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。在从老年动物获得的神经元中，离子（如钙）的稳态被破坏导致随后的神经元功能障碍，这可能有助于视觉衰老。然而，年龄相关的离子失调和视力下降之间的关系仍然没有在体内测试。我们的总体假设是，随着年龄的增长，视网膜和中央视觉结构表现出体内二价阳离子流入的逐渐增加，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。将使用创新的功能性MRI方法评估离子调节;锰增强MRI（MEMRI），以非侵入性方式测量成年大鼠脑和视网膜对锰离子（Mn 2+）的摄取。Mn 2+离子是一种强的MRI造影剂，通过L型电压门控钙通道进入神经元。全身注射无毒量的MnCl 2后其在神经元组织中的蓄积程度是离子调节的度量。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（一种血脑/视网膜屏障渗透性钙通道阻滞剂）进行修饰。 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设。我们将以3个月为间隔，从3到[24]月龄，对大鼠的视觉功能进行行为学测量。在每轮测试后，我们将暂时将一只眼睛贴上眼罩，并使用MEMRI测量视网膜和大脑对视觉刺激（未贴眼罩的眼睛）和黑暗（贴眼罩的眼睛）的Mn 2+摄取。Mn 2+摄取的年龄相关性增加将支持神经元Ca 2+内流的年龄相关性增加的离体结果。我们将比较年龄相关的视觉功能变化与纵向MEMRI数据和终点组织学数据从视网膜和中央视觉结构。 具体目标二：检验长期使用二氢吡啶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。我们将比较目标1中描述的视觉功能的纵向变化模式与长期给予尼莫地平的大鼠和相关对照组中测量的视觉功能的纵向变化模式。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功能保护支持先前关于二氢吡啶L型钙通道阻滞剂的神经保护作用的发现。 这些实验将阐明神经元离子调节的年龄相关变化与视觉功能的行为明显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，年龄相关的视力下降与通过L型电压门控Ca 2+通道进行性离子失调有关，这些下降可以通过药物干预得到改善。 公共卫生相关性：健康老龄化的视力丧失预示着记忆力下降、社会关系受损、日常生活活动受损以及抑郁症状增加。了解神经元生理学的变化如何与这种损伤相关，将有助于合理寻找旨在改善健康老龄化视力丧失的介入治疗。

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.