Cellular and Circuit Mechanisms of Neuropeptide Signaling

父项目摘要 大脑的功能源于神经元之间的交流。神经元的语言 交流是由从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，这些信号通过突触以毫秒的速度传递，以及100多种不同的突触 作用于更长时间尺度的神经调节剂。神经调节剂是MOST的主要靶标 神经精神药物以及滥用药物，它们的失调与医学有关 从肥胖到精神障碍的各种情况。然而，我们对这两个问题仍然缺乏明确的认识 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是如何 合作以产生大脑的不同行为输出。神经肽是最大的和 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，我们对支配和限制神经调节的一般规则知之甚少。 在任何生物体中发出信号。在这里，我建议使用线虫紧凑的神经系统作为一种 在整个动物模型中将神经肽信号和神经回路联系起来的独特范例。尽管它的 解剖结构简单，线虫丰富地利用神经肽信号来调节它的行为和 在生理上，与哺乳动物有相似数量的神经肽基因和保守的一组 调节神经肽的合成、加工、运输和胞吐的酶途径。我们的 目标是首次发现神经调节剂的生化网络如何与 修复了整个动物模型中的大脑解剖。理解这种关系是发展的关键 监控大脑活动的工具，最终发现认知和行为的治疗方法 功能障碍。在补贴期内，我们会继续推行家长助学金计划的目标。

Parent 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. We will continue to pursue the parent grant project goals during the supplement period.