Using Transport to Map the Brain

描述(申请人提供)：使用传输绘制大脑图理解大脑如何处理信息的主要挑战是定义将神经元连接到功能分布式并行处理网络的电路。细胞内运输是一个正常的生物过程，它被实验用来定义电路的解剖学。运输最近与许多神经系统疾病有关，包括阿尔茨海默氏症、亨廷顿氏症和帕金森氏病的神经退行性变，唐氏综合症和正常眼压性青光眼的视束。最近的开创性工作表明，核磁共振成像(MRI)的造影剂Mn2+可以在神经元内被提取和运输。因此，现在第一次可以用锰增强磁共振成像(MEMRI)来研究动物一生中的运输动态(速率、方向性、跨突触传递)和Mn2+分布的变化，即电路。在这里，三个在分子显微镜和神经病理学(布朗大学)、小动物5MRI成像(加州理工大学)和计算分析(加州大学洛杉矶分校计算生物学中心(国家生物计算中心之一)的计算生物学中心)方面拥有免费专业知识的实验室聚集在一起，开发和应用这项新技术，并培训年轻科学家应用它。首先，我们将研究视觉系统中Mn2+运输的生物学，以了解Mn2+对电活动的影响，它在轴突中的运输，以及突触活动的作用。将使用现有的、经过修改的和新的软件来分析传输速率的差异，以从多个个人中提取有意义的数据。其次，我们将应用MEMRI来研究海马区和基底前脑之间的回路。这个回路中特定的生物变化与阿尔茨海默病(AD)和唐氏综合症(DS)的认知障碍有关。我们将在Ts65Dn DS模型、APPsWE和KLC-/-AD模型等小鼠突变模型中，将Mn2+与传统的组织学示踪剂一起注入到精确的位置。在注射前和注射后的连续时间点，对活着的小鼠进行5MRI成像。MR图像将使用CCB软件进行对准/扭曲，并在逐个体素的基础上确定统计上显著的强度变化。大脑尸检的组织学检查将验证注射部位，监测损伤，并帮助识别电路沿线的单个神经元。该项目将在三个领域取得进展：1)明确理解Mn2+轨迹追踪的生物学基础，这是未来所有MEMRI数据分析的基础；2)对重要的海马体-前脑记忆回路中的运输动力学进行定量测量；以及3)应用和开发小鼠突变模型的统计图谱，以全面、无偏地分析回路随时间发生的表型变化。这里开发的技术将被证明对影响大脑解剖和电路的其他基因突变的转基因小鼠的大规模分析有用。 与公共健康相关：智力低下和衰老可能涉及大脑中相同的回路：海马体和基底前脑之间的连接。锰增强磁共振成像(MEMRI)使我们能够观察活着的大脑中这个回路内的解剖和活动。在这里，我们建议开发和应用这项技术来映射小鼠模型中的这一重要记忆电路，以了解两种常见疾病：唐氏综合症和阿尔茨海默病。

DESCRIPTION (provided by applicant): Using Transport to Map the Brain A major challenge in understanding how the brain processes information is defining the circuitry that links neurons into a functional distributed parallel processing network. Intracellular transport is a normal biological process that is experimentally exploited to define the anatomy of circuitry. Transport has recently been implicated in many neurological diseases, including neurodegeneration of Alzheimer's, Huntington's and Parkinson's disease and in Down's syndrome and in the optic tract in normal-pressure glaucoma. Recent ground-breaking work has demonstrated that Mn2+, a contrast agent for magnetic resonance imaging (MRI), is picked up and transported within neurons. Thus for the first time dynamics of transport (rates, directionality, trans-synaptic transmission) and changes in Mn2+distirbution, i.e. circuitry, over an animal's lifetime can now be studied with manganese-enhance MRI (MEMRI). Here three laboratories with complimentary expertise in molecular microscopy and neuropathology (Brown University), in small animal 5MRI imaging (Caltech), and in computational analysis (Center for Computational Biology (CCB) at UCLA, one of the centers of the National Centers for Biological Computing), are brought together to develop and apply this new technology and to train young scientists in its application. First we will investigate the biology of Mn2+ transport in the well-characterized visual system to learn about Mn2+ effects on electrical activity, its transport in axons, and the role of synaptic activity. Differences in transport rates will be analyzed using existing, modified and new software to extract meaningful data from multiple individuals. Second we will apply MEMRI to investigate the circuit between hippocampus and basal forebrain. Specific biological alterations in this circuit are implicated in cognitive impairment of both Alzheimer's disease (AD) and Down Syndrome (DS). We will inject Mn2+ together with traditional histologic tracers into precise locations in mouse mutant models, such as the Ts65Dn DS model, and APPswe and KLC-/- AD model. Living mice will be imaged by 5MRI at successive time points before and after injection. MR images will be align/warped using CCB software and statistically significant intensity changes determined on a voxel-by-voxel basis. Histological examination of brains post-mortem will verify injection sites, monitor injury, and assist in identifying individual neurons along the circuit. This project will result in progress in three areas: 1) Definitive understanding of the biologic basis of Mn2+ track tracing, a basis for all future MEMRI data analysis; 2) Quantitative measurements of transport dynamics in the important hippocampal-forebrain memory circuit; and 3) Application and development of statistical mapping to mouse mutant models for comprehensive unbiased analysis of phenotypic alterations in circuitry over time. The technology developed here will prove useful for large-scale analysis of transgenic mice mutated in other genes affecting the brain anatomy and circuitry. PUBLIC HEALTH RELEVANCE: Mental retardation and senility may involve the same circuits within the brain: connections between the hippocampus and basal forebrain. Manganese enhanced magnetic resonance imaging (MEMRI) allows us to observe the anatomy and activity within this circuit in living brains. Here we propose to develop and apply this technology to map this important memory circuit in mouse models towards gaining an understanding of two frequently occurring diseases: Down syndrome and Alzheimer's disease.