Research

The retina is not a video camera; it is the world’s most advanced image processing machine, refined over hundreds of millions of years of evolution. My lab seeks to understand the computations performed by retinal circuits. We are working toward a comprehensive classification of retinal ganglion cells, the output cells of the retina, that includes physiology, morphology and gene expression patterns for each cell type. Our catalog of mouse retinal ganglion cells is online at rgctypes.org.

From this “parts list” we work our way into the circuits of the retina to answer the “how” questions about the synaptic and circuit mechanisms of retinal computation.

Our understanding of the early visual system is at a crossroads; although we have a comprehensive list of brain areas that receive retinal input, we know very little about which retinal ganglion cell types project to each region. The canonical pathway in mammals from retina to dorsal lateral geniculate nucleus (dLGN) to cortex is required for visual perception. This pathway has been a research focus for decades, yet it represents only a small fraction of the visual input to the brain, and conscious perception is one one of the many behaviors influenced by retinal input.

A goal of my lab is to establish comprehensive connectivity maps from retina to brain at the level of identified cell types.

A mouse retina with specific cells (red) back-labeled from their brain projections. A single cell is filled in green.

Schematic of a subset of the known projection patterns from the retina to the brain.

A fluorescent virus (red) is injected in a specific location in the brain and transported back to the retina.

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Your ability to read the words on this page depends on the precise focus of each letter’s image onto the photoreceptors at the back of your retina. Maintaining proper focus is critical to vision, and we have evolved strategies to focus both dynamically – by adjusting our lens and pupil (accommodation) – and developmentally – by precisely regulating eye growth to match the optics of the lens and cornea (emmetropization). Because we rely on our high visual acuity to read and interact with our modern world, even minor dysfunction in these focus-regulation processes can lead to substantial deficits in quality of life.

Problems with the ability to focus are collectively called refractive disease, and the incidence of myopia, the most common refractive disease, has reached epidemic proportions, particularly in Asia/ More than 2 billion people are currently myopic, and that number is expected to rise to 5 billion (50% of the world population) by 2050. Importantly, myopia is more than just an expensive inconvenience that can be treated with glasses. Myopia increases the risk of a large variety of irreversible blinding diseases, including retinal detachment, and the incidence of ‘high myopia’, which cannot be corrected with glasses alone, has risen proportionally to the less severe cases.

Work in my lab has revealed a specific cell type in the retina that is exquisitely sensitive to defocus in an image. My ongoing research will establish causal links between this cell and circuits for accommodation and emmetropization. Spanning multiple levels of analysis, I will measure gene expression and light responses in individual cells, trace specific connections from the retina to the brain, design a behavioral paradigm to watch animals focus in real time, and track eye growth over development. My interdisciplinary approach combines electrophysiology, genetics, pharmacology, circuit tracing, behavior, and development. By solving a decades-old mystery about how defocus is detected in the eye, I hope to usher in a new era of targeted interventions to bring the world into better focus for millions of people.

Neurovascular coupling is the process by which neurons anticipate metabolic demand and communicate to blood vessels to alter blood flow. In the trilaminar capillary network of the retina (illustrated in the image on the right), light signals can alter patterns of blood flow within seconds. My lab is imaging these dynamic changes in retinal vasculature and testing the hypothesis that the abnormal blood glucose levels in diabetes interfere with neurovascular coupling, leading to diabetic retinopathy.

We have been able to see dynamic changes in calcium levels in pericytes (green) and corresponding changes in capillary diameter (red) triggered by light. This recording was taken from the middle capillary plexus.