Examination of the cell biology of the synapse and behavior

项目总结 关于突触的结构组织是如何在 发展，在学习以维持行为的过程中也可以灵活地修改。关于细胞生物学的知识 突触的建立和改变在记忆的激活中对我们渴望 了解神经系统的组成部分是如何结合在一起产生其功能输出的， 行为。我的研究项目的关键科学前提是我们对复杂程度的理解 突触的分子构建块发出的行为可以通过以下方式有意义地扩展 同时询问跨尺度的结构-功能关系，在分子上架起知识桥梁 单个细胞内单个突触的组成，回路内单个细胞的组织，以及 行为正常的动物大脑内回路的协调活动。实现这一综合观点是一项挑战 在提交给NIH主任的脑工作组报告中最好加以总结，并要求 新的方法，允许从亚细胞架构整合跨空间尺度的知识 与支配行为的电路的细胞结构的突触，以及2)来自 在发育过程中导致突触组装的事件，到在发育过程中导致突触可塑性的事件 习得的行为。为了应对这一挑战，我的实验室与网络科学家建立了战略合作关系， 微观学家和计算生物学家以及首创的集成方法，使前所未有的 了解线虫趋热回路中突触的细胞生物学。使用这些方法，我们 发现的概念重塑了我们如何理解体内突触的细胞生物学，现在定位 美国将解决神经科学中的三个基本问题：1)突触特异性是如何在 神经环的发育？2)突触如何满足不断变化的代谢需求以维持 功能？3)突触如何被修改以形成记忆和支持行为？我们建议回答 这些问题让趋热性电路定义了支配突触的基本机制 精确组装、维护和改装以维持行为。重要的是，由此产生的综合 跨规模的理解将产生关于项目之间相互作用的新概念，这些项目 在发育过程中建立突触结构，以及控制突触变化的可塑性程序 促进行为。我们预计，由于所研究的途径的分子保守性， 基于这些创新在我们理解上的进步将导致广泛的可转置的教训 生物学意义。

PROJECT SUMMARY A gap in knowledge remains regarding how structural organization of synapses, robustly established during development, is also flexibly modified during learning to sustain behaviors. Knowledge on how the cell biology of synapses is established and altered in the actuation of memories is of critical importance in our aspiration to understand how the building blocks of the nervous system come together to produce its functional output, behaviors. The key scientific premise of my research program is that our understanding of how complex behaviors emanate from the molecular building blocks of synapses could be meaningfully expanded by simultaneously interrogating structure-function relationships across scales, bridging knowledge on the molecular composition of individual synapses within single cells, the organization of single cells within circuits, and the coordinated activity of circuits within the brain of behaving animals. Achieving this integrated view is a challenge of critical importance best summarized in the BRAIN Working Group Report to the NIH Director, and requires new approaches that allow the integration of knowledge across 1) spatial scales, from the subcellular architecture of the synapse to the cellular architecture of the circuits governing behaviors, and 2) temporal scales, from the events leading to synaptic assembly during development, to the events leading to synaptic plasticity during learned behaviors. To address this challenge, my lab established strategic collaborations with network scientists, microscopists and computational biologists and pioneered integrated approaches that enable unprecedented access to the cell biology of the synapse in the thermotaxis circuit of C. elegans. Using these approaches we discovered concepts that reframed how we understand the cell biology of the synapse in vivo, and now position us to address three fundamental questions in neuroscience: 1) How is synaptic specificity achieved during the development of the nerve ring neuropil? 2) How are changing metabolic needs met at synapses to sustain function? 3) How are synapses modified to form memories and underpin behaviors? We propose to answer these questions for the thermotaxis circuit to define fundamental mechanisms that govern how synapses are precisely assembled, maintained, and modified to sustain behavior. Importantly, the resulting integrated understanding across scales will yield new concepts regarding the interplay between the programs that robustly establish synaptic architecture during development, and the plasticity programs that govern synaptic change to facilitate behavior. We anticipate, because of the molecular conservation of the examined pathways, that advancements in our understanding based on these innovations will result in transposable lessons of broad biological significance.