Neuroinformatics of the Hippocampus: From System-Level to Neuronal Arborizations

描述(由申请人提供)：定量神经解剖学受益于显微镜与日益强大的信息学的集成。大范围组织学准备的高分辨率图像被捕获并存储在千兆像素范围内，而在细胞水平上，神经元分支可以数字重建，用于形态计量分析和计算建模。然而，到目前为止，对系统和细胞水平神经解剖学之间的跨尺度关系的研究在很大程度上仅限于定性的考虑。目前的神经技术项目将填补这一空白，并将大脑区域的三维表示和神经元形态整合在一起，重点放在大鼠的海马体上，作为人们广泛感兴趣的样本结构。特别是，尼氏染色薄片将构建海马区复合体所有细胞构筑亚区的高分辨率空间地图。一百多个数字化重建的神经元(包括兴奋性和抑制性细胞)将被嵌入和复制到整个海马区，根据它们的适当位置和方向。将计算每一层的轴突和树突密度以及体积占有率，并沿横向和纵向计算。将测量每对主要细胞类别的轴突重叠，以估计完整海马网络的潜在突触连接矩阵。整个海马区复合体和完整细胞细节的地图将与基本的原始数据和软件源代码一起公开。由于海马体在学习和记忆中的作用以及在癫痫和阿尔茨海默病等疾病中的损伤，人们对其进行了深入的研究。关于它在生理和病理条件下的分子和生物物理性质的大量数据正在积累。该项目将为实验和计算神经科学家提供一个将海马体知识从细胞水平整合到系统水平的解剖学框架。在这项探索性/发育性研究中开发的技术和研究方法将扩展到大鼠的其他脑区，最终扩展到整个哺乳动物的中枢神经系统。公共卫生相关性神经解剖学分析中细胞和系统水平之间的联系是研究正常和疾病中枢神经系统结构-功能关系的基本因素。由于目前缺乏同时适用于单个细胞和整个脑区的分析工具和实验准备，这种跨尺度的联系很少被量化表征。通过在哺乳动物海马体的详细数字蒙太奇中几乎弥合这一差距，我们将展示合成大量神经科学数据的可行性，同时为参与学习、记忆和毁灭性疾病(如癫痫和阿尔茨海默病)的结构的基本特征提供精确的定量估计。

DESCRIPTION (provided by applicant): Quantitative neuroanatomy is benefiting greatly from the integration of microscopy with increasingly powerful informatics. High resolution images of wide field histological preparations are captured and stored in the gigapixel range, while, at the cellular level, neuronal arborizations can be digitally reconstructed for morphometric analysis and computational modeling. The investigation of the cross-scale relation between system and cellular level neuroanatomy, however, has been so far largely limited to qualitative considerations. The present neurotechnology project will fill this gap and integrate the three-dimensional representation of brain regions and neuronal morphology focusing on the rat hippocampus as an exemplar structure of wide interest. In particular, a high resolution spatial map of all cytoarchitectural subregions of the hippocampal complex will be constructed from Nissl stained thin sections. Over one hundred digitally reconstructed neurons (including both excitatory and inhibitory cells) will be embedded and replicated throughout the full septotemporal extent of the hippocampus according to their appropriate location and orientation. Axonal and dendritic densities and volume occupancies will be calculated for each layer and along the transverse and longitudinal directions. Axodendritic overlaps will be measured for each pair of major cellular classes to estimate the matrix of potential synaptic connectivity for the complete hippocampal network. The maps for the whole hippocampal complex and full cellular detail will be made publicly available along with the underlying raw data and software source code. The hippocampus is intensely studied for its role in learning and memory and impairment in diseases such as epilepsy and Alzheimer's. A wealth of data is accumulating on its molecular and biophysical properties both in physiological and pathological conditions. This project will provide an anatomical framework to integrate hippocampal knowledge from the cellular to the system level for both experimental and computational neuroscientists. The techniques and research approach developed in this exploratory/developmental study will be extensible to other rat brain regions, and eventually to the whole mammalian central nervous system. PUBLIC HEALTH RELEVANCE The connection between the cellular and system levels of neuroanatomical analysis is a fundamental factor in the structure-function relationship of both the normal and diseased central nervous system. This cross-scale connection can seldom be quantitatively characterized because of the current lack of analytical tools and experimental preparations simultaneously suited for both single cells and entire brain regions. By virtually bridging this gap in a detailed digital montage of the mammalian hippocampus, we will demonstrate the feasibility of synthesizing vast amounts of neuroscience data while providing precise quantitative estimates for essential features of a structure involved in learning, memory, and devastating conditions such as epilepsy and Alzheimer's disease.