Cholinergic Dysfunction in Glaucoma

About This Grant

Although intraocular pressure (IOP) is the only clinically modifiable risk factor for glaucoma, the exact role of IOP elevation in glaucomatous neurodegeneration is unclear, as the cause of glaucoma remains unknown. Even worse, glaucoma may progress in patients under controlled IOP, indicating that additional factors are pivotal to its pathogenesis. A critical barrier to progress in investigating glaucoma mechanisms is the limited comprehensive, quantitative, and non-invasive approaches for detecting and predicting the involvement of the entire visual system during glaucoma development. We recently developed these needed approaches using magnetic resonance imaging (MRI) and spectroscopy (MRS) to identify, for the first time, cholinergic dysfunction in the brains of glaucoma patients and experimental animal models. Despite the known importance of choline- containing compounds to the integrity of cell membrane and neurotransmission, very little is known about how changes in cholinergic signaling in glaucoma reflect the structural and functional damage along the visual pathway. Our primary objective is to investigate the role of this newly identified pathogenic cholinergic pathway in glaucoma patients and our novel rat models using advanced MRI and MRS techniques. We will test the central hypothesis that glaucoma is driven by impairments of the visual pathways that are mediated by the cholinergic nervous system. Aim 1: Test how cholinergic lesioning, neuromodulation, and supplementation contribute to glaucomatous damage and ameliorations in experimental rat models. Adult Long Evans rats will be induced with experimental glaucoma by chronic IOP elevation via intracameral hydrogel injection or lesioning of the basal forebrain followed by longitudinal eye, brain, and behavioral assessments. We will stimulate the cholinergic neurons of these animal models to examine their role in modulating IOP, visual brain activity, and visual function. We will also give different regimes of oral choline supplementation to determine their dose-dependency, therapeutic windows, and efficacy in ameliorating the deteriorations of glaucomatous visual pathways. Aim 2: Test the contribution of cholinergic nervous system to glaucomatous damage in patients. By examining the brains of healthy subjects and primary open-angle glaucoma patients with varying disease severity, we will determine the changes in neurochemicals relevant to the cholinergic system and how they alter with the structure and function of the visual system. To ascertain when cholinergic changes emerge in disease progression, we will define the relationships between cholinergic brain features across glaucoma stages using advanced statistical modeling and information gain assessment. Impact: Establishment and optimization of new, non-invasive glaucoma neuroimaging biomarkers and experimental modeling systems will open up opportunities to determine the neurodegenerative substrates of glaucoma in vivo and validate glaucoma neurotherapeutics. These findings will allow us to better monitor glaucoma progression and guide future studies to determine the cause or the effect of glaucoma for more targeted interventions.