Optometry and Vision Sciences - Research Publications
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ItemNo Preview AvailableReversibility of retinal ganglion cell dysfunction due to chronic IOP elevation.(Association for Research in Vision and Ophthalmology, 2018-07-01)Purpose : To determine the duration of chronic IOP elevation beyond which ganglion cell function can no longer recover using the mouse circumlimbal suture model. Methods : IOP elevation was induced in anaesthetized (isoflurane) adult male C57BL6/J mice by attaching a circumlimbal suture (nylon, 10/0) around the equator of one eye, with the contralateral eye serving as a control. The suture was left in place for 8, 12 and 16 weeks (n=27, 23 and 27), respectively, and animals underwent electroretinography and optical coherence tomography at these time points. In two other groups, the suture was removed after 8 and 12 weeks (n=26 and 28), and the capacity for recovery assessed 4 weeks later. IOP was measured weekly (Tonolab). Retinal ganglion cell (RGC) function (or integrity) was assessed with the positive scotopic threshold response (pSTR) and retinal nerve fibre layer (RNFL) thickness. Data (mean ± SEM) were compared using t-test (control vs. treatment) and one-way ANOVA (within groups). Results : IOP in sutured eyes was higher than control eyes (8wk: 17.1 ± 0.3 vs. 26.8 ± 0.6 mmHg, 12wk: 13.8 ± 0.3 vs. 19.5 ± 0.5 mmHg, 16wk: 17.1 ± 0.2 vs. 27.4 ± 0.6 mmHg; all P<0.001). After suture removal, IOP returned to levels comparable to control eyes (8+4wk: 16.9 ± 0.3 vs. 16.1 ± 0.3 mmHg; P=0.08, 12+4wk: 17.3 ± 0.2 vs. 17.1 ± 0.3 mmHg; P=0.5). With IOP elevation, RGC function declined to 75% ± 8% (8wk), 78% ± 7% (12wk) and 59% ± 4% (16wk, all P<0.001) of control eyes. RNFL thinning was also evident (8wk: 84% ± 4%, 12wk: 83% ± 5%; 16wk: 83% ± 3%; P<0.001) but no change in total retinal thickness was noted (P=0.33). Suture removal at week 8 facilitated full recovery of RGC function (97% ± 7%, P=0.9 vs. baseline) 4 weeks later. However, there was no recovery in RNFL thickness (87% ± 3%, P<0.001 vs. baseline). When the suture was removed at week 12, neither function (79% ± 9%, P<0.05) nor RNFL thickness recovered (89% ± 3%, P<0.01) 4 weeks later. Conclusions : RGC dysfunction can be recovered 4 weeks after an 8-week period of mild IOP elevation, but not after a 12-week period. Beyond 12 weeks, IOP reversal only served to prevent further functional decline. This identifies a critical chronic IOP duration that results in irreversible ganglion cell dysfunction. This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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ItemNo Preview AvailableResponse of the Rat Optic Nerve to Acute Intraocular and Intracranial Pressure Changes(Springer Singapore, 2019)Glaucoma is a neurodegenerative disease, characterized by the progressive death of retinal ganglion cells. Elevated intraocular pressure (IOP) is known to be an important risk factor for glaucoma; however, it is not the only force acting on the optic nerve. Intracranial pressure (ICP) also exerts an effect on the optic nerve head, effectively opposing the force applied by IOP. Indeed, this balance of forces creates a pressure gradient (or the translaminar pressure gradient) across the optic nerve head [1]. Increasingly it is thought that the pressure difference between IOP and ICP, the translaminar pressure (TLP), may be critical for the integrity of the retina and optic nerve [2], and thus ICP may be an important risk factor for glaucoma [2–6].
