Faculty Bibliography

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer's disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

Glaucoma is a group of ophthalmologic conditions characterized by progressive retinal ganglion cell death, optic nerve degeneration, and irreversible vision loss. While intraocular pressure is the only clinically modifiable risk factor, glaucoma may continue to progress at controlled intraocular pressure, indicating other major factors in contributing to the disease mechanisms. Recent studies demonstrated the feasibility of advanced diffusion magnetic resonance imaging (dMRI) in visualizing the microstructural integrity of the visual system, opening new possibilities for non-invasive characterization of glaucomatous brain changes for guiding earlier and targeted intervention besides intraocular pressure lowering. In this review, we discuss dMRI methods currently used in visual system investigations, focusing on the eye, optic nerve, optic tract, subcortical visual brain nuclei, optic radiations, and visual cortex. We evaluate how conventional diffusion tensor imaging, higher-order diffusion kurtosis imaging, and other extended dMRI techniques can assess the neuronal and glial integrity of the visual system in both humans and experimental animal models of glaucoma, among other optic neuropathies or neurodegenerative diseases. We also compare the pros and cons of these methods against other imaging modalities. A growing body of dMRI research indicates that this modality holds promise in characterizing early glaucomatous changes in the visual system, determining the disease severity, and identifying potential neurotherapeutic targets, offering more options to slow glaucoma progression and to reduce the prevalence of this world's leading cause of irreversible but preventable blindness.

BACKGROUND:administration into both native and transplanted eyes. RESULTS: No significant intraocular pressure difference was found between native and transplanted eyes, whereas comparable manganese enhancement was observed between native and transplanted intraorbital optic nerves, suggesting the presence of anterograde manganese transport after WET. No enhancement was detected across the coaptation site in the higher visual areas of the recipient brain. Comparison with Existing Methods: Existing imaging methods to assess WET focus on either the eye or local optic nerve segments without direct visualization and longitudinal quantification of physiological transport along the transplanted visual pathway, hence the development of in vivo MEMRI. CONCLUSION/CONCLUSIONS: Our established imaging platform indicated that essential physiological transport exists in the transplanted optic nerve after WET. As neuroregenerative approaches are being developed to connect the transplanted eye to the recipient's brain, in vivo MEMRI is well-suited to guide strategies for successful WET integration for vision restoration. Keywords (Max 6): Anterograde transport, magnetic resonance imaging, manganese, neuroregeneration, optic nerve, whole-eye transplantation.

Optic nerve health is essential for proper function of the visual system. However, the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve, such as glaucoma, is not fully understood. Recently, it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases. The ability to clear metabolic waste is essential for tissue homeostasis in mammals, including humans. While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions, there is growing evidence of a glymphatic system in the central nervous system, which structurally includes the optic nerve. Named to acknowledge the supportive role of astroglial cells, this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system. Herein, we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve. We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents, aquaporin 4-null rodents, and humans; glymphatic imaging studies in diseases where the optic nerve is impaired; and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health. We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.

Gpr125, encoded by Adgra3, is an orphan adhesion G-protein coupled receptor (aGPCR) implicated in modulating Wnt signaling and planar polarity. Here we establish both physiological and pathological roles for Gpr125. We show that mice lacking Gpr125 or its signaling domains display an ocular phenotype with many hallmarks of human dry eye syndrome. These include squinting, abnormal lacrimation, mucus accumulation, swollen eyelids and inflammatory infiltration of lacrimal and meibomian glands. Utilizing a Gpr125-β-gal reporter and scRNAseq, we identify Gpr125 expression in a discrete population of cells located at the tips of migrating embryonic lacrimal ducts. By lineage tracing we show these cells function as progenitors of the adult lacrimal myoepithelium. Beyond defining an essential role for Gpr125 in tear film and identifying its utility as a marker of lacrimal progenitors, this study implicates Gpr125 in the etiology of blepharitis and dry eye syndrome, and defines novel animal models of these common maladies

