Cellular and Circuit Mechanisms of Neuropeptide Signaling

项目概要 大脑的功能来自于神经元之间的交流。神经元的语言 沟通是由一个神经元释放并被另一个神经元感知的化学物质介导的。 这些化学信号与谷氨酸等经典的“快速作用”神经递质一致 和 GABA 在毫秒内向突触发出信号，以及 100 多种不同的信号 作用时间更长的神经调节剂。神经调节剂是大多数人的主要目标 神经精神药物以及滥用药物，它们的失调与医疗有关 从肥胖到精神疾病。但我们对这两个方面仍然缺乏清晰的认识 细胞和神经回路水平，这些神经调节剂及其快速作用的对应物如何 合作产生大脑的不同行为输出。神经肽是最大且 神经元用来相互交流和调节的最多样化的神经调节剂 行为。然而我们对控制和限制神经调节的一般规则知之甚少 任何生物体中的信号传导。在这里我建议使用秀丽隐杆线虫的紧凑神经系统作为 在整个动物模型中连接神经肽信号传导和神经回路的独特范例。尽管其 由于解剖结构简单，秀丽隐杆线虫充分利用神经肽信号传导来调节其行为 生理学上，与哺乳动物有相似数量的神经肽基因和一组保守的基因 调节神经肽合成、加工、运输和胞吐作用的酶途径。我们的 目标是首次发现神经调节剂的生化网络如何与 在整个动物模型中固定大脑的解剖结构。理解这种关系是发展的关键 监测大脑活动的工具，并最终发现认知和行为的治疗方法 功能障碍。

Project Summary The functions of the brain emerge from communication between neurons. The language of neuronal communication is mediated by chemicals that are released from one neuron and sensed by another. These chemical signals consistent of both classical “fast acting” neurotransmitters such as glutamate and GABA that signal across synapses in milliseconds, as well as more than 100 diverse neuromodulators that act on longer timescales. Neuromodulators are the major targets of most neuropsychiatric drugs as well as drugs of abuse, and their dysregulation is implicated in medical conditions ranging from obesity to psychiatric disorders. Yet we still lack a clear understanding, at both the cellular and neural circuit level, of how these neuromodulators and their fast acting counterparts cooperate to generate the diverse behavioral outputs of the brain. Neuropeptides are the largest and most diverse class of neuromodulators that neurons use to communicate with each other and regulate behavior. Yet we know little about the general rules that govern and constrain neuromodulatory signaling in any organism. Here I propose to use the compact nervous system of C. elegans as a unique paradigm to link neuropeptide signaling and neural circuits in a whole animal model. Despite its anatomical simplicity, C. elegans makes rich use of neuropeptide signaling to regulate its behavior and physiology and in shares a similar number of neuropeptide genes with mammals and a conserved set of enzymatic pathways that regulate neuropeptide synthesis, processing, transport, and exocytosis. Our goal is to discover, for the first time, how the biochemical network of neuromodulators relates to the fixed anatomy of the brain in a whole animal model. Understanding this relationship is key to develop tools to monitor brain activity, and ultimately to discover treatments for cognitive and behavioral dysfunction.