Tag Archives: connectomics

Retinal Connectomics: A Review

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We have a new manuscript out of the lab in Volume 10 of the Annual Review of Vision Science titled Retinal Connectomics: A Review by Crystal L. Sigulinsky, Rebecca L. Pfeiffer, and Bryan William Jones. A .pdf is here.

Abstract
The retina is an ideal model for understanding the fundamental rules for
how neural networks are constructed. The compact neural networks of
the retina perform all of the initial processing of visual information be-
fore transmission to higher visual centers in the brain. The field of retinal
connectomics uses high-resolution electron microscopy datasets to map
the intricate organization of these networks and further our understand-
ing of how these computations are performed by revealing the fundamental
topologies and allowable networks behind retinal computations. In this ar-
ticle, we review some of the notable advances that retinal connectomics
has provided in our understanding of the specific cells and the organi-
zation of their connectivities within the retina, as well as how these are
shaped in development and break down in disease. Using these anatomi-
cal maps to inform modeling has been, and will continue to be, instrumental
in understanding how the retina processes visual signals.

Preprint: Neural Circuit Revision in Retinal Remodeling, A Pathoconnectomics Approach

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We have a new preprint out, Neural Circuit Revision in Retinal Remodeling, A Pathoconnectomics Approach.

Authors: Rebecca L Pfeiffer, Jeebika Dahal, Crystal L Sigulinsky, James R Anderson, Isabel A Barrera, Jia-Hui Yang, Olivia Haddadin, Alexis R Houser, Jessica C Garcia, Bryan William Jones

Abstract: The Aii glycinergic amacrine cell (Aii) plays a central role in bridging rod pathways with cone pathways, enabling an increased dynamic range of vision from scotopic to photopic ranges. The Aii integrates scotopic signals via chemical synapses from rod bipolar cells (RodBCs) onto the arboreal processes of Aii ACs, injecting signals into ON-cone bipolar cells (CBbs) via gap junctions with Aiis on the arboreal processes and the waist of the Aii ACs. The CBbs then carry this information to ON and OFF ganglion cell classes. In addition, the Aii is involved in the surround inhibition of OFF cone bipolar cells (CBas) through glycinergic chemical synapses from Aii ACs onto CBas. We have previously shown changes in RodBC connectivity as a consequence of rod photoreceptor degeneration in a pathoconnectome of early retinal degeneration: RPC1. Here, we evaluated the impact of rod photoreceptor degeneration on the connectivity of the Aii to determine the impacts of photoreceptor degeneration on the downstream network of the neural retina and its suitability for integrating therapeutic interventions as rod photoreceptors are lost. Previously, we reported that in early retinal degeneration, prior to photoreceptor cell loss, Rod BCs make pathological gap junctions with Aiis. Here, we further characterize this altered connectivity and additional shifts in both the excitatory drive and gap junctional coupling of Aiis in retinal degeneration, along with discussion of the broader impact of altered connectivity networks. New findings reported here demonstrate that Aiis make additional gap junctions with CBas increasing the number of BC classes that make pathological gap junctional connectivity with Aiis in degenerating retina. In this study, we also report that the Aii, a tertiary retinal neuron alters their synaptic contacts early in photoreceptor degeneration, indicating that rewiring occurs in more distant members of the retinal network earlier in degeneration than was previously predicted. This rewiring impacts retinal processing, presumably acuity, and ultimately its ability to support therapeutics designed to restore image-forming vision. Finally, these Aii alterations may be the cellular network level finding that explains one of the first clinical complaints from human patients with retinal degenerative disease, an inability to adapt back and forth from photopic to scotopic conditions.

UCI Center For Translational Vision Research Talk on Retinal Connectomics and Pathoconnectomics

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Müller Cell Connectomics In Health And Disease

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This talk was presented today, April 25th at the 2023 Association for Research in Vision and Opthalmology (ARVO) meetings in New Orleans, Louisiana by Rebecca Pfeiffer as part of an ARVO Minisymposium Bryan William Jones organized.

Abstract: Muller cells are a critical component of retinal function and rapidly change metabolically and morphologically in retinal disease. Of Muller cell functions, many require close physical relationships between the Muller cell and the synapses of the neurons they support. Despite this required neuro-glial relationship, little is known about the direct contacts between Muller cells and synapses in healthy or diseased retinas. In order to address this, I use a connectomics/pathoconnectomics approach to reconstruct Muller cells and their neighboring synapses. The retinas evaluated are from a healthy rabbit, retinal connectome 1 (RC1), and from the P347L rabbit model of retinitis pigmentosa, retinal pathoconnectome 1 (RPC1). Preliminary data demonstrate an increase in endfoot entanglement in RPC1 when compared with RC1, and direct synaptic contact analysis of both connectomes is ongoing.

Species-Specific Connectivity In The Aii Connectome

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This talk was presented today, April 25th at the 2023 Association for Research in Vision and Opthalmology (ARVO) meetings in New Orleans, Louisiana by Crystal Sigulinsky as part of an ARVO Minisymposium organized by Bryan William Jones.