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ItemA Model of Glaucoma Induced by Circumlimbal Suture in Rats and Mice(Journal of Visualized Experiments, 2018)The circumlimbal suture is a technique for inducing experimental glaucoma in rodents by chronically elevating intraocular pressure (IOP), a well-known risk factor for glaucoma. This protocol demonstrates a step-by-step guide on this technique in Long Evans rats and C57BL/6 mice. Under general anesthesia, a "purse-string" suture is applied on the conjunctiva, around the equator and behind the limbus of the eye. The fellow eye serves as an untreated control. Over the duration of our study, which was a period of 8 weeks for rats and 12 weeks for mice, IOP remained elevated, as measured regularly by rebound tonometry in conscious animals without topical anesthesia. In both species, the sutured eyes showed electroretinogram features consistent with preferential inner retinal dysfunction. Optical coherence tomography showed selective thinning of the retinal nerve fiber layer. Histology of the rat retina in cross-section found reduced cell density in the ganglion cell layer, but no change in other cellular layers. Staining of flat-mounted mouse retinae with a ganglion cell specific marker (RBPMS) confirmed ganglion cell loss. The circumlimbal suture is a simple, minimally invasive and cost-effective way to induce ocular hypertension that leads to ganglion cell injury in both rats and mice.
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ItemNo Preview AvailableEvaluating retinal biomarkers in a mouse model of Parkinson's disease(Association for Research in Vision and Ophthalmology, 2019-07-01)Purpose : The retina, an accessible outpouching of the central nervous system, may manifest cortical changes that occur with Parkinson’s disease (PD), lending itself as a potential biomarker. PD is characterised by reduced dopamine levels, a neurotransmitter found in amacrine cells. Human PD patients have also shown structural changes in the outer retina. This work aims to determine if retinal function and structure are altered in a murine model of PD and whether deficits can be ameliorated with L-DOPA treatment. Methods : A PD model was induced in adult C57BL6/J mice using MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 4x i.p. injections, 20mg/kg) and vehicle control and examined at day 21 and 45. Another MPTP group was administered L-DOPA (L-3,4-dihydroxyphenylalanine 0.2 mg/ml) or control in their drinking water and assessed at day 45 (n=12–15/group). In ketamine:xylazine anaesthetised (80:10mg/kg) mice full-field dark- and light-adapted electroretinography (ERG) was assessed to target dopamine-related responses. Optical coherence tomography (OCT) was used to quantify thickness of retinal layers. Retinal and cortical tissue were collected for immunohistochemical assessment of changes in tyrosine hydroxylase (TH)and imaged using confocal microscopy. Data (mean±SEM) were compared using unpaired ANOVA and t-tests as appropriate. Results : At day 21 no retinal changes were found. At day 45 dark and light adapted ERGs showed slower amacrine cell responses (oscillatory potential, p<0.05), a finding which reversed with L-DOPA treatment (p<0.05). Other components of the ERG were unchanged. TH staining showed a trend towards decreased retinal levels in MPTP mice but this did not reach significance (p=0.10). Reduced levels of TH were found in the ventral hippocampus of MPTP mice compared with control (p<0.05). OCT revealed thinning of the outer plexiform layer at day 45, and the L-DOPA group exhibited a thinning of the outer nuclear layer (p<0.05). Conclusions : This study shows for the first time that the MPTP model recapitulates key dopaminergic changes previously reported in humans. In particular, electroretinographic changes that correspond with dopaminergic retinal cells occur in the Parkinson’s model and reverse with therapeutic treatment. Structural thinning of the outer retinal layers also occur, which parallels some human findings. This work paves the way for retinal measures as preclinical screening tools in drug development.
