Measuring Deformation in the Mouse Optic Nerve Head and Peripapillary Sclera

Nguyen, Cathy; Midgett, Dan; Kimball, Elizabeth; Steinhart, Matthew R.; Nguyen, Thao D.; Pease, Mary Ellen; Oglesby, Ericka; Jefferys, Joan L.; Quigley, Harry A.

doi:10.1167/iovs.16-20620

Cited by 34 publications

(40 citation statements)

References 51 publications

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“…The increase in the ON area in R1 was also demonstrated in a prior study. 38 In addition, the OHT nerves in R1 exhibited a decrease in the GFAP area fraction, decrease in process width, increase in the number of axonal compartments, and increase in axonal area. Greater IOP elevations relative to the baseline produced greater morphologic changes in R1.…”

Section: Discussionmentioning

confidence: 94%

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Pressure-Induced Changes in Astrocyte GFAP, Actin, and Nuclear Morphology in Mouse Optic Nerve

Ling

Pease

Jefferys

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose To conduct quantitative analysis of astrocytic glial fibrillary acidic protein (GFAP), actin and nuclei distribution in mouse optic nerve (ON) and investigate changes in the measured features after 3 days of ocular hypertension (OHT). Method Serial cross-sections of 3-day microbead-induced OHT and control ONs were fluorescently labelled and imaged using confocal microscope. Eighteen structural features were measured from the acquired images, including GFAP coverage, actin area fraction, process thickness, and aspect ratio of cell nucleus. The measured features were analyzed for variations with axial locations along ON and radial zones transverse to ON, as well as for the correlations with degree of intraocular pressure (IOP) change. Results The most significant changes in structural features after 3-day OHT occurred in the unmyelinated ON region (R1), and the changes were greater with greater IOP elevation. Although the GFAP, actin, axonal, and ON areas all increased in 3-day OHT ONs in R1 ( P ≤ 0.004 for all), the area fraction of GFAP actually decreased ( P = 0.02), the actin area fraction was stable and individual axon compartments were unchanged in size. Within R1, the number of nuclear clusters increased ( P < 0.001), but the mean size of nuclear clusters was smaller ( P = 0.02) and the clusters became rounder ( P < 0.001). In all cross-sections of control ONs, astrocytic processes were thickest in the rim zone compared with the central and peripheral zones ( P ≤ 0.002 for both), whereas the overall process width in R1 decreased after 3 days of OHT ( P < 0.001). Conclusions The changes in structure elucidated IOP-generated alterations that underlie astrocyte mechanotranslational responses relevant to glaucoma.

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Section: Discussionmentioning

confidence: 94%

“…There were also large changes in strain response after 3 days of OHT. 38 Some of the changes may be reversible if the IOP were lowered, or may progress over a longer period of time. At longer times, the remodeling of the connective tissue structure of the sclera may also alter the mechanical loading on the astrocytic lamina.…”

Section: Discussionmentioning

confidence: 99%

Pressure-Induced Changes in Astrocyte GFAP, Actin, and Nuclear Morphology in Mouse Optic Nerve

Ling

Pease

Jefferys

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…However, DVC can be used with a variety of imaging methods. For example, we are developing an inflation method to map the deformation of the astrocytic lamina of GFP-glutamate transporter-GLT1 CD1 mice [71]. The method uses two-photon fluorescence, a nonlinear optical microscopy method, to provide a natural speckle pattern for DVC correlation.…”

Section: Discussionmentioning

confidence: 99%

The pressure-induced deformation response of the human lamina cribrosa: Analysis of regional variations

et al. 2017

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The objective of this study was to measure the pressure-induced deformation response of the human lamina cribrosa (LC) and analyze for variations with age and anatomical region. The posterior scleral cup of 8 eyes from 6 human donors was mounted onto a custom inflation chamber. A laser-scanning microscope was used for second harmonic generation (SHG), imaging the collagen structure in the posterior volume of the LC at pressures from 5 mmHg to 45 mmHg. The SHG volumes were analyzed by the Fast-Fourier Iterative Digital Volume Correlation (DVC) algorithm for the three dimensional (3D) displacement field. The components of the Green-Lagrange strain tensor and the in-plane principal and maximum shear strains were evaluated from the DVC displacement field for the central and peripheral regions of the LC and the nasal, temporal, inferior, and superior quadrants surrounding the central retinal artery and vein. Among the major findings were that older age was associated with lower strains, the maximum shear strain was larger in the peripheral than central region, and the maximum principal strain was lower in the nasal quadrant. The elliptical shape of the LC was also predictive of the biaxial strain ratio. Age-related and structure-related variations in the pressure-induced strains of the LC may contribute to the susceptibility and severity of optic nerve damage in glaucoma, and regional variations may explain the progression of axonal damage and tissue remodeling observed in the LC in glaucoma.

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“…Lastly, the surgical approach may also be used to deliver small molecules to the posterior ocular sclera, or the retina (if coupled with scleral fenestration). Such an approach may be useful to research taking place currently to examine the contribution of scleral mechanics and modulation in glaucoma models 64 – 67 .…”

Section: Discussionmentioning

confidence: 99%

In Vivo Small Molecule Delivery to the Optic Nerve in a Rodent Model

Tehrani

Delf

Cepurna

et al. 2018

Sci Rep

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Small molecule delivery to the optic nerve would allow for exploration of molecular and cellular pathways involved in normal physiology and optic neuropathies such as glaucoma, and provide a tool for screening therapeutics in animal models. We report a novel surgical method for small molecule drug delivery to the optic nerve head (ONH) in a rodent model. In proof-of-principle experiments, we delivered cytochalasin D (Cyt D; a filamentous actin inhibitor) to the junction of the superior optic nerve and globe in rats to target the actin-rich astrocytic cytoskeleton of the ONH. Cyt D delivery was quantified by liquid chromatography and mass spectrometry of isolated optic nerve tissue. One day after Cyt D delivery, anterior ONH filamentous actin bundle content was significantly reduced as assessed by fluorescent-tagged phalloidin labeling, relative to sham delivery. Anterior ONH nuclear counts and axon-specific beta-3 tubulin levels, as well as peripapillary retinal ganglion cell layer nuclear counts were not significantly altered after Cyt D delivery relative to sham delivery. Lastly, the surgical delivery technique caused minimal observable axon degeneration up to 10 days post-surgery. This small molecule delivery technique provides a new approach to studying optic neuropathies in in vivo rodent models.

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Measuring Deformation in the Mouse Optic Nerve Head and Peripapillary Sclera

Cited by 34 publications

References 51 publications

Pressure-Induced Changes in Astrocyte GFAP, Actin, and Nuclear Morphology in Mouse Optic Nerve

Pressure-Induced Changes in Astrocyte GFAP, Actin, and Nuclear Morphology in Mouse Optic Nerve

The pressure-induced deformation response of the human lamina cribrosa: Analysis of regional variations

In Vivo Small Molecule Delivery to the Optic Nerve in a Rodent Model

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