The goal of this study was to quantify the association between sensory integration abilities relevant for standing balance and disease stage in glaucoma. The disease stage was assessed using both functional (visual field deficit) and structural (retinal nerve fiber layer thickness) deficits in the better and worse eye. Balance was assessed using an adapted version of the well-established Sensory Organization Test (SOT). Eleven subjects diagnosed with mild to moderate glaucoma stood for 3 min in 6 sensory challenging postural conditions. Balance was assessed using sway magnitude and sway speed computed based on center-of-pressure data. Mixed linear regression analyses were used to investigate the associations between glaucoma severity and balance measures. Findings revealed that the visual field deficit severity in the better eye was associated with increased standing sway speed. This finding was confirmed in eyes open and closed conditions. Balance was not affected by the extent of the visual field deficit in the worse eye. Similarly, structural damage in either eye was not associated with the balance measures. In summary, this study found that postural control performance was associated with visual field deficit severity. The fact that this was found during eyes closed as well suggests that reduced postural control in glaucoma is not entirely attributed to impaired peripheral visual inputs. A larger study is needed to further investigate potential interactions between visual changes and central processing changes contributing to reduced balance function and increased incidence of falls in adults with glaucoma.

The visual system retains profound plastic potential in adulthood. In the current review, we summarize the evidence of preserved plasticity in the adult visual system during visual perceptual learning as well as both monocular and binocular visual deprivation. In each condition, we discuss how such evidence reflects two major cellular mechanisms of plasticity: Hebbian and homeostatic processes. We focus on how these two mechanisms work together to shape plasticity in the visual system. In addition, we discuss how these two mechanisms could be further revealed in future studies investigating cross-modal plasticity in the visual system.

Purpose:To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI). Methods:Two experimentally induced and three genetically determined models of glaucoma were evaluated. For inducible models, chronic IOP elevation was achieved via intracameral injection of microbeads or laser photocoagulation of the trabecular meshwork in adult rodent eyes. For genetic models, the DBA/2J mouse model of pigmentary glaucoma, the LTBP2 mutant feline model of congenital glaucoma, and the transgenic TBK1 mouse model of normotensive glaucoma were compared with their respective genetically matched healthy controls. DTI parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, were evaluated along the optic nerve and optic tract. Results:Significantly elevated IOP relative to controls was observed in each animal model except for the transgenic TBK1 mice. Significantly lower fractional anisotropy and higher radial diffusivity were observed along the visual pathways of the microbead- and laser-induced rodent models, the DBA/2J mice, and the LTBP2-mutant cats compared with their respective healthy controls. The DBA/2J mice also exhibited lower axial diffusivity, which was not observed in the other models examined. No apparent DTI change was observed in the transgenic TBK1 mice compared with controls. Conclusions:Chronic IOP elevation was accompanied by decreased fractional anisotropy and increased radial diffusivity along the optic nerve or optic tract, suggestive of disrupted microstructural integrity in both inducible and genetic glaucoma animal models. The effects on axial diffusivity differed between models, indicating that this DTI metric may represent different aspects of pathological changes over time and with severity.

This study employed in vivo 7-T magnetic resonance imaging (MRI) to evaluate the postnatal ocular growth patterns under normal development or neonatal impairments in Sprague-Dawley rats. Using T2-weighted imaging on healthy rats from postnatal day (P) 1 (newborn) to P60 (adult), the volumes of the anterior chamber and posterior chamber (ACPC), lens, and vitreous humor increased logistically with ACPC expanding by 33-fold and the others by fivefold. Intravitreal potassium dichromate injection at P1, P7, and P14 led to T1-weighted signal enhancement in the developing retina by 188-289%. Upon unilateral hypoxic-ischemic encephalopathy at P7, monocular deprivation at P15, and monocular enucleation at P1, T2-weighted imaging of the adult rats showed decreased ocular volumes to different extents. In summary, in vivo high-field MRI allows for non-invasive evaluation of early postnatal development in the normal and impaired rat eyes. Chromium-enhanced MRI appeared effective in examining the developing retina before natural eyelid opening at P14 with relevance to lipid metabolism. The reduced ocular volumes upon neonatal visual impairments provided evidence to the emerging problems of why some impaired visual outcomes cannot be solely predicted by neurological assessments and suggested the need to look into both the eye and the brain under such conditions.