Synaptomes of Mouse and Man

描述（由申请人提供）：突触是大脑神经元回路的主要活跃信号组成部分。突触是高度复杂、可塑性强、强调制和深度多样化的实体，其分子复杂性和多样性是所有突触回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的根源是大脑中巨大且高度异质的突触群的异常。不幸的是，由于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，并且由于目前使用的大多数有限的工具只能应用于实验动物，如小鼠，因此对这些疾病的了解很少，难以诊断、预防和治疗。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出了一个雄心勃勃的“突触组”分析管道的发展，这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。这种新颖的高通量管道，基于强大的新型阵列断层扫描方法，将以前所未有的精度测量、分析和建模异质突触和神经调节纤维群。突触组管道将首先通过开发“突触组”来模拟小鼠和人类额叶和颞叶的异质突触群来证明。管道资源和数据将通过开放突触组项目共享，这将促进突触组的发展，描述其他大脑区域和物种的突触种群。这些努力有望为理解哺乳动物脑功能的基本机制提供新的基础，并为小鼠和人类大脑的异同提供新的定量视角，这将对利用动物研究机会改善人类心理健康至关重要。由于突触异常及其神经调节是许多人类精神健康障碍的主要嫌疑人，因此本文提出的突触管道资源和数据的开发和共享可能会促进临床神经科学的快速发展。

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.