About the Lab

The Samuel Lab: On the Hunt for Neural Road Signs

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Neurons in retina comprise distinct populations that form precise connections in synaptic layers.

Our neural cells form the road map that defines who we are and what we experience. What makes these cells chose a particular synaptic partner and how are these choices maintained? Addressing these questions requires a well-defined and accessible neural circuit. Toward that end, we focus our studies on retina and visual areas of the brain. Using these systems we center on studies on three areas: development, adulthood and disease.

Retina: The Right Model for the Job

The first steps of vision occur when photoreceptors (green) detect light and relay those signals to bipolar neurons (red).

The neural retina processes visual information and relays it to the brain. It provides an excellent system for many of our studies for several reasons:1) the visual system undergoes complex developmental patterning as well as clinically significant age-associated decline; 2) much is known about retinal circuit formation; and 3) retinal neurons themselves are accessible to study in vivo. 

There are five general neuron types in the retina. Photoreceptors detect visual stimuli. Interneurons (horizontal, bipolar and amacrine cells),  process these signals, and retinal ganglion cells (RGCs) integrate this information and send it to the brain. Retinal neurons can be further subdivided into ~70 distinct functional subtypes. While this number of subtypes is comparable to that of other brain regions, markers for a majority these cells have been well defined only in retina. Moreover, specific types of retinal neurons pattern and connect in precise nuclear and synaptic layers.

Because the circuitry of the retina is well understood, molecular, cellular and functional studies can be completed in parallel and readily interpreted. This is more challenging in the brain where cells and synapses of many types are closely intermingled. 

Areas of Interest

How to Make the Right Choice: Neural Development and Synaptic Connectivity

Individual rod photoreceptor viewed in cross section.

During neural development, cells undergo fate decisions that determine cellular identity and impact connectivity. Making these choices correctly is critical for normal neural function, yet the molecules that regulate these processes are not well understood. Here, the advantages the retina provides are indispensable. It's precise organization allows us to undertake mechanistic studies aimed at defining neural wiring pathways. Further, we hypothesize that some of the molecules responsible for initial patterning of the nervous system may play roles in maintaining the organization of this system in normal adulthood and disease.

Mature Adult Seeks Long-Term Relationship: Neural Maintenance in Adults and Old Age

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In normal aged retina, rod bipolar cells and horizontal cells remodel aberrantly, sending long processes into outer retina.

As we age, our nervous system undergoes many deleterious alterations: sensory, motor and cognitive functions decrease, while the risk of disease increases. Although progress has been made in defining the pathogenesis of specific neurological diseases, the biological mechanisms responsible for healthy aging of the nervous system remain unknown.

To address this problem, we focus our studies on the aging of synapses. Synapses are key elements of neural circuitry, and age-related synaptic dysfunction may precipitate cognitive degeneration. Using retina and retinorecipient regions of brain, we have found that some neurons age more gracefully than others. These studies have begun to uncover the molecular pathways that regulate synaptic aging, including the energy homeostasis molecules LKB1 and AMPK. Current work seeks to further define how this pathway regulates cell and synaptic fate and discover additional molecules that play related roles. In parallel, we use this molecular information to test ways to attenuate neural changes.

From Molecules to Therapies: Understanding Neural Cancers and Disease

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Single mouse horizontal cell neuron visualized using AAV.

In the nervous system, maintenance pathways appear especially vulnerable to old age, as specific neural subsets become misregulated over time. In parallel, older adults are most at risk for developing cognitive diseases, including Alzheimer’s, as well as cellular diseases such as brain cancer.

The goal of our work is to help solve these problems using retina and brain to: 1) understand the molecular events that predispose the nervous system to disease; 2) identify the factors that influence cancer formation; and 3) test ways to attenuate these changes.