Powering the Brain: the Cell Biology of Neuroenergetics

项目摘要 突触是一种保守的结构，控制着通过神经回路的信息流。我的实验室是 有兴趣了解突触是如何在体内组装和维持的，以建立 行为的基础，以及它们如何被修改以存储记忆。我们最近有了一个意想不到的发现 这与我们的研究计划是正交的，并重新构筑了我们对支配突触的原则的理解 功能。我们发现，在能量胁迫期间，线虫体内的糖酵解蛋白动态地重新定位到 突触以满足局部能量需求，并为突触囊泡周期提供动力。我们的发现强调了一个 个体突触与其局部能量环境之间的重要关系。基于这些 我们提出了一个大胆的假设，即能量代谢的局部调节是塑料 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常规的。虽然功能磁共振波谱研究 已经证明，大脑新陈代谢与神经元功能在电路水平上密切相关，能量是如何 新陈代谢在亚细胞水平上的调节还不清楚，或者在突触的背景下被考虑 生理学和可塑性。能量代谢能否在细胞内被划分为优先供能 特定的细胞功能？神经元内能量流动的局部调节(神经能量学)是否会限制，或者 增强、信息处理和电路功能？了解神经能量学是如何在当地受到监管的 在神经元内部，可能是范式转换，重新构建我们关于调控机制的知识 突触功能，无论是在生理上还是在疾病上。 在这个先锋提案中，我们将使用新的细胞生物学探针严格检验我们的假设 在体内，在特定的神经元中，在线虫的行为中，了解单个突触的神经能量学。我们 检查无膜代谢亚室是如何通过液相转变形成的，以及 它们定位于亚细胞区域的生理学意义。拟议工作的完成可以 具有超越神经科学领域的影响，因为它可能广泛地重新构建局部新陈代谢的重要性 以及它在满足细胞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.