Faculty Bibliography

Glaucoma is an age-related neurodegenerative disease of the visual system, affecting both the eye and the brain. Yet its underlying metabolic mechanisms and neurobehavioral relevance remain largely unclear. Here, using proton magnetic resonance spectroscopy and functional magnetic resonance imaging, we investigated the GABAergic and glutamatergic systems in the visual cortex of glaucoma patients, as well as neural specificity, which is shaped by GABA and glutamate signals and underlies efficient sensory and cognitive functions. Our study shows that among the older adults, both GABA and glutamate levels decrease with increasing glaucoma severity regardless of age. Further, our study shows that the reduction of GABA but not glutamate predicts the neural specificity. This association is independent of the impairments on the retina structure, age, and the gray matter volume of the visual cortex. Our results suggest that glaucoma-specific decline of GABA undermines neural specificity in the visual cortex and that targeting GABA could improve the neural specificity in glaucoma.

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.

Plasticity in the brain is impacted by an individual's age at the onset of the blindness. However, what drives the varying degrees of plasticity remains largely unclear. One possible explanation attributes the mechanisms for the differing levels of plasticity to the cholinergic signals originating in the nucleus basalis of Meynert. This explanation is based on the fact that the nucleus basalis of Meynert can modulate cortical processes such as plasticity and sensory encoding through its widespread cholinergic projections. Nevertheless, there is no direct evidence indicating that the nucleus basalis of Meynert undergoes plastic changes following blindness. Therefore, using multiparametric magnetic resonance imaging, we examined if the structural and functional properties of the nucleus basalis of Meynert differ between early blind, late blind and sighted individuals. We observed that early and late blind individuals had a preserved volumetric size and cerebrovascular reactivity in the nucleus basalis of Meynert. However, we observed a reduction in the directionality of water diffusion in both early and late blind individuals compared to sighted individuals. Notably, the nucleus basalis of Meynert presented diverging patterns of functional connectivity between early and late blind individuals. This functional connectivity was enhanced at both global and local (visual, language and default-mode networks) levels in the early blind individuals, but there were little-to-no changes in the late blind individuals when compared to sighted controls. Furthermore, the age at onset of blindness predicted both global and local functional connectivity. These results suggest that upon reduced directionality of water diffusion in the nucleus basalis of Meynert, cholinergic influence may be stronger for the early blind compared to the late blind individuals. Our findings are important to unravelling why early blind individuals present stronger and more widespread cross-modal plasticity compared to late blind individuals.

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.

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.

The visual system, consisting of the eyes and the visual pathways of the brain, receives and interprets light from the environment so that we can perceive the world around us. A wide variety of disorders can affect human vision, ranging from ocular to neurologic to systemic in nature. While other noninvasive imaging techniques such as optical coherence tomography and ultrasound can image particular sections of the visual system, magnetic resonance imaging (MRI) offers high resolution without depth limitations. MRI also gives superior soft-tissue contrast throughout the entire pathway compared to computed tomography. By leveraging different imaging sequences, MRI is uniquely capable of unveiling the intricate processes of ocular anatomy, tissue physiology, and neurological function in the human visual system from the microscopic to macroscopic levels. In this review we discuss how structural, metabolic, and functional MRI can be used in the clinical assessment of normal and pathologic states in the anatomic structures of the visual system, including the eyes, optic nerves, optic chiasm, optic tracts, visual brain nuclei, optic radiations, and visual cortical areas. We detail a selection of recent clinical applications of MRI at each position along the visual pathways, including the evaluation of pathology, plasticity, and the potential for restoration, as well as its limitations and key areas of ongoing exploration. Our discussion of the current and future developments in MR ocular and neuroimaging highlights its potential impact on our ability to understand visual function in new detail and to improve our protection and treatment of anatomic structures that are integral to this fundamental sensory system. LEVEL OF EVIDENCE 3:   TECHNICAL EFFICACY STAGE 3:  .

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.