The overall goal of our research is to improve treatment of age-related vision loss. In neurons obtained from aged animals, disrupted homeostasis of ions such as calcium causes subsequent neuronal dysfunction which may contribute to visual senescence. However, the relationship between age-related ion dysregulation and visual decline remains untested in vivo. Our overarching hypothesis is that with increasing age the retina and central visual structures demonstrate progressively increased divalent cation influx in vivo, which contributes to clinically detectable declines in vision and changes in histology. In the first Aim, we will establish a baseline relationship between visual performance, ion regulation, and histology. Ion regulation will be assessed using an innovative functional MRI method;manganese enhanced MRI (MEMRI), to non-invasively measure brain and retinal uptake of manganese ion (Mn2+) in adult rats. Mn2+ ion is a strong MRI contrast agent and enters neurons through L-type voltage-gated calcium channels. The extent of its accumulation in neuronal tissue following systemic injection of a non-toxic amount of MnCl2 is a metric of ion regulation. In the second Aim, neuronal cation influx will be modified through chronic administration of nimodipine, a blood-brain/retina barrier-permeable calcium channel blocker.
Specific Aim 1 : To test the hypothesis that higher levels of manganese uptake in retina and brain correlate with progressive age-related changes in the visual system. We will behaviorally measure rats'visual function in three-month intervals, from 3 to  months of age. After each round of testing, we will temporarily patch one eye and measure retinal and brain Mn2+ uptake in response to visual stimulation (unpatched eye) and darkness (patched eye) with MEMRI. Age-related increases in Mn2+ uptake would support ex vivo findings of age-related increases in neuronal Ca2+ influx. We will compare age-related changes in visual function with longitudinal MEMRI data and endpoint histological data from the retina and central visual structures.
Specific Aim 2 : To test the hypothesis that chronic administration of a dihydropyridine L-type calcium channel blocker ameliorates age-related declines in the visual system. We will compare the pattern of longitudinal changes in visual function described in Aim 1 with that measured in rats chronically administered nimodipine and in relevant controls. Following the last vision testing session, we will compare histological data from each group. Preservation of visual function in the nimodipine-treated group would support previous findings of neuroprotective effects of dihydropyridine L-type calcium channel blockers. These experiments will clarify the hypothesized link between age-related changes in neuronal ion regulation and behaviorally-evident changes in visual function. Positive findings would provide strong evidence that age-related vision declines are linked to progressive ion dysregulation via L-type voltage gated Ca2+ channels, and that these declines can be ameliorated through pharmacologic intervention.
Vision loss of healthy aging predicts memory decline, impaired social relations, impaired activities of daily living, as well as an increase in depressive symptoms. Understanding how changes in neuron physiology relate to this impairment will facilitate the rational search for interventional therapies aimed at ameliorating vision loss in healthy aging.
|Berkowitz, Bruce A; Kern, Timothy S; Bissig, David et al. (2015) Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice. Invest Ophthalmol Vis Sci 56:6294-303|
|Bissig, David; Berkowitz, Bruce A (2014) Testing the calcium hypothesis of aging in the rat hippocampus in vivo using manganese-enhanced MRI. Neurobiol Aging 35:1453-8|
|Berkowitz, Bruce A; Bissig, David; Dutczak, Oliver et al. (2013) MRI biomarkers for evaluation of treatment efficacy in preclinical diabetic retinopathy. Expert Opin Med Diagn 7:393-403|
|Bissig, David; Goebel, Dennis; Berkowitz, Bruce A (2013) Diminished vision in healthy aging is associated with increased retinal L-type voltage gated calcium channel ion influx. PLoS One 8:e56340|
|Bissig, David; Berkowitz, Bruce A (2012) Light-dependent changes in outer retinal water diffusion in rats in vivo. Mol Vis 18:2561-xxx|
|Braun, Rod D; Bissig, David; North, Robert et al. (2012) Human tumor cell proliferation evaluated using manganese-enhanced MRI. PLoS One 7:e30572|
|Berkowitz, Bruce A; Bissig, David; Ye, Yongquan et al. (2012) Evidence for diffuse central retinal edema in vivo in diabetic male Sprague Dawley rats. PLoS One 7:e29619|
|Berkowitz, Bruce A; Bissig, David; Patel, Priya et al. (2012) Acute systemic 11-cis-retinal intervention improves abnormal outer retinal ion channel closure in diabetic mice. Mol Vis 18:372-6|
|Li, Xiaoman; McClellan, Mark E; Tanito, Masaki et al. (2012) Loss of caveolin-1 impairs retinal function due to disturbance of subretinal microenvironment. J Biol Chem 287:16424-34|
|Berkowitz, Bruce A; Bissig, David; Bergman, Deborah et al. (2011) Intraretinal calcium channels and retinal morbidity in experimental retinopathy of prematurity. Mol Vis 17:2516-26|
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