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ItemProgressive impairments in executive function in the APP/PS1 model of Alzheimer’s disease as measured by translatable touchscreen testing( 2019-08-21)Executive function deficits in Alzheimer’s disease (AD) occur early in disease progression and may be predictive of cognitive decline. However, no preclinical studies have identified deficits in rewarded executive function in the commonly used APP/PS1 mouse model. To address this, we assessed 12-26 month old APP/PS1 mice on rewarded reversal and/or extinction tasks. 16-month-old, but not 13- or 26-month-old, APP/PS1 mice showed an attenuated rate of extinction. Reversal deficits were seen in 22-month-old, but not 13-month-old APP/PS1 animals. We then confirmed that impairments in reversal were unrelated to previously reported visual impairments in both AD mouse models and humans. Age, but not genotype, had a significant effect on markers of retinal health, indicating the deficits seen in APP/PS1 mice were directly related to cognition. This is the first characterisation of rewarded executive function in APP/PS1 mice, and has great potential to facilitate translation from preclinical models to the clinic.
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ItemNo Preview AvailableThe effect of TrkB receptor knockdown on mouse retinal ganglion cell function and their response to acute mild intraocular pressure stress(Association for Research in Vision and Ophthalmology, 2019-07-01)Purpose : To examine the effect of tropomyosin receptor kinase B (TrkB) receptor removal on basal retinal ganglion cell (RGC) function and recovery from acute intraocular pressure (IOP) stress following conditional deletion of neuronal-specific TrkB receptors in adult mice. Methods : Conditional TrkB receptor knockout (KO) from Thy-1 positive neurons was induced via daily tamoxifen injections (100 ul i.p. 75mg/kg, 5 days) in 3-month old Thy1-GFP CreERT2+/- TrkBfl/fl transgenic (TrkB KO n=12) and control CreERT2-/- TrkBfl/fl mice (n=12). Four weeks later, one eye was exposed to controlled IOP stress of 50mmHg for 30 minutes, achieved via anterior chamber cannulation (50 μm glass micropipette connected to height-adjustable Hanks balanced salt solution reservoir; 80:10mg/kg ketamine:xylazine). After 7 days of recovery, retinal function (full-field electroretinogram -5.53 – 2.07 log cd.s/m2) and structure (optical coherence tomography) were assessed in sedated mice. Following in vivo assays, eyes were enucleated for immunohistochemical assessment of TrkB receptor KO efficiency using confocal microscopy. Unpaired t-test and two-way ANOVA were used for statistical analysis. Results : TrkB receptor expression was largely confined to the ganglion cell layers and reduced by 81.3±5.8% in TrkB KO retinas compared to controls (P<0.05). Deletion of TrkB receptors significantly reduced RGC-mediated negative scotopic threshold response (nSTR -39.1±13.7% P<0.05, positive STR -38.0±12.1% P=0.05). No changes in photoreceptor (amplitude P>0.05, sensitivity P>0.05) and bipolar cell (amplitude P>0.05, sensitivity P>0.05) function. At day 7 post-IOP stress, photoreceptor and bipolar cell responses recovered back to baseline whilst RGC function did not (pSTR P<0.05; nSTR P<0.05). This effect was similar for both genotypes. TrkB KO did not affect total retinal, retinal nerve fibre, ganglion cell and inner plexiform layer thicknesses compared with control retina (P>0.05). Conclusions : Conditional removal of TrkB receptors in adult mice suggests that TrkB is critical for the ongoing maintenance of ganglion cell function. Specific changes in RGC morphology, synapse expression or intrinsic excitability associated with TrkB deficiency remain to be elucidated. It appears that TrkB receptors do not play an integral role in recovery from a single episode of mild IOP stress.
