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Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact.
Ray TA, Roy S, Kozlowski C, Wang J, Cafaro J, Hulbert SW, Wright CV, Field GD, Kay JN
(2018) Elife 7:
MeSH Terms: Amacrine Cells, Animals, Membrane Proteins, Mice, Neuropil, Retina, Retinal Ganglion Cells
Show Abstract · Added May 1, 2018
A common strategy by which developing neurons locate their synaptic partners is through projections to circuit-specific neuropil sublayers. Once established, sublayers serve as a substrate for selective synapse formation, but how sublayers arise during neurodevelopment remains unknown. Here, we identify the earliest events that initiate formation of the direction-selective circuit in the inner plexiform layer of mouse retina. We demonstrate that radially migrating newborn starburst amacrine cells establish homotypic contacts on arrival at the inner retina. These contacts, mediated by the cell-surface protein MEGF10, trigger neuropil innervation resulting in generation of two sublayers comprising starburst-cell dendrites. This dendritic scaffold then recruits projections from circuit partners. Abolishing MEGF10-mediated contacts profoundly delays and ultimately disrupts sublayer formation, leading to broader direction tuning and weaker direction-selectivity in retinal ganglion cells. Our findings reveal a mechanism by which differentiating neurons transition from migratory to mature morphology, and highlight this mechanism's importance in forming circuit-specific sublayers.
© 2018, Ray et al.
2 Communities
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7 MeSH Terms
Pigmented and albino rats differ in their responses to moderate, acute and reversible intraocular pressure elevation.
Gurdita A, Tan B, Joos KM, Bizheva K, Choh V
(2017) Doc Ophthalmol 134: 205-219
MeSH Terms: Acute Disease, Albinism, Analysis of Variance, Animals, Dark Adaptation, Electroretinography, Intraocular Pressure, Male, Ocular Hypertension, Rats, Rats, Inbred BN, Rats, Long-Evans, Rats, Sprague-Dawley, Retina, Retinal Ganglion Cells, Tomography, Optical Coherence
Show Abstract · Added March 19, 2018
PURPOSE - To compare the electrophysiological and morphological responses to acute, moderately elevated intraocular pressure (IOP) in Sprague-Dawley (SD), Long-Evans (LE) and Brown Norway (BN) rat eyes.
METHODS - Eleven-week-old SD (n = 5), LE (n = 5) and BN (n = 5) rats were used. Scotopic threshold responses (STRs), Maxwellian flash electroretinograms (ERGs) or ultrahigh-resolution optical coherence tomography (UHR-OCT) images of the rat retinas were collected from both eyes before, during and after IOP elevation of one eye. IOP was raised to ~35 mmHg for 1 h using a vascular loop, while the other eye served as a control. STRs, ERGs and UHR-OCT images were acquired on 3 days separated by 1 day of no experimental manipulation.
RESULTS - There were no significant differences between species in baseline electroretinography. However, during IOP elevation, peak positive STR amplitudes in LE (mean ± standard deviation 259 ± 124 µV) and BN (228 ± 96 µV) rats were about fourfold higher than those in SD rats (56 ± 46 µV) rats (p = 0.0002 for both). Similarly, during elevated IOP, ERG b-wave amplitudes were twofold higher in LE and BN rats compared to those of SD rats (947 ± 129 µV and 892 ± 184 µV, vs 427 ± 138 µV; p = 0.0002 for both). UHR-OCT images showed backward bowing in all groups during IOP elevation, with a return to typical form about 30 min after IOP elevation.
CONCLUSION - Differences in the loop-induced responses between the strains are likely due to different inherent retinal morphology and physiology.
0 Communities
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16 MeSH Terms
The challenge of regenerative therapies for the optic nerve in glaucoma.
