Moran Eye Center Lab Produces World’s First ‘Pathoconnectome’

Sep 10, 2020 9:00 AM


Scientists from the John A. Moran Eye Center at the University of Utah have achieved another first in the field of connectomics, which studies the synaptic connections between neurons.

Moran’s Marclab for Connectomics was the first to complete a map of the circuitry of the retina, or connectome in 2011. Now, the National Institutes of Health (NIH)-funded lab has produced the first pathoconnectome, showing how eye disease alters retinal circuitry.

The implications of the published research, A pathoconnectome of early neurodegeneration: Network changes in retinal degeneration, extend far beyond eye diseases. The eye holds lessons applicable to a host of neurodegenerative diseases including Alzheimer’s, Parkinson’s, epilepsy, and Lou Gehrig's disease.

   A 2-D pathoconnectome image showing two retinal neurons (rod bipolar cell in blue, Aii amacrine cell in green). A gap junction connection (lower inset image) is not normally present between them but formed as the degenerating retina rewired itself during disease.
A 2-D pathoconnectome image showing two retinal neurons (rod bipolar cell in blue, Aii amacrine cell in green). A gap junction connection (lower inset image) is not normally present between them but formed as the degenerating retina rewired itself during disease.

“The components of neurodegeneration we see in the eye seem to mimic those we see in the brain,” explained the paper’s lead author, Moran’s Rebecca L. Pfeiffer, PhD. “So this pathoconnectome is allowing us to learn fundamental rules of how neurodegenerative diseases alter neural networks in general. The ultimate goal is to identify how we might develop new therapies based on preventing or interfering with the network rewiring prompted by disease.”

The Marclab developed the pathoconnectome from a model of early-stage retinitis pigmentosa (RP), an inherited retinal disease that can lead to blindness. The immense data set compiled to construct the pathoconnectome has taken years to assemble and is open for use by other scientists. The Marclab is working on a second and third pathoconnectome that will show how the retina rewires itself in later stages of RP.

In addition to Pfeiffer, 12 other Marclab researchers are authors on the publication: James R. Anderson, PhD; Jeebika Dahal; Jessica C. Garcia; Jia-Hui Yang; Crystal L. Sigulinsky PhD; Kevin Rapp; Daniel P. Emrich; Carl B. Watt, PhD;  Hope AB Johnstun; Alexis R. Houser; Robert E. Marc, PhD; and lab director Bryan W. Jones, PhD.

A 2-D pathoconnectome image shows rod bipolar cell dendrites and their synapse locations with rod (red), cone (blue), and indeterminate (yellow) photoreceptors.
A 2-D pathoconnectome image shows rod bipolar cell dendrites and their synapse locations with rod (red), cone (blue), and indeterminate (yellow) photoreceptors.

The Marclab constructed the pathoconnectome by studying 946 tissue sections with two transmission electron microscopes, which work nonstop nearly every day of the year to produce an unprecedented amount of data to understand retinal circuitry. In 2018, the Lawrence T. and Janet T. Dee Foundation generously funded the lab's second transmission electron microscope. The first was provided by Moran donor Martha Ann Dumke Healy.

The lab is the nation’s only NIH-funded connectomics research group. The pathoconnectome research was supported by NIH grants RO1 EY015128(BWJ)RO1 EY028927(BWJ)P30 EY014800(Core)T32 EY024234(RLP)], and an Unrestricted Research Grant from Research to Prevent Blindness, New York, NY to the Department of Ophthalmology & Visual Sciences, University of Utah.

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