Abstract: Biomedical research relies heavily on animal models to study human disease and develop therapeutics. Understanding the architectural diversity in neural networks between humans and these model species is essential for choosing a relevant study model and interpreting conflicting results. Using comparative connectomics, we sought to map and compare the local neural network architecture of rabbit and mouse retinal Aii amacrine cells. This specialized narrow-field, multistratified, glycinergic interneuron has critical feedforward and feedback roles in both the photopic and scotopic retinal networks spanning the ON and OFF pathways, making it an ideal candidate for investigating species-specific differences in retinal networks. High-resolution, serial-section transmission electron microscopy (TEM) volumes of rabbit (RC1: female, 13- month, Dutch Belted) and mouse (RC2: female, 5-month, C57BL/6J) retinal tissue provided spatially-registered synaptic maps of Aii connectivity at directly comparable resolution and completeness. These reveal that despite species-specific morphologies, gross synaptology and compartmentalization appear conserved. Yet, rabbit and mouse Aii cells diverge in the weighting of their partnerships, most notably in their coupling profiles. Opposing biases in gap junction partnerships and their respective sizing rules indicate a greater relative output by mouse Aii cells to ON pathways than in rabbit. However, a unique topological conformation for a subset of conventional presynapses formed by Aii cell lobular dendrites with species-specific features and prevalence may influence signal output to specific partner classes within the OFF pathway and either nullify or exacerbate this difference in ON/OFF output. Additionally, rabbit Aii cells in RC1 showed greater Aii-Aii coupling than in mouse, which may suggest greater signal-to-noise compensation. Lastly, preliminary data suggest mouse Aii cells receive greater excitatory, but not inhibitory input/feedback from the OFF pathway than in rabbit. Together these data indicate that precise neural circuit architectures diverge between species and require detailed, comprehensive mapping to begin to dissect potential influence on signal flow.

Distinctive Synaptic Structural Motifs Link Excitatory Retinal Interneurons To Diverse Postsynaptic Partner Types

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We have a new manuscript from the lab in Cell Reports, Distinctive Synaptic Structural Motifs Link Excitatory Retinal Interneurons To Diverse Postsynaptic Partner Types. This manuscript is in collaboration with the first author, Wan-Qing Yu @wanqing_yu, then co-authors Rachael Swanstrom, Crystal L. Sigulinsky @CSigulinsky, Richard M. Ahlquist, along with Sharm Knecht, myself Bryan W. Jones @BWJones. David M. Berson, and Rachel O. Wong. The PDF is here.

Abstract:
Neurons make converging and diverging synaptic connections with distinct partner types. Whether synapses involving separate partners demonstrate similar or distinct structural motifs is not yet well understood. We thus used serial electron microscopy in mouse retina to map output synapses of cone bipolar cells (CBCs) and compare their structural arrangements across bipolar types and postsynaptic partners. Three presynaptic configurations emerge—single-ribbon, ribbonless, and multiribbon synapses. Each CBC type exploits these arrangements in a unique combination, a feature also found among rabbit ON CBCs. Though most synapses are dyads, monads and triads are also seen. Altogether, mouse CBCs exhibit at least six motifs, and each CBC type uses these in a stereotypic pattern. Moreover, synapses between CBCs and particular partner types appear biased toward certain motifs. Our observations reveal synaptic strategies that diversify the output within and across CBC types, potentially shaping the distinct functions of retinal microcircuits.

A pathoconnectome of early neurodegeneration: Network changes in retinal degeneration

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We have a new manuscript out in Experimental Eye Research, A pathoconnectome of early neurodegeneration: Network changes in retinal degeneration. (pdf here)

Authors: Rebecca L. Pfeiffer @BeccaPfeiffer19, James R. Anderson, Jeebika Dahal, Jessica C. Garcia, Jia-Hui Yang, Crystal L. Sigulinsky @CLSigulinsky, Kevin Rapp, Daniel P. Emrich, Carl B. Watt, Hope AB Johnstun, Alexis R. Houser, Robert E. Marc @robertmarc60, and Bryan W. Jones @BWJones.

Abstract: Connectomics has demonstrated that synaptic networks and their topologies are precise and directly correlate with physiology and behavior. The next extension of connectomics is pathoconnectomics: to map neural network synaptology and circuit topologies corrupted by neurological disease in order to identify robust targets for therapeutics. In this report, we characterize a pathoconnectome of early retinal degeneration. This pathoconnectome was generated using serial section transmission electron microscopy to achieve an ultrastructural connectome with 2.18nm/px resolution for accurate identification of all chemical and gap junctional synapses. We observe aberrant connectivity in the rod-network pathway and novel synaptic connections deriving from neurite sprouting. These observations reveal principles of neuron responses to the loss of network components and can be extended to other neurodegenerative diseases.