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ItemEffect of intraocular pressure on vascular autoregulation of the mouse trilaminar network(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2019-07-01)PURPOSE. The purpose of this study was to test the hypothesis that the superficial, intermediate, and deep retinal vascular plexus show different responses to intraocular pressure (IOP) elevation. METHODS. Anesthetized adult Long Evans rats (n = 14) were imaged using optical coherence tomography angiography (OCTA; Spectralis) at baseline (IOP 10 mm Hg) and in follow-up mode to examine the vasculature during IOP elevation (10 to 110 mm Hg, 10 mm Hg steps, each step 3 minutes). A 20° × 10° field was imaged. Vessel density within a 2D projection image was determined (%) for the superficial vascular complex (SVC), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Comparisons were made between layers using 2-way repeated measures ANOVA (layer versus IOP) following normalization to baseline (% relative to 10 mm Hg). RESULTS. The three vascular layers responded differently to IOP elevation. For IOPs between 40 and 60 mm Hg, DCP and ICP capillaries were significantly more resistant to IOP elevation than those in the SVC. When IOP was elevated above 70 mm Hg, all layers showed reduced vessel density. IOP induced change in SVC vessel density closely followed reductions in thickness of the inner retinal layers (nerve fiber, ganglion cell, and inner plexiform layer). This close relationship between reductions in tissue thickness and vessel density was less apparent for the ICP and DCP. CONCLUSIONS. These data show that the intermediate and deep vascular plexus in the rat retina have a greater capacity for autoregulation against mild IOP elevation but are more affected at high IOP.
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ItemReversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2019-09)PURPOSE: To test the hypothesis that the capacity for retinal ganglion cells to functionally recover from chronic IOP elevation is dependent on the duration of IOP elevation. METHODS: IOP elevation was induced in one eye in anesthetized (isoflurane) adult C57BL6/J mice using a circumlimbal suture. Sutures were left in place for 8 and 16 weeks (n = 30 and 28). In two other groups the suture was cut after 8 and 12 weeks (n = 30 and 28), and ganglion cell function (electroretinography) and retinal structure (optical coherence tomography) were assessed 4 weeks later. Ganglion cell density was quantified by counting RBPMS (RNA-binding protein with multiple splicing)-stained cells. RESULTS: With IOP elevation (∼10 mm Hg above baseline), ganglion cell function declined to 75% ± 8% at 8 weeks and 59% ± 4% at 16 weeks relative to contralateral control eyes. The retinal nerve fiber layer was thinner at 8 (84% ± 4%) and 16 weeks (83% ± 3%), without a significant difference in total retinal thickness. Ganglion cell function recovered with IOP normalization (suture removal) at week 8 (97% ± 7%), but not at week 12 (73% ± 6%). Ganglion cell loss was found in all groups (-8% to -13%). CONCLUSIONS: In the mouse circumlimbal suture model, 12 weeks of IOP elevation resulted in irreversible ganglion cell dysfunction, whereas retinal dysfunction was fully reversible after 8 weeks of IOP elevation.
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ItemBehold the Eye in Parkinson's Disease & Alzheimer’s Disease(Frontiers Media SA, 2016-11)Consequently, AD/PD patients can gradually develop vision problems. This neurological and ophthalmological disorder creates a pressing need for developing therapy to treat vision impairment in AD/PD.
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ItemAge-related changes in the response of retinal structure, function and blood flow to pressure modification in rats(NATURE PORTFOLIO, 2018-02-13)Age-related changes to the balance between the pressure inside the eye (intraocular pressure, IOP) and the pressure inside the brain (intracranial pressure, ICP) can modify the risk of glaucoma. In this study, we consider whether the optic nerve in older rat eyes is more susceptible to acute IOP and ICP modification. We systematically manipulate both ICP and IOP and quantify their effects on ganglion cell function (electroretinography, ERG), optic nerve structure (optical coherence tomography, OCT) and retinal blood flow (Doppler OCT). We show that ganglion cell function in older eyes was more susceptible to a higher optic nerve pressure difference (ONPD = IOP - ICP). This age-related susceptibility could not be explained by poorer blood flow with elevated ONPD. Rather, as ONPD increased the retinal nerve fibre layer showed greater compression, and the retinal surface showed less deformation in older eyes. Our data suggest that age-related changes to connective tissues in and around the rat optic nerve make it less flexible, which may result in greater strain on ganglion cell axons. This may account for greater functional susceptibility to higher optic nerve pressure differences in older rat eyes. Further studies in a species with a well-developed lamina cribrosa are needed to determine the clinical importance of these observations.