Biology subjects

Nickerson, J. M.

Publications and source records attributed to Nickerson, J. M..

6 recordsLinked to original sources

bioRxiv2025

Effects of treadmill exercise on retinal vascular morphology, function, and circulating immune factors in a mouse model of retinal degeneration

PurposeExercise is neuroprotective in rodents undergoing retinal degeneration (RD). However, the effects of exercise on retinal vasculature remain unexplored. Here, we investigate whether treadmill exercise influences retinal vascular morphology, function, gene expression, and circulating factors in a light-induced retinal degeneration (LIRD) mouse model. Methods6-week-old female BALB/c mice were assigned to inactive+dim, active+dim, inactive+LIRD and active+LIRD groups (n=20 per group). Active mice were treadmill exercised (1hr/d 10m/min) for two weeks, then LIRD was induced (5000 lux/4hrs). Inactive mice were placed on a static treadmill. Retinal neurovascular coupling was measured with functional hyperemia (FH) and vascular morphology using OCT-A. Vascular gene expression was quantified from isolated retinal endothelial cells using ddPCR five days following LIRD. Serum was collected for circulating cytokine and chemokine analyses. Data were analyzed using 2-way ANOVA. ResultsRetinal vessel vasodilation was significantly increased in active+LIRD mice compared to inactive+LIRD mice. Superficial and intermediate/deep vascular plexi from inactive+LIRD mice had significantly decreased vessel density and total vessel length, with increased numbers of end points and lacunarity compared to active groups. Isolated retinal endothelial cell gene expression varied among groups. Most notably, Active+LIRD mice had a distinct immune response profile, with increased expression of IL-6, KC, and VEGF-A. ConclusionsTreadmill exercise maintained retinal vascular morphology and function, modestly altered endothelial gene expression, and is associated with a specific circulating immune response profile in a LIRD mouse model. These data indicate therapeutic effects of exercise on retinal vasculature in RD.

neuroscience↗

bioRxiv2024

Loss of Pigment Epithelium Derived Factor Sensitizes C57BL/6J Mice to Light-Induced Retinal Damage

5.1PurposePigment epithelium-derived factor (PEDF) is a neurotrophic glycoprotein secreted by the retinal pigment epithelium (RPE) that supports retinal photoreceptor health. Deficits in PEDF are associated with increased inflammation and retinal degeneration in aging and diabetic retinopathy. We hypothesized that light-induced stress in C57BL/6J mice deficient in PEDF would lead to increased retinal neuronal and RPE defects, impaired expression of neurotrophic factor Insulin-like growth factor 1 (IGF-1), and overactivation of Galectin-3-mediated inflammatory signaling. MethodsC57BL/6J mice expressing the RPE65 M450/M450 allele were crossed to PEDF KO/KO and wildtype (PEDF +/+) littermates. Mice were exposed to 50,000 lux light for 5 hours to initiate acute damage. Changes in visual function outcomes were tracked via electroretinogram (ERG), confocal scanning laser ophthalmoscopy(cSLO), and spectral domain optical coherence tomography (SD-OCT) on days 3, 5, and 7 post-light exposure. Gene and protein expression of Galectin-3 were measured by digital drop PCR (ddPCR) and western blot. To further investigate the role of galectin-3 on visual outcomes and PEDF expression after damage, we also used a small-molecule inhibitor to reduce its activity. ResultsFollowing light damage, PEDF KO/KO mice showed more severe retinal thinning, impaired visual function (reduced a-, b-, and c-wave amplitudes), and increased Galectin-3 expressing immune cell infiltration compared to PEDF +/+. PEDF KO/KO mice had suppressed damage-associated increases in IGF-1 expression. Additionally, baseline Galectin-3 mRNA and protein expression were reduced in PEDF KO/KO mice compared to PEDF +/+. However, after light damage, Galectin-3 expression decreases in PEDF +/+ mice but increases in PEDF KO/KO mice without reaching PEDF +/+ levels. Galectin-3 inhibition worsens retinal degeneration, reduces PEDF expression in PEDF +/+ mice, and mimics the effects seen in PEDF knockouts. ConclusionsLoss of PEDF alone does not elicit functional defects in C57BL/6J mice. However, under light stress, PEDF deficiency significantly increases severe retinal degeneration, visual deficits, Galectin-3 expression, and suppression of IGF-1 than PEDF +/+. PEDF deficiency reduced baseline expression of Galectin-3, and pharmacological inhibition of Galectin-3 worsens outcomes and suppresses PEDF expression in PEDF +/+, suggesting a novel co-regulatory relationship between the two proteins in mitigating light-induced retinal damage.

molecular biology↗

bioRxiv2024

High resolution imaging and interpretation of three-dimensional RPE sheet structure

The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell to cell contact, barrier function, and conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers. We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (alpha-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misinterpreting multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO3 oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes.

molecular biology↗

bioRxiv2021

Treadmill exercise promotes retinal astrocyte plasticity and protects against retinal degeneration

