Tag Archives: retina

The AII Amacrine Cell Connectome: A Dense Network Hub

Leave a reply

AII-connectome

We have a new publication in Frontiers in Neuroscience, The AII Amacrine Cell Connectome: A Dense Network Hub.  Authors are Robert E. Marc, James R. Anderson, Bryan W. Jones, Crystal Sigulinsky and J. Scott Lauritzen.

Abstract:  The mammalian AII retinal amacrine cell is a narrow-field, multistratified glycinergic neuron best known for its role in collecting scotopic signals from rod bipolar cells and distributing them to ON and OFF cone pathways in a crossover network via a combination of inhibitory synapses and heterocellular AII::ON cone bipolar cell gap junctions. Long considered a simple cell, a full connectomics analysis shows that AII cells possess the most complex interaction repertoire of any known vertebrate neuron, contacting at least 28 different cell classes, including every class of retinal bipolar cell. Beyond its basic role in distributing rod signals to cone pathways, the AII cell may also mediate narrow-field feedback and feedforward inhibition for the photopic OFF channel, photopic ON-OFF inhibitory crossover signaling, and serves as a nexus for a collection of inhibitory networks arising from cone pathways that likely negotiate fast switching between cone and rod vision. Further analysis of the complete synaptic counts for five AII cells shows that (1) synaptic sampling is normalized for anatomic target encounter rates; (2) qualitative targeting is specific and apparently errorless; and (3) that AII cells strongly differentiate partner cohorts by synaptic and/or coupling weights. The AII network is a dense hub connecting all primary retinal excitatory channels via precisely weighted drive and specific polarities. Homologs of AII amacrine cells have yet to be identified in non-mammalians, but we propose that such homologs should be narrow-field glycinergic amacrine cells driving photopic ON-OFF crossover via heterocellular coupling with ON cone bipolar cells and glycinergic synapses on OFF cone bipolar cells. The specific evolutionary event creating the mammalian AII scotopic-photopic hub would then simply be the emergence of large numbers of pure rod bipolar cells.

 

A Multi-Scale Computational Model For The Study Of Retinal Prosthetic Stimulation

Leave a reply

Multiscale-model-of-retina

We have a new publication in IEEE, A Multi-Scale Computational Model For The Study Of Retinal Prosthetic Stimulation.  Authors are: Kyle Loizos, Gianluca Lazzi, J. Scott Lauritzen, James R. Anderson, Bryan W. Jones and Robert E. Marc.

Abstract: An implantable retinal prosthesis has been developed to restore vision to patients who have been blinded by degenerative diseases that destroy photoreceptors. By electrically stimulating the surviving retinal cells, the damaged photoreceptors may be bypassed and limited vision can be restored. While this has been shown to restore partial vision, the understanding of how cells react to this systematic electrical stimulation is largely unknown. Better predictive models and a deeper understanding of neural responses to electrical stimulation is necessary for designing a successful prosthesis. In this work, a computational model of an epi-retinal implant was built and simulated, spanning multiple spatial scales, including a large-scale model of the retina and implant electronics, as well as underlying neuronal networks.

 

Retinal Prosthetics, Optogenetics and Photoswitches

Leave a reply

Retinal-Prosthetics-Optogenetics-and-Photoswitches

We have a new publication, Retinal Prosthetics, Optogenetics and Photoswitches in ACS Chemical Neuroscience.  Authors are:  Robert E. Marc, Rebecca L. Pfeiffer, and Bryan W. Jones.

Abstract:

