Human Retina

The discovery will enable researchers to better understand eye movement disorders that cause significant visual impairment.

Article by Emily L Ward

Herbert Wertheim School of Optometry & Vision Science researchers have discovered rare neurons in the eye that are crucial for our visual system to maintain a sharp, steady image of the world. These findings will impact our understanding of the human retina and likely provide insights into the pathology of eye movement disorders.

The study, recently published in Nature, was led by Teresa Puthussery, OD, PhD, an assistant professor at the Herbert Wertheim School of Optometry & Vision Science and the Helen Wills Neuroscience Institute. First author, Anna Yao Mei Wang, PhD, is a postdoctoral scholar in The Puthussery Lab.

Gaze Stabilization in a Moving World

The neurons identified are involved in a fundamental feature of everyday vision. As one walks down a busy street or looks out the window of a train, the gaze stabilization system operates below our conscious awareness causing the eyes to reflexively follow the direction in which the visual scene is moving. This visual mechanism works in concert with the vestibular system to maintain a sharp image of a moving world. Clinical conditions that interfere with gaze stabilization can therefore lead to significant visual impairment.

The new findings demonstrate for the first time that retinal neurons underlying gaze stabilization in other mammals are also present in primates, including humans. Neurons that send visual signals from the eye to the brain are called retinal ganglion cells. In humans, there are around 20 different retinal ganglion cell types, each of which responds to specific features of the visual scene, such as form, color, and motion (1–3).

Teresa Puthussery

The researchers discovered a highly-specialized retinal ganglion cell type known as direction-selective ganglion cells (DSGCs). They respond to motion in the visual field by increasing their activity when movement occurs in their “preferred” direction, while showing little activity to motion in the opposite direction. Collectively, responses from these neurons tell the gaze stabilization system which way the visual scene is moving.

“This cell type in particular—the direction-selective ganglion cell—had not been discovered previously in primate despite concerted effort, leading the field to conclude it must not be there,” said Marla Feller, PhD, a distinguished professor at UC Berkeley and an elected member of the National Academy of Sciences. Dr. Feller is an expert in retinal circuit development and function.

Finding the Needle in the Haystack

DSGCs were discovered in the rabbit retina in 1964 by another Berkeley Optometry faculty member, Horace Barlow, and his colleagues (4). However, in the decades since, the lack of evidence for DSGCs in higher species led scientists to speculate that primate direction selectivity was computed in the brain. But when new evidence emerged suggesting that some human gaze stabilization disorders could be linked to abnormal activity of DSGCs (5), Puthussery’s lab renewed their efforts to find them. “That was a tipping point. We thought DSGCs had to be there, but that they made up a very low percentage of retinal ganglion cells. Our challenge was to work out how to find the needle in the haystack,” said Dr. Puthussery.

The researchers used a multi-pronged approach to overcome this problem. First, they leveraged data from state-of-the-art genetic tools (2) to track down retinal neurons with molecular features resembling DSGCs in other animals. The researchers then labeled these neurons with fluorescent markers to show that they had the expected anatomical features. Finally, the team built a customized imaging system to track the activity of hundreds of retinal ganglion cells and show that the fluorescently tagged cells responded selectively to images moving in specific directions. This combination of molecular, anatomical, and functional evidence provided unequivocal identification of the long sought-after DSGCs.

“The Puthussery Lab was successful where others failed because of their novel approach,” said Dr. Marla Feller. She continued, “I also cannot overstate the high quality of the data, which is critical for such a breakthrough finding.”

New Insights into Common Visual Disorders

Anna Wang

These findings will enable researchers to better understand how retinal mechanisms contribute to gaze stabilization in the normal visual system and in disorders that cause unstable gaze. For example, nystagmus is a repetitive, uncontrolled movement of the eyes that can lead to unsteady and blurry vision. Nystagmus can occur in isolation or can accompany other eye problems such as albinism and certain inherited retinal diseases. While many forms of nystagmus are caused by problems in the brain or inner ear, the results of this study suggest that some forms of nystagmus could originate from abnormal activity of DSGCs in the retina (5).

