Age-related Changes in Eye, Brain and Visuomotor Behavior in the DBA/2J Mouse Model of Chronic Glaucoma

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.

Changes of Ocular Dimensions as a Marker of Disease Progression in a Murine Model of Pigmentary Glaucoma

“…These conditions are believed to be mainly induced by exposure to environmental conditions (Smith et al, 1994). The C57BL/6J strain is also widely used as a control strain for DBA/2J mice (Wong and Brown, 2007;Yang et al, 2018). Not surprisingly, in neither of these strains did we observe a sudden increase in IOP between the third and sixth months of life.…”

“…At this stage of pathology, retinal degeneration was already visible as optic disc cupping visible in T2w images and optic disc cupping was not visible in either of the control strains. Additionally, other groups reported various hallmarks of degeneration at this stage, including decrease of visuomotor function, alterations within the optic nerve, and the optic tract demonstrated by diffusion-weighted MRI (Yang et al, 2018).…”

Manganese Enhanced MRI for Use in Studying Neurodegenerative Diseases

“…The DBA/2J mouse model is a late onset, hereditary glaucoma model associated with age dependent increase in intraocular pressure. MEMRI studies with DBA/2J mice showed changes in ocular anatomy due to glaucoma (Calkins et al, 2008) and decreased manganese enhancement in superior colliculus, ON and lateral geniculate nucleus compared to control mice that was further decreased with age (Fiedorowicz et al, 2018; Yang et al, 2018). Similar results were obtained in an induced ocular hypertension rat model of chronic glaucoma, where decreased Mn 2+ enhancement in the ON of the glaucomatous eye was observed after intravitreal injection (Chan et al, 2008).…”

Manganese-Enhanced Magnetic Resonance Imaging: Application in Central Nervous System Diseases

“…Retinal Mn 2+ uptake decreases with age in old DBA/2J mice, and loss of axonal transport occurs before changes in retinal thickness (130). The visual pathway showed a significant reduction in Mn 2+ enhancement at 9 months and little enhancement by 12 months in DBA/2J mice (131), and early axonal transport may be impaired before elevated intraocular pressure develops (132). These MEMRI findings help us understand the pathogenesis of glaucoma and monitor the effects of drug interventions and provide an in vivo global perspective for investigations of the primary visual conduction system in rats.…”