Powering the Brain: the Cell Biology of Neuroenergetics

项目摘要 突触是保守的结构，它控制着神经回路中的信息流。我的实验室是 有兴趣了解突触是如何组装和维持在体内建立电路， 行为的基础，以及它们如何被修改以存储记忆。我们最近有个意外发现 这与我们的研究计划是正交的，并重新构建了我们对控制突触的原理的理解。 功能我们发现，在能量胁迫下，C. elegans动态地重新定位到 突触以满足局部能量需求并为突触囊泡循环提供动力。我们的研究结果强调， 突触和它们的局部能量环境之间的重要关系。基于这些 研究结果我们提出了大胆的假设，即能量代谢的局部调节是塑料的基础。 特定神经元和突触的特性，从而控制电路功能和动物行为。 我们提出的假设是非传统的。而功能磁共振波谱研究 已经证明，大脑代谢在电路水平上与神经元功能紧密相关，能量如何 代谢在亚细胞水平上被调节的事实还不清楚，或者在突触的背景下考虑。 生理学和可塑性。能量代谢是否可以在细胞内进行划分， 特定的细胞功能？神经元内能量流的局部调节（神经能量学）是否会限制， 增强，信息处理和电路功能？了解神经能量学是如何局部调节的 可能是范式转变，重新构建我们关于调节机制的知识， 突触功能，无论是在生理学上还是在疾病中。 在这个先驱者的建议中，我们用新的细胞生物探针严格地检验了我们的假设 in vivo体内，in specific特定neurons神经元and in behavingC.来理解单个突触中的神经能量学。我们 检查如何膜无代谢亚隔室形成通过液相转变，和 它们定位于亚细胞区域的生理意义。完成拟议的工作可以 其影响超出了神经科学领域，因为它可以广泛地重新定义局部代谢的重要性， 以及其在满足细胞中局部能量需求方面的功能作用。

Project Summary Synapses are conserved structures that govern information flow through neural circuits. My laboratory is interested in understanding how synapses are assembled and maintained in vivo to build the circuits that underlie behavior, and how they are modified to store memories. We recently made an unexpected discovery that is orthogonal to our research program and reframes our understanding of the principles governing synaptic function. We discovered that during energy stress, glycolytic proteins in C. elegans dynamically relocalize to synapses to meet local energy demands and power the synaptic vesicle cycle. Our findings underscore an important relationship between individual synapses and their local energy environments. Based on these findings we propose the bold hypothesis that local regulation of energy metabolism underlies the plastic properties of specific neurons and synapses, thereby governing circuit function and animal behavior. Our proposed hypothesis is unconventional. While functional magnetic resonance spectroscopy studies have demonstrated that brain metabolism is tightly linked to neuronal function at a circuit level, how energy metabolism is regulated at a subcellular level is not understood, or considered in the context of synaptic physiology and plasticity. Could energy metabolism be compartmentalized within cells to preferentially power specific cellular functions? Could local regulation of energy flow within neurons (neuroenergetics) restrict, or potentiate, information processing and circuit function? Understanding how neuroenergetics is locally regulated within neurons could be paradigm shifting, reframing our knowledge regarding the mechanisms that regulate synaptic function, both in physiology and in disease. In this Pioneer proposal, we rigorously examine our hypothesis with new cell biological probes to be used in vivo, in specific neurons and in behaving C. elegans to understand neuroenergetics in single synapses. We examine how membrane-less metabolic subcompartments form through liquid-phase transition, and the physiological implications of their localization to subcellular regions. Completion of the proposed work could have impact beyond the field of neuroscience, as it could broadly reframe the importance of local metabolism and its functional role in meeting local energy demands in cells.