Manganese-Enhanced MRI Studies of Vision Loss with Aging

描述(申请人提供)：我们研究的总体目标是改善年龄相关性视力丧失的治疗。在从老年动物获得的神经元中，钙等离子的动态平衡被破坏会导致随后的神经元功能障碍，这可能导致视觉衰老。然而，与年龄相关的离子调节失调与视力下降之间的关系仍未在体内得到验证。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显示出体内二价阳离子流入逐渐增加，这有助于临床上可检测到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。将使用一种创新的功能磁共振方法--锰增强磁共振成像(MEMRI)--来评估离子调节，以非侵入性地测量成年大鼠大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。在全身注射无毒量的MnCl2后，它在神经元组织中积累的程度是离子调节的一个指标。在第二个目标中，神经元阳离子内流将通过长期给予尼莫地平来改变，尼莫地平是一种血-脑/视网膜屏障钙通道阻滞剂。具体目标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说。我们将在三个月的间隔内，从3个月到[24]个月，对大鼠的视觉功能进行行为测量。在每一轮测试后，我们将暂时修补一只眼睛，并使用MEMRI测量视网膜和大脑对视觉刺激(未修补的眼睛)和黑暗(修补的眼睛)的Mn2+摄取。与年龄相关的Mn2+摄取增加将支持体外发现的与年龄相关的神经元钙内流增加。我们将从视网膜和中央视觉结构的纵向MEMRI数据和终点组织学数据中比较与年龄相关的视觉功能变化。具体目标2：验证长期服用二氢吡啶L类钙通道阻滞剂可改善与年龄相关的视觉系统衰退的假设。我们将比较目标1中描述的视觉功能纵向变化的模式与长期服用尼莫地平的大鼠和相关对照组的测量结果。在最后一次视力测试后，我们将比较每组的组织学数据。尼莫地平治疗组的视觉功能的保护将支持先前关于二氢吡啶L类钙通道阻滞剂的神经保护作用的发现。这些实验将澄清与年龄相关的神经元离子调节变化和行为明显的视觉功能变化之间的假设联系。积极的发现将提供强有力的证据，表明年龄相关性视力下降与通过L类型的电压门控钙通道进行的离子失调有关，并且这些下降可以通过药物干预得到改善。

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.