Neuropeptides and the Mammalian Circadian System

神经肽和哺乳动物昼夜节律系统

• 批准号: 6694059
• 负责人: CHRISTOPHER SCOTT COLWELL
• 金额: $ 36万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6694059
• 关键词: biological signal transduction; calcium flux; circadian rhythms; electrophysiology; gene expression; genetically modified animals; glutamates; immunocytochemistry; in situ hybridization; laboratory mouse; membrane potentials; neuropeptides; polymerase chain reaction; protooncogene; suprachiasmatic nucleus; vasoactive intestinal peptide; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanisms by which environmental signals regulate circadian oscillators as well as how circadian oscillators are coupled to each other, using neurons in the rodent suprachiasmatic nucleus (SCN) as a model system. A variety of evidence suggests that glutamate plays a critical role in the transmission of photic information from the environment to the SCN and that the peptide PACAP is a co-transmitter with glutamate at the RHT/SCN synaptic connection. A major goal of this application is to understand the mechanisms by which PACAP modulates glutamate-induced signaling in SCN neurons. We will present data indicating that PACAP enhances AMPA currents in SCN neurons from mice. Furthermore, data from a new line of transgenic animals in which the PACAP gene has been inactivated demonstrate a reduction in the magnitude of the effects of light on the circadian system. Thus, we feel confident that both glutamate and PACAP play a role, be it as yet undetermined, in mediating the effects of light on the circadian system. Many of the retino-recipient SCN neurons receiving this photic information themselves express the peptide VIP as well as GABA. These SCN cells synapse largely onto other SCN cells and presumably use these molecules to communicate photic information to other cells in the SCN. Thus, a second goal is to understand the mechanisms by which VIP modulates GABA-induced signaling pathways in SCN neurons. For this project, we will present data consistent with our hypothesis that VIP acts to modulate GABA currents in SCN neurons in mice. Encouragingly, data from a new line of transgenic animals in which the VIP gene has been inactivated demonstrate major disruptions in the circadian system that are consistent with VIP's role as a coupling agent within the SCN. By carrying out this research, we will address important questions about how SCN cells are coupled to the environment as well as how SCN cells are coupled to each other. In addition, we hope to use the SCN as model system to better understand the role of peptide co-transmitters in mediating cell-to-cell communication. These questions will be addressed using electrophysiological and calcium imaging techniques on SCN neurons in a mouse brain slice preparation. In addition, transgenic mice lacking PACAP and VIP will be analyzed with behavioral and anatomical tools. These newly developed mice are likely to prove a useful tool for circadian rhythms research.

描述（由申请人提供）：我们的长期目标是了解环境信号调节昼夜节律振荡器的机制以及昼夜节律振荡器如何彼此耦合，并使用啮齿动物上表相关核（SCN）中的神经元作为模型系统。各种证据表明，谷氨酸在从环境到SCN的光学信息传输中起着至关重要的作用，并且肽PACAP是在RHT/SCN突触连接下具有谷氨酸的co-晶卷。该应用的主要目标是了解PACAP调节SCN神经元中谷氨酸诱导的信号传导的机制。我们将提供数据，表明PACAP增强了小鼠SCN神经元中的AMPA电流。此外，来自新的转基因动物系列的数据已被灭活，在该系列中，PACAP基因被灭活的数据表明，光对昼夜节律系统的影响的幅度降低了。因此，我们对谷氨酸和PACAP都起着作用，无论它尚未确定，都在调解光对昼夜节律系统的影响时都发挥了作用。接收此光学信息本身的许多视网膜转化SCN神经元本身表达了肽VIP和GABA。这些SCN细胞在很大程度上突触到其他SCN细胞，并大概使用这些分子将光学信息传达给SCN中的其他细胞。因此，第二个目标是了解VIP调节SCN神经元中GABA诱导的信号通路的机制。对于这个项目，我们将介绍与我们的假设相一致的数据，即VIP行为可以调节小鼠SCN神经元中的GABA电流。令人鼓舞的是，来自新的转基因动物系列的数据已被灭活，该数据表明，昼夜节律系统中的重大破坏与VIP在SCN中作为耦合剂的作用是一致的。通过进行这项研究，我们将解决有关如何将SCN细胞耦合到环境以及如何相互耦合的重要问题。此外，我们希望将SCN用作模型系统，以更好地了解肽共发射器在介导细胞间通信中的作用。这些问题将使用小鼠脑切片制剂中的SCN神经元上的电生理和钙成像技术解决。此外，缺乏PACAP和VIP的转基因小鼠将使用行为和解剖工具进行分析。这些新开发的小鼠可能证明是昼夜节律研究的有用工具。