Exercise has been shown to be an effective neuroprotective intervention that preserves retinal function and structure in several animal models of retinal degeneration. However, retinal cell morphology and cell types governing exercise-induced retinal neuroprotection remain elusive. Previously, we found that the protective effects of exercise in animal models of retinal disease were accompanied by increased levels of circulating and retinal brain derived neurotrophic factor (BDNF) and required intact signal transduction with its high-affinity receptor, tropomyosin kinase B (TrkB). Studies of neurodegenerative diseases in the brain demonstrate that neurons and astrocytes express BDNF and TrkB. Additionally, astrocytes have been shown to alter their morphology in response to exercise. Here, we have investigated the role of retinal astrocytes as mediators of exercise-induced retinal neuroprotection in a light-induced retinal degeneration mouse model (LIRD). We found that treadmill exercise in both our dim (control maintenance light levels) and LIRD groups promote increased retinal astrocytic population, GFAP expression, branching and endpoints, dendritic complexity, and promotes BDNF-astrocyte interaction. In contrast, LIRD animals that were inactive had significant reductions in all measured parameters. Our findings indicate that exercise is sufficient to rescue retinal astrocyte morphology in a LIRD model maintaining branching and dendritic arborization similar to retinal astrocytes that are not undergoing degeneration. These studies provide essential information to current knowledge gaps in regards to exercise-induced neuroprotection and will additionally provide knowledge in exercise intervention optimization as a rehabilitative method. Significance statementThis study represents an essential step in determining the cell-types governing and morphological alterations elicited from exercise which may provide neural repair and protection. Similar to astrocytes in the brain, retinal astrocytes alter their morphology in response to exercise. Our studies demonstrate exercise promotes increased interactions between retinal astrocytes and neural growth factors in healthy retinas as well as in retinas undergoing degeneration, which may ultimately protect dying retinal neurons. These studies provide insight into the potential neuroprotective role astrocytes play in neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Systemic Treatment with Nicotinamide Riboside is Protective in Three Mouse Models of Retinal Degeneration

Purpose: The retina is highly metabolically active, suggesting that metabolic dysfunction could underlie many retinal degenerative diseases. Nicotinamide adenine dinucleotide (NAD+) is a cofactor and a co-substrate in several cellular energetic metabolic pathways. Maintaining NAD+ levels may be therapeutic in retinal disease since retinal NAD+ levels decline with age and during retinal damage or degeneration. The purpose of this study was to investigate whether systemic treatment with nicotinamide riboside (NR), a NAD+ precursor, is protective in disparate models of retinal damage or degeneration. MethodsThree mouse models of retinal degeneration were tested: an albino mouse model of light-induced retinal degeneration (LIRD) and two models of retinitis pigmentosa (RP), including a mouse line deficient in interphotoreceptor binding protein (IRBP) gene expression (IRBP KO), and a naturally-occuring cGMP phosphodiesterase 6b mutant mouse model of RP (the Pde6brd10 mouse). Mice were intraperitoneally (IP) injected with PBS or NR at various times relative to damage or degeneration onset. One to two weeks later, retinal function was assessed by electroretinograms (ERGs) and retinal morphology was assessed by optical coherence tomography (OCT). Afterwards, retina sections were H&E stained for morphological analysis or by terminal deoxynucleiotidyl transferase dUTP nick and labeling (TUNEL). Retinal NAD+/NADH levels were enzymatically assayed. ResultsThe retinal degeneration models exhibited significantly suppressed retinal function, and where examined, severely disrupted photoreceptor cell layer and significantly decreased numbers of nuclei and increased accumulation of DNA breaks as measured by TUNEL-labeled cells in the outer nuclear layer (ONL). These effects were prevented by various NR treatment regimens. IP treatment with NR also resulted in increased levels of NAD+ in retina. ConclusionsThis is the first study to report protective effects of NR treatment in mouse models of retinal degeneration. The positive outcomes in several models, coupled with human tolerance to NR dosing, suggest that maintaining retinal NAD+ via systemic NR treatment should be further explored for clinical relevance.

molecular biology↗

bioRxiv2019

Effect of systemic treatment with Tauroursodeoxycholic Acid (TUDCA) on retinal ganglion cell death following optic nerve crush

The aim of this study was to investigate the protective effects of systemically administered N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) or tauroursodeoxycholic acid (TUDCA) in an optic nerve crush (ONC) mouse model. HIOC (50 mg/kg) or TUDCA (500mg/kg) were intraperitoneally (i.p.) injected into adult C57BL/6 mice three times per week. Two weeks after treatment (6 injections), unilateral optic nerve crush was conducted followed by treatment at the same day. The treatment was continued until 1 week or 2 weeks after ONC. A control cohort was identically treated with drug vehicle (phosphate-buffered saline; PBS). Retinas were harvested for whole mount immunofluorescence staining with RGC markers and imaged by fluorescent confocal microscopy at 40x magnification. Fluorescing cells were counted by computer-assisted automated identification and counting software (CellProfiler). Cohort sampling sizes were N=4 and statistical tesing was by the Wilcoxon-Mann-Whitney Test. Significant loss (80%85%) occurred in the PBS-injected group 1 and 2 weeks after ONC. This loss was partially but significantly prevented in drug-treated cohorts (P < 0.05). Delivery of HIOC or TUDCA by i.p. injection increased survival of RGCs after ONC. Protection was similar between treatment with either drug. These data suggest that it is worthwhile to further explore possible protective effects of HIOC or TUDCA on RGC subtypes with regards to structure and function and in additional disease models that involve RGC loss.

neuroscience↗