Each layer contains different neuron types that synapse onto the layer below, from the top layer that detects light to the bottom layer where axons transmit visual information to the brain.

In this research, Dr. Samuel and colleagues selected a sub-set of animal lines from the IMPC in which individual genes had been modified to eliminate their function. They then developed a specialized pipeline of high-throughput retinal screening to examine the role of these genes in more detail. The criteria for selecting candidate genes included those with human orthologues and those with expression in the retina or brain.

The availability of broad based and comprehensive phenotyping data from the IMPC helped researchers focus their search for genes relating to the retina.

In-depth analysis included examining gene expression, synapse organisation, cell morphology and the patterning of blood vessels.

Of the 102 mutant lines analysed, 16 genes were identified that regulated retinal function, 15 of these were novel and not previously associated with retina function.

A range of diverse observations were seen. Lines were found with altered vessel density and branching, disrupted synaptic organisation and neuron loss.

Here, analysis of blood vessels in the retina shows abnormalities including decreased vessel number (Rnf10) and tortuosity (Adsl) in comparison to the wild type image on the left hand side.

Here, analysis of blood vessels in the retina shows abnormalities including decreased vessel number (Rnf10) and tortuosity (Adsl) in comparison to the wild type image on the left hand side.

Many of the genes displayed a wide range of cellular functions and may also be important elsewhere in the body. Data available through the IMPC database supported this, as many of the lines had additional phenotypes, including body composition and central nervous system regulation deficits (suggested by altered body composition and open field tests, respectively).

“The results from the study highlight the kind of discoveries that are possible through harnessing the remarkable data and resources available from the IMPC.  With these efforts, we hope to continue to map the compendium of genes that regulate the retina and the brain so that we can make progress in treating human neural diseases,” said corresponding author, Dr. Samuel, assistant professor of neuroscience and the Huffington Center on Aging at Baylor College of Medicine.

To read the research click here

Interested in learning more? Dr. Samuel recently told us about her lab’s research in the video ‘What makes us unique? Exploring the role of genetics and neural function’


Other contributors to this work include Nicholas E. Albrecht, Jonathan Alevy, Danye Jiang, Courtney A. Burger, Brian I. Liu, Fenge Li, Julia Wang, Seon-Young Kim, Chih-Wei Hsu, Sowmya Kalaga, Uchechukwu Udensi, Chinwe Asomugha, Ritu Bohat, Angelina Gaspero, Mónica J. Justice, Peter D. Westenskow, Shinya Yamamoto and John R. Seavitt. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, and the Hospital for Sick Children, Toronto.

 

Researchers funded by the National Eye Institute (NEI) have reversed congenital blindness in mice by changing supportive cells in the retina called Müller glia into rod photoreceptors. The findings advance efforts toward regenerative therapies for blinding diseases such as age-related macular degeneration and retinitis pigmentosa. A report of the findings appears online today in Nature. NEI is part of the National Institutes of Health.

“This is the first report of scientists reprogramming Müller glia to become functional rod photoreceptors in the mammalian retina,” said Thomas N. Greenwell, Ph.D., NEI program director for retinal neuroscience. “Rods allow us to see in low light, but they may also help preserve cone photoreceptors, which are important for color vision and high visual acuity. Cones tend to die in later-stage eye diseases. If rods can be regenerated from inside the eye, this might be a strategy for treating diseases of the eye that affect photoreceptors.”

Photoreceptors are light-sensitive cells in the retina in the back of the eye that signal the brain when activated. In mammals, including mice and humans, photoreceptors fail to regenerate on their own. Like most neurons, once mature they don’t divide.

Scientists have long studied the regenerative potential of Müller glia because in other species, such as zebrafish, they divide in response to injury and can turn into photoreceptors and other retinal neurons. The zebrafish can thus regain vision after severe retinal injury. In the lab, however, scientists can coax mammalian Müller glia to behave more like they do in the fish. But it requires injuring the tissue.

“From a practical standpoint, if you’re trying to regenerate the retina to restore a person’s vision, it is counterproductive to injure it first to activate the Müller glia,” said Bo Chen, Ph.D., associate professor of ophthalmology and director of the Ocular Stem Cell Program at the Icahn School of Medicine at Mount Sinai, New York.

“We wanted to see if we could program Müller glia to become rod photoreceptors in a living mouse without having to injure its retina,” said Chen, the study’s lead investigator.

In the first phase of a two-stage reprogramming process Chen’s team spurred Müller glia in normal mice to divide by injecting their eyes with a gene to turn on a protein called beta-catenin. Weeks later, they injected the mice’s eyes with factors that encouraged the newly divided cells to develop into rod photoreceptors.

The researchers used microscopy to visually track the newly formed cells. They found that the newly formed rod photoreceptors looked structurally no different from real photoreceptors. In addition, synaptic structures that allow the rods to communicate with other types of neurons within the retina had also formed. To determine whether the Müller glia-derived rod photoreceptors were functional, they tested the treatment in mice with congenital blindness, which meant that they were born without functional rod photoreceptors.

In the treated mice that were born blind, Müller glia-derived rods developed just as effectively as they had in normal mice. Functionally, they confirmed that the newly formed rods were communicating with other types of retinal neurons across synapses. Furthermore, light responses recorded from retinal ganglion cells–neurons that carry signals from photoreceptors to the brain–and measurements of brain activity confirmed that the newly-formed rods were in fact integrating in the visual pathway circuitry, from the retina to the primary visual cortex in the brain.

Chen’s lab is conducting behavioral studies to determine whether the mice have regained the ability to perform visual tasks such as a water maze task. Chen also plans to see if the technique works on cultured human retinal tissue.

 

Research article: Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas

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By IMPC

Published 16th August 2018

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