Synaptomes of Mouse and Man

描述(申请人提供)：突触是大脑神经回路的主要活跃信号组件。突触是高度复杂、可塑性、强调制和高度多样化的实体，它们的分子复杂性和多样性是所有突触电路发育和功能的基础。此外，许多或大多数神经发育、精神和神经退行性疾病都源于大脑庞大且高度异质性的突触群体的异常。不幸的是，人们对这种疾病的了解很少，很难诊断、预防和治疗，因为我们缺乏足够的工具来测量大脑中庞大而高度多样化的突触群体，而且今天使用的大多数有限的工具只能应用于实验动物，如小鼠。一个由神经生物学家、生物物理学家、临床医生、数学家和计算机科学家组成的跨学科联盟在这里提议开发一种非常雄心勃勃的“突触”分析管道，它将改变实验动物和人类大脑中突触网络功能和紊乱的科学。这条新的高通量管道基于强大的新阵列断层扫描方法，将能够以前所未有的精度测量、分析和建模不同种类的突触和神经调制纤维群体。突触管道最初将通过开发“突触”来对小鼠和人类额叶和颞叶的不同突触群体进行建模来展示。管道资源和数据将通过开放突触组项目共享，该项目将促进描述其他大脑区域和物种突触群体的突触的开发。这些努力有望为理解哺乳动物大脑功能的基本机制提供新的基础，并为研究小鼠和人类大脑的异同提供新的量化视角，这对于利用动物研究机会改善人类心理健康至关重要。由于突触及其神经调节的异常是许多人类精神健康疾病的主要原因，本文提出的突触管道资源和数据的开发和共享可能会催化临床神经科学的快速进步。

DESCRIPTION (provided by applicant): The synapse is the principle active signaling component of the brain's neuronal circuitry. Synapses are highly complex, plastic, strongly modulated and deeply diverse entities, and their molecular complexity and diversity are fundamental to all synaptic circuit development and function. Moreover, many or most neurodevelopmental, psychiatric, and neurodegenerative disorders are rooted in abnormalities of the brain's vast and highly heterogeneous synapse populations. Unfortunately, such disorders are poorly understood and difficult to diagnose, prevent, and treat because we lack adequate tools to measure the brain's vast and highly diverse synapse populations, and because most of the limited tools in use today can be applied only to experimental animals such as mice. An interdisciplinary consortium comprising neurobiologists, biophysicists, clinicians, mathematicians and computer scientists here proposes development of a very ambitious "synaptomic" analysis pipeline that will transform the science of synaptic network function and disorders in both experimental animal and human brains. This novel high-throughput pipeline, based on powerful new array tomography methods, will enable measurement, analysis, and modeling of heterogeneous synapse and neuromodulatory fiber populations with unprecedented precision. The synaptomic pipeline will be demonstrated initially by developing "synaptomes" to model the heterogeneous synapse populations of mouse and human frontal and temporal lobes. Pipeline resources and data will then be shared via an Open Synaptome Project that will facilitate the development of synaptomes describing synapse populations of additional brain regions and species. These efforts are expected to provide a new foundation for understanding the basic mechanisms of mammalian brain function, and to offer new quantitative perspectives on both similarities and differences between mouse and human brain that will be critical to leveraging animal research opportunities for the improvement of human mental health. Because abnormalities of synapses and their neuromodulation are prime suspects in numerous human mental health disorders, the development and sharing of synaptomic pipeline resources and data proposed here are likely to catalyze rapid progress in clinical neuroscience.