Calkins DJ, Pekny M, Cooper ML, Benowitz L, Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants
(2017) Exp Eye Res 157: 28-33
MeSH Terms: Animals, Glaucoma, Humans, Nerve Degeneration, Nerve Regeneration, Neuroglia, Optic Disk, Optic Nerve Diseases, Regenerative Medicine, Retinal Ganglion Cells
Show Abstract · Added April 18, 2017
This review arose from a discussion of regenerative therapies to treat optic nerve degeneration in glaucoma at the 2015 Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration. In addition to the authors, participants included Jonathan Crowston, Andrew Huberman, Elaine Johnson, Richard Lu, Hemai Phatnami, Rebecca Sappington, and Don Zack. Glaucoma is a neurodegenerative disease of the optic nerve, and is the leading cause of irreversible blindness worldwide. The disease progresses as sensitivity to intraocular pressure (IOP) is conveyed through the optic nerve head to distal retinal ganglion cell (RGC) projections. Because the nerve and retina are components of the central nervous system (CNS), their intrinsic regenerative capacity is limited. However, recent research in regenerative therapies has resulted in multiple breakthroughs that may unlock the optic nerve's regenerative potential. Increasing levels of Schwann-cell derived trophic factors and reducing potent cell-intrinsic suppressors of regeneration have resulted in axonal regeneration even beyond the optic chiasm. Despite this success, many challenges remain. RGC axons must be able to form new connections with their appropriate targets in central brain regions and these connections must be retinotopically correct. Furthermore, for new axons penetrating the optic projection, oligodendrocyte glia must provide myelination. Additionally, reactive gliosis and inflammation that increase the regenerative capacity must be outweigh pro-apoptotic processes to create an environment within which maximal regeneration can occur.
Copyright © 2017 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
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10 MeSH Terms
Glial coverage in the optic nerve expands in proportion to optic axon loss in chronic mouse glaucoma.
Bosco A, Breen KT, Anderson SR, Steele MR, Calkins DJ, Vetter ML
(2016) Exp Eye Res 150: 34-43
MeSH Terms: Animals, Astrocytes, Axons, Chronic Disease, Disease Models, Animal, Female, Glaucoma, Gliosis, Male, Mice, Mice, Inbred DBA, Microscopy, Confocal, Neuroglia, Optic Nerve, Optic Nerve Diseases, Photomicrography, Retinal Ganglion Cells
Show Abstract · Added February 8, 2016
Within the white matter, axonal loss by neurodegeneration is coupled to glial cell changes in gene expression, structure and function commonly termed gliosis. Recently, we described the highly variable expansion of gliosis alebosco@neuro.utah.edu in degenerative optic nerves from the DBA/2J mouse model of chronic, age-related glaucoma. Here, to estimate and compare the levels of axonal loss with the expansion of glial coverage and axonal degeneration in DBA/2J nerves, we combined semiautomatic axon counts with threshold-based segmentation of total glial/scar areas and degenerative axonal profiles in plastic cross-sections. In nerves ranging from mild to severe degeneration, we found that the progression of axonal dropout is coupled to an increase of gliotic area. We detected a strong correlation between axon loss and the aggregate coverage by glial cells and scar, whereas axon loss did not correlate with the small fraction of degenerating profiles. Nerves with low to medium levels of axon loss displayed moderate glial reactivity, consisting of hypertrophic astrocytes, activated microglia and normal distribution of oligodendrocytes, with minimal reorganization of the tissue architecture. In contrast, nerves with extensive axonal loss showed prevalent rearrangement of the nerve, with loss of axon fascicle territories and enlarged or almost continuous gliotic and scar domains, containing reactive astrocytes, oligodendrocytes and activated microglia. These findings support the value of optic nerve gliotic expansion as a quantitative estimate of optic neuropathy that correlates with axon loss, applicable to grade the severity of optic nerve damage in mouse chronic glaucoma.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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17 MeSH Terms
Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma.
Cooper ML, Crish SD, Inman DM, Horner PJ, Calkins DJ
(2016) Exp Eye Res 150: 22-33
MeSH Terms: Animals, Astrocytes, Axons, Disease Models, Animal, Glaucoma, Open-Angle, Imaging, Three-Dimensional, Mice, Mice, Inbred DBA, Nerve Degeneration, Optic Nerve, Optic Nerve Diseases, Photomicrography, Retinal Ganglion Cells, Time Factors
Show Abstract · Added February 8, 2016
Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45-0.50 μm(2)), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
The RNA Binding Protein Igf2bp1 Is Required for Zebrafish RGC Axon Outgrowth In Vivo.
