Week in Review: Number 30

Regenerative Therapies for Glaucoma and Neurotrauma
Researchers will begin two translational studies aimed at restoring vision by regenerating the photoreceptors and retinal ganglion cells (RGCs) of the retina. Vision loss through death of RGCs is irreversible; however, cell replacement therapy could offer a potential solution for vision restoration. The projects will span five years and will involve labs at multiple institutions. Some of the researchers will establish and validate a squirrel monkey model of glaucoma. One of the authors explains, “We hope to develop systems that are closer to human visual anatomy, function and disease than current models...Rodent models are limited by critical differences in retinal physiology, and proof of concept in non-human primates would greatly increase confidence and aid in therapeutic development before moving to human testing.” Others will study models of glaucoma and neurotrauma in tree shrews, which they say have features that are relevant to humans. According to the researchers, studying both models of glaucoma and neurotrauma will provide more nuanced information, since retinal environments and cell survivability may differ between the two conditions. For example, glaucoma, being a more slowly progressing disease than neurotrauma, has a wider window in which transplantation of stem cells may be effective. Some of the researchers will focus on developing and characterizing pluripotent stem cells that can be converted into either eye organoids or directly to RGCs, and others will quantify changes in cytokine levels, glial reactivity, axon degeneration and RGC death over time. The project aims to tie the various studies together in the context of studying RGC transplant: differentiation, migration, local integration and synapse formation, growth down the optic nerve, and targeting to distal brain nuclei. The investigators from the various institutions plan to meet several times a year to encourage collaboration.

Cooking with Coal or Wood is Associated with Increased Risk of Ocular Surface Diseases
A population-based cohort study involving nearly half a million people in China found a clear correlation between cooking with solid fuels, such as coal or wood, and an increased risk of eye diseases. The data was collected from the China Kadoorie Biobank, whose study participants completed questionnaires about their cooking habits, then were tracked for hospital admissions of major eye diseases over a ten-year follow-up period. The data showed 4,877 cases of conjunctiva disorders, 13,408 cases of cataracts, 1,583 disorders of the sclera, cornea, iris and ciliary body (DSCIC), and 1,534 cases of glaucoma among the study participants. After accounting for factors such as age, sex, location of residence, and level of education, the results showed that long-term use of solid fuels for cooking was associated with 32% higher risk of conjunctivitis, 17% higher risk of cataracts, and 35% higher risk of DSCIC compared with those who cooked using clean fuels such as electricity or gas. Despite a few cases of glaucoma in the sample, there was no association between solid fuels use and increased risk of glaucoma. There was no difference of risk between using coal or wood for the other eye diseases, and no difference between cooking with or without cookstove ventilation (including chimneys). Furthermore, people who switched from solid fuels to clean fuels exhibited lower elevated risk. The lead author of the study explains, "The increased risks may be caused by exposure to high levels of fine particulate matter (PM2.5) and carbon monoxide, which can damage the eye surface and cause inflammation." They suggest that there was no association with increased risk for glaucoma because it is a disease that affects internal eye structures rather than the eye surface. With regard to practical applications, the senior author of the study comments, "Switching to clean fuels appeared to mitigate the risks, underscoring the global health importance of promoting universal access to clean fuels." Additionally, the study highlights that eye problems can result from a variety of factors, including environmental factors as seen in this study, and raises awareness about reducing avoidable causes and increasing access to health services.

