Manganese-Enhanced MRI Studies of Vision Loss with Aging

描述（由申请人提供）：我们研究的总体目标是改善与年龄相关的视力丧失的治疗。在年老动物的神经元中，钙等离子的体内平衡被破坏，导致随后的神经元功能障碍，这可能导致视觉衰老。然而，与年龄相关的离子失调与视力下降之间的关系尚未在体内得到验证。我们的主要假设是，随着年龄的增长，视网膜和中央视觉结构在体内表现出逐渐增加的二价阳离子流入，这有助于临床可检测的视力下降和组织学变化。在第一个目标中，我们将建立视觉表现，离子调节和组织学之间的基线关系。离子调节将使用创新的功能性MRI方法进行评估；锰增强MRI (MEMRI)，用于无创测量成年大鼠脑和视网膜对锰离子（Mn2+）的摄取。Mn2+离子是一种强磁共振造影剂，通过l型电压门控钙通道进入神经元。在全身注射无毒性的MnCl2后，其在神经元组织中的积累程度是离子调节的一个指标。在第二个目标中，神经元阳离子流将通过长期给予尼莫地平（一种血脑/视网膜屏障渗透性钙通道阻滞剂）来改变。具体目的1：验证视网膜和大脑中较高水平的锰摄取与视觉系统中与年龄相关的进行性变化相关的假设。我们将每隔3个月对大鼠的视觉功能进行行为测量，从3个月到100个月。在每一轮测试后，我们将临时蒙住一只眼睛，用MEMRI测量视网膜和大脑对视觉刺激（未蒙住的眼睛）和黑暗（蒙住的眼睛）的Mn2+摄取。年龄相关的Mn2+摄取增加将支持年龄相关的神经元Ca2+内流增加的离体发现。我们将通过纵向MEMRI数据和视网膜和中央视觉结构的终点组织学数据，比较年龄相关的视觉功能变化。具体目的2：验证长期服用二氢吡啶l型钙通道阻滞剂可改善视觉系统年龄相关性衰退的假设。我们将比较Aim 1中描述的视觉功能纵向变化模式与长期服用尼莫地平的大鼠和相关对照的测量结果。在最后一次视力测试之后，我们将比较各组的组织学数据。尼莫地平治疗组视觉功能的保存将支持先前关于二氢吡啶l型钙通道阻滞剂神经保护作用的发现。这些实验将阐明与年龄相关的神经元离子调节变化与视觉功能明显的行为变化之间的假设联系。阳性结果将提供强有力的证据，表明年龄相关的视力下降与通过l型电压门控Ca2+通道的进行性离子失调有关，并且这些下降可以通过药物干预来改善。

DESCRIPTION (provided by applicant): 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 [24] 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. PUBLIC HEALTH RELEVANCE: 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.