Looking Forward: Testing for Blinding Diseases

Overall, these results provide a vivid demonstration that a rare retinal ganglion cell type may nonetheless have a profound impact on our overall visual experience. The approach used in this study can now be applied to determine the roles of other human ganglion cell types whose functions are unknown. This will be an important step toward designing more sensitive tests for the detection of blinding diseases that cause ganglion cell degeneration such as glaucoma, which afflicts 80 million people worldwide and is the leading cause of irreversible blindness (7,8). For example, if direction-selective ganglion cells are damaged early in glaucoma, changes in eye movements might serve as an objective biomarker for early damage.

Remarkably, half of all individuals with glaucoma are unaware that they have it (7,8). Ultimately, detecting early changes in ganglion cell activity is vital to diagnosing disease and preventing vision loss in our aging population.

About the Study

The research was supported by the National Eye Institute (EY024265), Glaucoma Research Foundation (Shaffer Grant) and the Hellman Fellows Fund.

Wang, A.Y.M., Kulkarni, M.M., McLaughlin, A.J., Gayet J, Smith BE, Hauptschein M, McHugh CF, Yao YY, Puthussery T. An ON-type direction-selective ganglion cell in primate retina. Nature (2023).

Read in Nature

Related Information

The Puthussery Lab

Emily L Ward, who wrote this web article, is a PhD student at UC Berkeley’s Herbert Wertheim School of Optometry & Vision Science.

About the Photos

Top: A human retina labeled with a marker for all retinal ganglion cells in magenta. The sparse subset of retinal ganglion cells involved in gaze stabilization are labeled with a selective marker in green. Center: Teresa Puthussery, OD, PhD, heads the research group, which studies how retinal neurons process visual information before sending signals to the brain. Bottom: Anna Yao Mei Wang, PhD, is a postdoctoral scholar working in the Puthussery lab, and is first author of the study, which was published in Nature. Center and bottom photos by Elena Zhukova

1. Yan W, Peng YR, van Zyl T, et al. Cell Atlas of The Human Fovea and Peripheral Retina. Scientific Reports. 2020;10(1):9802.

2. Peng YR, Shekhar K, Yan W, et al. Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina. Cell. 2019;176(5):1222-1237.e22.

3. Wensel TG. Chapter 51 – Molecular Biology of Vision. Editor(s): Brady ST, Siegel GJ, Albers RW, Price DL. Basic Neurochemistry (Eighth Edition). Academic Press. 2012:889–903.

4. Barlow, HB, Hill, RM, Levick, WR. Retinal ganglion cells responding selectively to direction and speed of image motion in the rabbit. The Journal of Physiology. 1964;173.

5. Kamermans M, Winkelman BHJ, Hölzel MB, Howlett MHC, Kamermans W, Simonsz HJ, de Zeeuw CI. A retinal origin of nystagmus—a perspective. Frontiers in Ophthalmology. 2023;3.

6. Yonehara K, Fiscella M, Drinnenberg A, Esposti F, Trenholm S, Krol J, et al. Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity. Neuron. 2016;89:177–193.

7. Heijl A, Bengtsson B, Oskarsdottir SE. Prevalence and severity of undetected manifest glaucoma: results from the early manifest glaucoma trial screening. Ophthalmology. 2013;120(8):1541–1545.

8. “Glaucoma Worldwide: A Growing Concern.” Glaucoma.Org. https://glaucoma.org/glaucoma-worldwide-a-growing-concern/. Accessed October 25, 2023. Reviewed March 23, 2022.

Contacts

Eric Craypo, Chief Communications Officer


ecraypo@berkeley.edu

Teresa Puthussery, Assistant Professor


tputhussery@berkeley.edu

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