Topographic Offset of Human Gaze from the Fovea
Unlike the photosensitive pixels of a camera, with which the human retina is often analogized, the photoreceptors of the eye, rods and cones, vary in size and spacing. Despite the large variability in foveal topography between individuals, however, there is surprising precision with which fixation is repeatedly directed to a small cluster of cones in the foveola, according to a new study. As part of a doctoral thesis, the study suggests that when we fixate an object, its image is shifted slightly nasally and upwards from the cellular peak at the fovea, contrary to the general assumption. This finding was observed in both eyes of 20 study participants and was made possible by technological and methodological advances over the past two decades, since the observed image shifts were very small. On average about 5 minutes of arc of visual angle, the shift is mirrored between the two eyes. Specifically, the researchers used a laser-based adaptive optics ophthalmoscope to directly see the individual cones in the eyes of the participants and see exactly which cells were used to fixate an object. According to the study's first author, "The offsets were a little larger for some and smaller for others; yet the direction was always the same, and symmetrically so between the two eyes. We also found that same spot when we repeated the measurement a year later." She speculates that the paradox is an adaptation for binocular vision, explaining, "When we look at horizontal surfaces, such as the floor, objects above fixation are farther away...Objects located higher appear a little smaller. Shifting our gaze in that fashion might enlarge the area of the visual field that is seen sharply." The researchers think the functional link between the cellular mosaic of the fovea and visual behavior can help to develop cell-targeted vision testing to better understand health and disease.

Predictive Motion Encoding Begins in the Retina
Predictive motion encoding is an aspect of visually guided behavior that allows animals to estimate the trajectory of moving objects. New research shows that information to predict the path of a moving object is generated at the level of the retinal ganglion cells well before the information is relayed to the visual cortex. To study how this happens, the researchers projected patterns of approaching or receding objects (i.e., whether they appeared to be moving either away from or toward the retina) and recorded the signals generated by the ganglion cells in response to the movements, analyzing the signals for patterns reflective of predictive motion encoding. The researchers then compared the performance of the ganglion cells to computer programs created to solve such problems, and found the the retinal ganglion cells were nearly as effective as the computer programs at transmitting predictive information. The authors state, "We report here that four of the parallel output pathways in the primate retina encode predictive motion information, and this encoding occurs for several classes of spatiotemporal correlation that are found in natural vision...[T]hese neural circuit mechanisms efficiently separate predictive information from nonpredictive information during the encoding process." They speculate that the predictive information is made possible by crosstalk among the bipolar cells upstream from the retinal ganglion cells. When one bipolar cell receives an excitatory signal from the photoreceptors upstream from it, in addition to relaying that information to the retinal ganglion cells, it also relays some of the excitatory signal to adjacent bipolar cells. These neighboring cells are then "primed" so that when they receive an excitatory signal from their own photorceptors, they are more likely to send a strong signal to the(ir) retinal ganglion cell. In this way, as a moving object passes over a visual field, information about that movement "ripples" through the network of bipolar cells. Ultimately, the retinal ganglion cells gather the information from the many bipolar cells and encodes it into signals to relay to the visual cortex, which in turn processes the information to predict the path of the object.

How Decisions about Sight are Relayed in the Brain
Researchers studying how decisions based on visual information is made, in both forward and backward pathways, is broadcast widely to neurons in the visual system. Feedback, such as visual information about color or shape, help the brain to focus on visual information relevant to decision-making. When a decision is based on what we see, information about expectation (such as a pedestrian on a crosswalk) or attention (like the color of a shirt) is relayed to brain regions involved in visual processing, raising the activity of neurons involved in that object or event. Such feedback might help the brain to focus on difficult-to-see features or help stabilize the decision being made. Some scientists have wondered what happens when two different types of information are relevant to a decision at the same time. To test the question of whether feedback is specific to each type of information, and selective for each decision, the researchers trained monkeys to distinguish whether an object on a screen in a particular location looked concave or convex, while ignoring objects in irrelevant locations. The researchers measured the monkeys' neuronal activity involved in processing visual information while the animals were performing the task. They then tested whether decision-related feedback was selective for both location and depth. According to the news article, "Similar to previous studies, they found that location feedback is selective, but location feedback didn’t vary depending on the decision the animal made, it was only associated the location that the animal was paying attention to. Conversely, feedback related to the object’s depth was associated with the decision, but was spatially unselective, meaning that even depth-sensing neurons that couldn’t possibly be used to make the decision got extra decision-related feedback anyway."

In Other News
(1) Comparative anatomy: Tardigrades may see only in black and white
(2) Keeping your glasses clear while wearing a mask
(3) Myopia on the rise during COVID-19 lockdown (Related)