Search for: All records

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.

 

In retinal degenerative diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), the photoreceptors become stressed and start to degenerate in the early stages of the disease. Retinal prosthetic devices have been developed to restore vision in patients by applying electrical stimulation to the surviving retinal cells. However, these devices provide limited visual perception as the therapeutic interventions are generally considered in the later stages of the disease when only inner retinal layer cells are left. A potential treatment option for retinal degenerative diseases in the early stages can be stimulating bipolar cells, which receive presynaptic signals from photoreceptors. In this work, we constructed computational models of healthy and degenerated (both ON and OFF-type) cone bipolar cells (CBCs) with realistic morphologies extracted from connectomes of the healthy and early-stage degenerated rabbit retina. We examined these cells’ membrane potential and axon terminal calcium current differences when subjected to electrical stimulation. In addition, we investigated how differently healthy and degenerated cells behave with respect to various stimulation parameters, including pulse durationand cells’ distance from the stimulating electrode. The results suggested that regardless of the position of the OFF CBCs in the retina model, there is not a significant difference between the membrane potential of healthy and degenerate cells when electrically stimulated. However, the healthy ON CBC axon terminal membrane potential rising time-constant is shorter (0.29 ± 0.03 ms) than the degenerated cells (0.8 ± 0.07 ms). Moreover, the ionic calcium channels at the axon terminals of the cells have a higher concentration and higher current in degenerated cells (32.24 ± 6.12 pA) than the healthy cells (13.64 ± 2.88 pA) independently of the cell’s position. 

The inability to re‐process thermosets hinders their utility and sustainability. An ideal material should combine closed‐loop recycling and upcycling capabilities. This trait is realized in polydimethylsiloxane bottlebrush networks using thermoreversible Diels–Alder cycloadditions to enable both reversible disassembly into a polymer melt and on‐demand reconfiguration to an elastomer of either lower or higher stiffness. The crosslink density was tuned by loading the functionalized networks with a controlled fraction of dormant crosslinkers and crosslinker scavengers, such as furan‐capped bis‐maleimide and anthracene, respectively. The resulting modulus variations precisely followed the stoichiometry of activated furan and maleimide moieties, demonstrating the lack of side reactions during reprocessing. The presented circularity concept is independent from the backbone or side chain chemistry, making it potentially applicable to a wide range of brush‐like polymers.

 

The inability to re‐process thermosets hinders their utility and sustainability. An ideal material should combine closed‐loop recycling and upcycling capabilities. This trait is realized in polydimethylsiloxane bottlebrush networks using thermoreversible Diels–Alder cycloadditions to enable both reversible disassembly into a polymer melt and on‐demand reconfiguration to an elastomer of either lower or higher stiffness. The crosslink density was tuned by loading the functionalized networks with a controlled fraction of dormant crosslinkers and crosslinker scavengers, such as furan‐capped bis‐maleimide and anthracene, respectively. The resulting modulus variations precisely followed the stoichiometry of activated furan and maleimide moieties, demonstrating the lack of side reactions during reprocessing. The presented circularity concept is independent from the backbone or side chain chemistry, making it potentially applicable to a wide range of brush‐like polymers.