Cellular and Circuit Mechanisms of Neuropeptide Signaling

项目摘要 NIGMS资助的研究在我的实验室的总体目标是了解细胞和电路机制， 哪种神经肽信号会影响控制行为的神经回路。神经肽是最 它是中枢神经系统中常见的信号分子，也是中枢神经系统中细胞类型的最佳标志物之一。 个脑袋这些内源性肽在大脑内和全身传递信息， 生理过程，如能量稳态，以及动机和情绪状态，包括睡眠， 性唤起疼痛压力和情绪肽能信号转导失调与医学状况有关 从肥胖到精神疾病大量的科学文献研究了 几十年来，神经肽在生理学和行为学中的作用一直很重要，但即使是对许多研究得很好的回路， 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结构的限制 接线图，也不是暂时的快速重新摄取或降解，描绘精确的连接， 在整个动物中的神经肽回路被证明是具有挑战性的。我的实验室试图通过开发 在活体动物中监测和选择性操纵神经肽信号传导的新方法， 调节神经肽通讯的基本酶。我们使用先进的成像技术，基因技术， 和生物化学方法来研究这些问题，使用蠕虫和小鼠模型系统， 从亚细胞水平一直到行为输出。我们的目标是了解电路的生化逻辑 神经肽的神经调节与我们理解快速神经传递的清晰度相同， 突触这项研究将为长期存在的空间和环境问题提供新的见解。 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。神经肽及其受体 药物靶点涉及广泛的疾病，我们预计，对它们的机制的洞察力， 信号传导对于以行为功能障碍为特征的疾病可能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.