Cellular and Circuit Mechanisms of Neuropeptide Signaling

项目摘要 我实验室由NIGMS资助的研究的总体目标是通过 哪些神经肽信号会影响控制行为的神经回路。神经肽是最多的 中枢神经系统中常见的信号分子，也是最好的细胞类型标记之一 大脑。这些内源性多肽在大脑内和整个身体内传递信息，以控制至关重要的 生理过程，如能量动态平衡，以及动机和情绪状态，包括睡眠， 性唤醒、疼痛、压力和情绪。肽能信号的失调与医学状况有关 从肥胖到精神障碍都有。一份大量的科学文献研究了 几十年来，神经肽在生理和行为中的作用，但即使对许多研究良好的电路来说，它们的 功能意义仍然是一个悬而未决的问题。因为它们在空间上不受解剖学的限制 接线图也不会在时间上通过快速重新吸收或退化，描绘出准确的连接 事实证明，在整个动物中建立神经肽回路是具有挑战性的。我的实验室试图通过开发 监测和选择性操纵活体动物神经肽信号的新方法，并识别 调节神经肽通讯的基本酶。我们采用了先进的成像技术，基因， 和生化方法来研究这些问题，使用蠕虫和小鼠模型系统从 从亚细胞水平一直到行为输出。我们的目标是理解电路的生化逻辑 神经肽对神经的调节作用，与我们了解的快速神经传递一样清晰 突触。这项研究将为长期存在的关于空间和空间的问题提供新的见解 神经肽信号的时间组织，并导致对长期变化的理解 影响神经系统，导致不同的行为。因为神经肽及其受体 可药物靶点牵涉到广泛的疾病，我们预计对其机制的洞察 信号可能与以行为功能障碍为特征的疾病具有广泛的临床相关性。

Project Summary The overall goal of NIGMS-funded research in my lab is to understand the cellular and circuit mechanisms by which neuropeptide signaling influences the neural circuits that control behavior. Neuropeptides are the most common signaling molecule in the central nervous system and among the best markers for cell types in the brain. These endogenous peptides transmit messages within the brain and across the body to control vital physiologic processes like energy homeostasis, as well as motivational and emotional states including sleep, arousal, pain, stress, and mood. Dysregulation of peptidergic signaling is implicated in medical conditions ranging from obesity to psychiatric disorders. A vast scientific literature has investigated the role of neuropeptides in physiology and behavior over decades, yet even for many well-studied circuits, their functional significance is still an open question. Because they are not restricted spatially by the anatomical wiring diagram nor temporally by rapid re-uptake or degradation, delineating the precise connectivity of neuropeptide circuits in whole animals has proved challenging. My lab seeks to address this gap by developing novel methods to monitor and selectively manipulate neuropeptide signaling in living animals, and to identify the fundamental enzymes that regulate neuropeptide communication. We employ advanced imaging, genetic, and biochemical approaches to investigate these questions using both worm and mouse model systems from the subcellular level all the way to behavioral output. Our goal is to understand the biochemical logic of circuit neuromodulation by neuropeptides with the same clarity that we understand fast neurotransmission at synapses. This research will provide fundamental new insight into longstanding questions about the spatial and temporal organization of neuropeptide signaling and lead to an understanding of how long-term changes are affected in the nervous system that result in different behaviors. As neuropeptides and their receptors are druggable targets implicated in a wide-range of diseases, we anticipate that mechanistic insight into their signaling is likely to have broad clinical relevance for diseases characterized by behavioral dysfunction.