Connectome
Connectome
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连接组
DOI：
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发表时间：
2013
影响因子：
11.1
通讯作者：
P. Nair
中科院分区：
文献类型：
--
作者：
P. Nair
自从19世纪西班牙病理学家圣地亚哥·拉蒙·卡哈尔蚀刻出第一幅深褐色的被染色的脑细胞作为电连接节点的插图以来，神经科学家们一直在热衷于探索整个人类大脑的网络观。他们希望，有一天，这样的观点将有助于破译人类的状况，并战胜神经生物学疾病。考虑到人脑中的数十亿个神经元及其数万亿个不断变化的连接，近几十年来，得益于成像技术的进步，这项研究一直在缓慢推进。2005年，印第安纳大学神经学家奥拉夫·斯波恩斯和他的同事们创造了“连接体”一词，表示人类大脑的全面结构蓝图(1)。研究人员设想，这样一个连接矩阵将有助于在大脑的结构和功能之间建立联系。以其最具描述性的形式，人类连接组--一旦绘制出来--将为神经科学家提供三个层面的解剖细节：不同大脑区域和神经元路径的全景图，神经元群体及其电路的重点图，以及单个神经元及其所谓的突触连接的精细观察(2)。虽然这个术语在本世纪头十年才被印刷出来，但第一个动物连接组是在20世纪80年代完成的，当时遗传学家西德尼·布伦纳和其他人使用电子显微镜绘制了土壤线虫线虫神经系统中的每个连接，这种线虫的大约300个神经元只形成了5000个突触，绘制出了一张完全在可行范围内的接线图。构建一个人类连接体，其丰富的神经元密集地交织在一起，就像Gordian结一样，无疑需要巨大的劳动，但这项任务最终会是西西弗式的吗？远非如此，哈佛大学神经生物学家杰夫·利希特曼说，他正试图构建一个具有前所未有分辨率的完整的老鼠连接体。选择“连接组”这个名字是为了向人类基因组计划致敬，该计划曾被一些人认为是一项有问题的努力，现在已被证明有益于现代医学。利希特曼说，与人类基因组类似，人类连接体可以帮助研究人员收集不受假设约束的数据，从而为他们提供大量信息，有助于形成对大脑发育、衰老和疾病的研究。至少，这样的地图可能有助于指导神经外科手术和揭开精神疾病的面纱。然而，利希特曼承认，与人类基因组的类比有其局限性：尽管人类基因组的规模令人震惊，但人类基因组是一个由大约30亿个核苷酸碱基对组成的线性字符串，其中包含20,000到30,000个蛋白质编码基因。相比之下，人类的连接体拥有隐藏在极其复杂的结构中的3D信息。此外，任何两个个体的基因组在序列上都超过99%相似，而参考人类连接组的用途目前尚不清楚(3)。再加上学习和经验对人脑连接性质的影响，绘制人类连接组的任务被证明比对人类基因组进行测序要艰巨得多。利希特曼说，尽管存在这些挑战，但鉴于管理大脑中信息加密的规则在很大程度上是通用的，绘制人类连接体-或其模拟物-可能会产生对大脑的丰富见解。“如果我们对接线图有足够的了解，我们就能找到其中的一些编码规则，”他推测。
Ever since the 19th century Spanish pathologist Santiago Ramón y Cajal etched the first sepia-toned illustrations of stained brain cells as electrically connected nodes, neuroscientists have been hotly pursuing a network view of the entire human brain. Such a view, they hope, will someday help decipher the human condition and defeat neurobiological disease. Given the billions of neurons in the human brain and their trillions of shifting connections, the pursuit has inched forward in recent decades, thanks to gains in imaging technology. In 2005, Indiana University neuroscientist Olaf Sporns and his colleagues coined the term “connectome” to denote a comprehensive, structural blueprint of the human brain (1). Such a connection matrix, the researchers envision, would help establish links between the brain’s structure and function. In its most descriptive form, the human connectome—once charted—would provide neuroscientists three levels of anatomical detail: a panoramic view of different brain regions and neuronal pathways, a focused picture of populations of neurons and their circuitry, and a fine-grained look at single neurons and their so-called synaptic connections (2). Although the term was committed to print in the 2000s, the first animal connectome was completed in the 1980s when geneticist Sydney Brenner and others used electron microscopy to map every connection in the nervous system of the soil-dwelling nematode worm Caenorhabdidtis elegans, whose roughly 300 neurons make a mere 5,000 synapses, rendering a wiring diagram well within the realm of feasibility. Building a human connectome, with its superabundance of neurons densely intertwined like Gordian knots, no doubt calls for Herculean labors, but will the task turn out to be Sisyphean? Far from it, says Harvard University neurobiologist Jeff Lichtman, who is trying to construct a complete mouse connectome of unprecedented resolution. The name “connectome” was chosen as a nod to the Human Genome Project, once thought by some to be a questionable endeavor that has now proved to benefit modern medicine. Similar to the human genome, says Lichtman, the human connectome could help researchers gather data unfettered by hypothesis, thus providing them with a trove of information that could help shape forays into brain development, aging, and disease. At the very least, such a map might help guide neurosurgery and unravel mental illness. Yet the analogy of the human genome, concedes Lichtman, has its limits: For all its staggering scale, the human genome is a linear string of some three billion nucleotide base pairs harboring between 20,000 and 30,000 protein-coding genes. In contrast, the human connectome holds 3D information hidden in exquisitely complex structures. Furthermore, the genomes of any two individuals are more than 99% similar in sequence, whereas the utility of a reference human connectome currently remains unclear (3). Add to these challenges the effects of learning and experience on the nature of connections in the human brain, and the task of mapping a human connectome proves far more daunting than sequencing the human genome. Despite those challenges, says Lichtman, mapping the human connectome—or a simulacrum thereof—could yield bountiful insights into the brain, given that the rules that govern the encryption of information in the brain are largely universal. “If we get enough detail about the wiring diagram, we’ll be able to find some of these encoding rules,” he speculates.