Three technologies have emerged as therapies to restore light sensing to profoundly blind patients suffering from late-stage retinal degenerations: (1) retinal prosthetics, (2) optogenetics, and (3) chemical photoswitches. Prosthetics are the most mature and the only approach in clinical practice. Prosthetic implants require complex surgical intervention and provide only limited visual resolution but can potentially restore navigational ability to many blind patients. Optogenetics uses viral delivery of type 1 opsin genes from prokaryotes or eukaryote algae to restore light responses in survivor neurons. Targeting and expression remain major problems, but are potentially soluble. Importantly, optogenetics could provide the ultimate in high-resolution vision due to the long persistence of gene expression achieved in animal models. Nevertheless, optogenetics remains challenging to implement in human eyes with large volumes, complex disease progression, and physical barriers to viral penetration. Now, a new generation of photochromic ligands or chemical photoswitches (azobenzene-quaternary ammonium derivatives) can be injected into a degenerated mouse eye and, in minutes to hours, activate light responses in neurons. These photoswitches offer the potential for rapidly and reversibly screening the vision restoration expected in an individual patient. Chemical photoswitch variants that persist in the cell membrane could make them a simple therapy of choice, with resolution and sensitivity equivalent to optogenetics approaches. A major complexity in treating retinal degenerations is retinal remodeling: pathologic network rewiring, molecular reprogramming, and cell death that compromise signaling in the surviving retina. Remodeling forces a choice between upstream and downstream targeting, each engaging different benefits and defects. Prosthetics and optogenetics can be implemented in either mode, but the use of chemical photoswitches is currently limited to downstream implementations. Even so, given the high density of human foveal ganglion cells, the ultimate chemical photoswitch treatment could deliver cost-effective, high-resolution vision for the blind.

A Synaptic Basis for Small World Network Design in the ON Inner Plexiform Layer of the Rabbit Retina

Leave a reply

Bipolar cells_

This abstract was presented today at the 2014 Association for Research in Vision and Opthalmology (ARVO) meetings in Orlando, Florida by J Scott Lauritzen, Noah T. Nelson, Crystal L. Sigulinsky, Nathan Sherbotie, John Hoang, Rebecca L. Pfeiffer, James R. Anderson, Carl B. Watt, Bryan W. Jones and Robert E. Marc.

Purpose: Converging evidence suggests that large- and intermediate-scale neural networks throughout the nervous system exhibit small world’ design characterized by high local clustering of connections yet short path length between neuronal modules (Watts & Strogatz 1998 Nature; Sporns et al.2004 Trends in Cog Sci). It is suspected that this organizing principle scales to local networks (Ganmor et al. 2011 J Neurosci; Sporns 2006 BioSystems) but direct observation of synapses and local network topologies mediating small world design has not been achieved in any neuronal tissue. We sought direct evidence for synaptic and topological substrates that instantiate small world network architectures in the ON inner plexiform layer (IPL) of the rabbit retina. To test this we mined ≈ 200 ON cone bipolar cells (BCs) and ≈ 500 inhibitory amacrine cell (AC) processes in the ultrastructural rabbit retinal connectome (RC1).

Methods: BC networks in RC1 were annotated with the Viking viewer and explored via graph visualization of connectivity and 3D rendering (Anderson et al. 2011 J Microscopy). Small molecule signals embedded in RC1 e.g. GABA glycine and L-glutamate combined with morphological reconstruction and connectivity analysis allow for robust cell classification. MacNeil et al. (2004 J Comp Neurol) BC classification scheme used for clarity.

Results: Homocellular BC coupling (CBb3::CBb3 CBb4::CBb4 CBb5::CBb5) and within-class BC inhibitory networks (CBb3 → AC –| CBb3 CBb4 → AC –| CBb4 CBb5 → AC –| CBb5) in each ON IPL strata form laminar-specific functional sheets with high clustering coefficients. Heterocellular BC coupling (CBb3::CBb4 CBb4::CBb5 CBb3::CBb5) and cross-class BC inhibitory networks (CBb3 → AC –| CBb4 CBb4 → AC –| CBb3 CBb4 → AC –| CBb5 CBb5 → AC –| CBb4 CBb3 → AC –| CBb5 CBb5 → AC –| CBb3) establish short synaptic path lengths across all ON IPL laminae.

Conclusions: The retina contains a greater than expected number of synaptic hubs that multiplex parallel channels presynaptic to ganglion cells. The results validate a synaptic basis (ie. direct synaptic connectivity) and local network topology for the small world architecture indicated at larger scales providing neuroanatomical plausibility of this organization for local networks and are consistent with small world design as a fundamental organizing principle of neural networks on multiple spatial scales.

Support:  NIH EY02576 (RM), NIH EY015128 (RM), NSF 0941717 (RM), NIH EY014800 Vision Core (RM), RPB CDA (BWJ), Thome AMD Grant (BWJ).