Gaynes JA, Otsuna H, Campbell DS, Manfredi JP, Levine EM, Chien CB
(2015) PLoS One 10: e0134751
MeSH Terms: Actins, Animals, Axons, Gene Knockdown Techniques, RNA-Binding Proteins, Retinal Ganglion Cells, Zebrafish, Zebrafish Proteins
Show Abstract · Added November 2, 2015
Attractive growth cone turning requires Igf2bp1-dependent local translation of β-actin mRNA in response to external cues in vitro. While in vivo studies have shown that Igf2bp1 is required for cell migration and axon terminal branching, a requirement for Igf2bp1 function during axon outgrowth has not been demonstrated. Using a timelapse assay in the zebrafish retinotectal system, we demonstrate that the β-actin 3'UTR is sufficient to target local translation of the photoconvertible fluorescent protein Kaede in growth cones of pathfinding retinal ganglion cells (RGCs) in vivo. Igf2bp1 knockdown reduced RGC axonal outgrowth and tectal coverage and retinal cell survival. RGC-specific expression of a phosphomimetic Igf2bp1 reduced the density of axonal projections in the optic tract while sparing RGCs, demonstrating for the first time that Igf2bp1 is required during axon outgrowth in vivo. Therefore, regulation of local translation mediated by Igf2bp proteins may be required at all stages of axon development.
0 Communities
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8 MeSH Terms
Genetic chimeras reveal the autonomy requirements for Vsx2 in embryonic retinal progenitor cells.
Sigulinsky CL, German ML, Leung AM, Clark AM, Yun S, Levine EM
(2015) Neural Dev 10: 12
MeSH Terms: Animals, Cell Division, Chimera, Embryo Transfer, Female, Genes, Reporter, Homeodomain Proteins, LIM-Homeodomain Proteins, Male, Mice, Mice, Transgenic, Microphthalmia-Associated Transcription Factor, Mosaicism, Neural Stem Cells, Neurogenesis, Neuroglia, Organ Specificity, Retina, Retinal Ganglion Cells, Transcription Factors
Show Abstract · Added November 2, 2015
BACKGROUND - Vertebrate retinal development is a complex process, requiring the specification and maintenance of retinal identity, proliferative expansion of retinal progenitor cells (RPCs), and their differentiation into retinal neurons and glia. The homeobox gene Vsx2 is expressed in RPCs and required for the proper execution of this retinal program. However, our understanding of the mechanisms by which Vsx2 does this is still rudimentary. To define the autonomy requirements for Vsx2 in the regulation of RPC properties, we generated chimeric mouse embryos comprised of wild-type and Vsx2-deficient cells.
RESULTS - We show that Vsx2 maintains retinal identity in part through the cell-autonomous repression of the retinal pigment epithelium determinant Mitf, and that Lhx2 is required cell autonomously for the ectopic Mitf expression in Vsx2-deficient cells. We also found significant cell-nonautonomous contributions to Vsx2-mediated regulation of RPC proliferation, pointing to an important role for Vsx2 in establishing a growth-promoting extracellular environment. Additionally, we report a cell-autonomous requirement for Vsx2 in controlling when neurogenesis is initiated, indicating that Vsx2 is an important mediator of neurogenic competence. Finally, the distribution of wild-type cells shifted away from RPCs and toward retinal ganglion cell precursors in patches of high Vsx2-deficient cell density to potentially compensate for the lack of fated precursors in these areas.
CONCLUSIONS - Through the generation and analysis of genetic chimeras, we demonstrate that Vsx2 utilizes both cell-autonomous and cell-nonautonomous mechanisms to regulate progenitor properties in the embryonic retina. Importantly, Vsx2's role in regulating Mitf is in part separable from its role in promoting proliferation, and proliferation is excluded as the intrinsic timer that determines when neurogenesis is initiated. These findings highlight the complexity of Vsx2 function during retinal development and provide a framework for identifying the molecular mechanisms mediating these functions.
0 Communities
1 Members
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20 MeSH Terms
Activation of transient receptor potential vanilloid-1 (TRPV1) influences how retinal ganglion cell neurons respond to pressure-related stress.
