Abstract
Although elevated intraocular pressure (IOP) and age are major risk factors for glaucoma, their effects on glaucoma pathogenesis remain unclear. This study examined the onset and progression of glaucomatous changes to ocular anatomy and physiology, structural and physiological brain integrity, and visuomotor behavior in the DBA/2J mice via non-invasive tonometry, multi-parametric magnetic resonance imaging (MRI) and optokinetic assessments from 5 to 12 months of age. Using T2-weighted MRI, diffusion tensor MRI, and manganese-enhanced MRI, increasing IOP elevation at 9 and 12 months old coincided with anterior chamber deepening, altered fractional anisotropy and radial diffusivity of the optic nerve and optic tract, as well as reduced anterograde manganese transport along the visual pathway respectively in the DBA/2J mice. Vitreous body elongation and visuomotor function deterioration were observed until 9 months old, whereas axial diffusivity only decreased at 12 months old in diffusion tensor MRI. Under the same experimental settings, C57BL/6J mice only showed modest age-related changes. Taken together, these results indicate that the anterior and posterior visual pathways of the DBA/2J mice exhibit differential susceptibility to glaucomatous neurodegeneration observable by in vivo multi-modal examinations.
Highlights
The DBA (“dilute brown non-agouti”) mouse line is a commonly used animal model for hereditary glaucoma[10]
We confirmed the onset and evolution of intraocular pressure (IOP) elevation in D2 mice at ages consistent with those reported in the literature[12]
In vivo multi-parametric magnetic resonance imaging (MRI) assessments revealed the extent of early eye and brain changes in the D2 mice, some of which progressed along with increasing IOP elevation
Summary
The DBA (“dilute brown non-agouti”) mouse line is a commonly used animal model for hereditary glaucoma[10]. A tyrosinase-related protein 1 (Tyrp1) mutation causes iris stromal atrophy, while a premature stop codon in glycosylated protein nmb (Gpnmb) drives iris pigment dispersion[11] Together, this results in pigment and cell debris blocking drainage of fluid within the eye and increasing IOP over time, and allows the D2 mouse to model many pertinent features of neurodegeneration in studying www.nature.com/scientificreports/. We utilized tonometry, multi-parametric magnetic resonance imaging (MRI) and behavioral assessments to non-invasively probe the onset of glaucomatous changes and their progression by longitudinally measuring IOP, ocular anatomy, structural and physiological brain integrity, and visuomotor function in the D2 mouse model of chronic glaucoma. Examinations were performed on D2 and age-matched wild type C57BL/6J (B6) mice These in vivo imaging findings may help determine if glaucoma involves early pathophysiological events in both the eye and the brain, and whether such events progress with age and IOP elevation
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