Retinal connectomics: A New Era For Connectivity Analysis in The New Visual Neurosciences

Leave a reply

New-Visual-Neurosciences

We have a new publication, this one a chapter titled: Retinal connectomics: A New Era For Connectivity Analysis in The New Visual Neurosciences (A little cheaper on Amazon here) textbook.  Authors are Robert E. Marc, Bryan W. Jones, James S. Lauritzen, Carl B. Watt and James R. Anderson.

FASEB Bio-Art Competition Winner 2013

Leave a reply

1254_40X_GBY_72dpi-1

Bryan W. Jones and Robert E. Marc and were selected as 2013 FASEB BioArt Winners (Press release here).  This image shows a region of an amazingly complex retina from a goldfish (Carassius auratus auratus) analyzed using tools called Computational Molecular Phenotyping (CMP) that reveal the metabolic state of the all cell types in tissues.  These cells were labeled with antibodies for the presence of two fundamental amino acid metabolites (anti-glycine in red, anti-GABA in blue) and an amino acid tracer of physiologic activity (anti-AGB in green).   These labels allow us to visualize the metabolic state and therefore, classes of bipolar, amacrine and horizontal cells.  More details on the image here.

 

Constructive Retinal Plasticity After Selective Ablation of the Photoreceptors

Leave a reply

This abstract was presented today at the Association for Research in Vision and Opthalmology (ARVO) meetings in Seattle, Washington by Corinne N. Beier, Bryan W. Jones, Philip Huie, Yannis M. Paulus, Daniel Lavinsky, Loh-Shan B. Leung, Hiroyuki Nomoto,  Robert E. Marc, Daniel V. Palanker, and Alexander Sher.

Purpose: In the rabbit retina there is evidence of constructive retinal plasticity in response to focal ablation of a small patch of the photoreceptor layer by laser photocoagulation. After a two-month healing period, healthy photoreceptors migrate inwards filling the damaged area and restoring visual sensitivity to the lesion site. We investigated the integrity and function of the neural populations above the lesion, whether the migrating photoreceptors formed new connections with deafferented bipolar cells, and to what degree the new function resembled normal retinal function.

Methods: Retinal photocoagulation lesions of Moderate and Barely Visible clinical grades were produced in rabbits with a 532-nm laser, using beam diameter of 200 and 400 μm. Retinal ganglion cell (RGC) responses to spatio-temporal white noise stimulus were recorded on a 512-electrode array. Inner retinal neuron cell types were identified using Computational Molecular Phenotyping (CMP). Light evoked activity of the inner retinal neurons was measured through 1-amino-4-guanidobutane (AGB) labeling. Synaptic structure between photoreceptors and bipolar cells was characterized through transmission electron microscopy (TEM) imaging.

Results: The lesioned areas of the retina, after a two-month healing period, regained visual sensitivity. There was no significant difference between the response kinetics of RGCs with receptive fields covering the lesioned area and RGCs with receptive fields unaffected by the lesion. Furthermore, the average receptive field sizes of RGCs covering the lesion were consistent with the average receptive field sizes of RGCs unaffected by the lesion. CMP showed that all major inner retinal neuron cell types are present above both acute and healed lesions. Light evoked activity in the retina, as measured by AGB concentration levels, was diminished in the acute lesion but returned to within 10% of normal after two months. TEM images showed normal photoreceptor synaptic structure inside the healed lesion area.

Conclusions: Migrating photoreceptors establish new functional connectivity to deafferented bipolar cells and have normal synaptic structure. The new circuitry results in spatial and temporal properties of the RGC responses that resemble those of the healthy retina. In summary, the rewiring restores normal visual response in the lesioned area, indicating constructive retinal plasticity.

Support: Burroughs Wellcome Fund Career Award at the Scientific Interface; the Pew Charitable Trusts Scholarship in the Biomedical Sciences (A.S.), RPB CDA, Thome Foundation (BWJ), NIH EY02576, NIH EY015128, NSF 0941717, NIH EY014800 Vision Core (R.M.); NIH 5R01EY18608, AFOSR FA9550- 10-1-0503, DoD W81XWH-12-10575, Stanford University Bio-X (D.P.), Edward N. and Della L. Thome Memorial Foundation grant for Age-Related Macular Degeneration Research (BWJ) RPB unrestricted award (Moran Eye Center)