Sappington RM, Sidorova T, Ward NJ, Chakravarthy R, Ho KW, Calkins DJ
(2015) Channels (Austin) 9: 102-13
MeSH Terms: Animals, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Mice, Transgenic, Neurons, Retinal Ganglion Cells, Stress, Physiological, TRPV Cation Channels
Show Abstract · Added February 4, 2016
Our recent studies implicate the transient receptor potential vanilloid-1 (TRPV1) channel as a mediator of retinal ganglion cell (RGC) function and survival. With elevated pressure in the eye, TRPV1 increases in RGCs, supporting enhanced excitability, while Trpv1 -/- accelerates RGC degeneration in mice. Here we find TRPV1 localized in monkey and human RGCs, similar to rodents. Expression increases in RGCs exposed to acute changes in pressure. In retinal explants, contrary to our animal studies, both Trpv1 -/- and pharmacological antagonism of the channel prevented pressure-induced RGC apoptosis, as did chelation of extracellular Ca(2+). Finally, while TRPV1 and TRPV4 co-localize in some RGC bodies and form a protein complex in the retina, expression of their mRNA is inversely related with increasing ocular pressure. We propose that TRPV1 activation by pressure-related insult in the eye initiates changes in expression that contribute to a Ca(2+)-dependent adaptive response to maintain excitatory signaling in RGCs.
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2 Members
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10 MeSH Terms
Delayed vision loss and therapeutic intervention after blast injury.
Rex TS
(2014) Invest Ophthalmol Vis Sci 55: 8342
MeSH Terms: Animals, Blast Injuries, Brain Injuries, Carbazoles, Male, Neuroprotective Agents, Retinal Ganglion Cells, Vision Disorders
Added January 20, 2015
0 Communities
1 Members
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8 MeSH Terms
Short-term increases in transient receptor potential vanilloid-1 mediate stress-induced enhancement of neuronal excitation.
Weitlauf C, Ward NJ, Lambert WS, Sidorova TN, Ho KW, Sappington RM, Calkins DJ
(2014) J Neurosci 34: 15369-81
MeSH Terms: Action Potentials, Animals, Calcium, Capsaicin, Cell Survival, Disease Models, Animal, Diterpenes, Dopamine, Glaucoma, Intraocular Pressure, Mice, Mice, Knockout, Primary Cell Culture, Retinal Ganglion Cells, Stress, Physiological, TRPV Cation Channels
Show Abstract · Added February 12, 2015
Progression of neurodegeneration in disease and injury is influenced by the response of individual neurons to stressful stimuli and whether this response includes mechanisms to counter declining function. Transient receptor potential (TRP) cation channels transduce a variety of disease-relevant stimuli and can mediate diverse stress-dependent changes in physiology, both presynaptic and postsynaptic. Recently, we demonstrated that knock-out or pharmacological inhibition of the TRP vanilloid-1 (TRPV1) capsaicin-sensitive subunit accelerates degeneration of retinal ganglion cell neurons and their axons with elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Here we probed the mechanism of the influence of TRPV1 on ganglion cell survival in mouse models of glaucoma. We found that induced elevations of ocular pressure increased TRPV1 in ganglion cells and its colocalization at excitatory synapses to their dendrites, whereas chronic elevation progressively increased ganglion cell Trpv1 mRNA. Enhanced TRPV1 expression in ganglion cells was transient and supported a reversal of the effect of TRPV1 on ganglion cells from hyperpolarizing to depolarizing, which was also transient. Short-term enhancement of TRPV1-mediated activity led to a delayed increase in axonal spontaneous excitation that was absent in ganglion cells from Trpv1(-/-) retina. In isolated ganglion cells, pharmacologically activated TRPV1 mobilized to discrete nodes along ganglion cell dendrites that corresponded to sites of elevated Ca(2+). These results suggest that TRPV1 may promote retinal ganglion cell survival through transient enhancement of local excitation and axonal activity in response to ocular stress.
Copyright © 2014 the authors 0270-6474/14/3415369-13$15.00/0.
0 Communities
2 Members
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16 MeSH Terms