Electrical Signaling in a Circadian Pacemaker Circuit

昼夜节律起搏器电路中的电信号

• 批准号: 7490210
• 负责人: Todd C Holmes
• 金额: $ 24.01万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490210
• 关键词: Drosophilidae; Xenopus; antiserum; biological clocks; biological signal transduction; circadian rhythms; electrophysiology; ethology; evoked potentials; gap junctions; genetic mapping; immunocytochemistry; laboratory rabbit; membrane potentials; neuroanatomy; neuroimaging; neurophysiology; neuroregulation; potassium channel; sodium channel; voltage /patch clamp

DESCRIPTION (provided by applicant): While much is known about the core components and the operation of the circadian molecular clock and its neuroanatomical location in the model organism Drosophila, very little is known about how this circadian molecular clock interacts with electrical signaling in the pacemaker neurons. It is an open questions as to how circadian molecular clock controls pacemaker neuronal electrical activity and synaptic output that ultimately controls animal behavior. The physiological interactions between pacemaker neuron electrical signaling and the circadian molecular clock and animal behavior will be studied by direct physiological analysis using patch clamp and imaging of adult whole brain neurons as well as transgenic expression of modified ion channels in the circadian pacemaker neurons of Drosophila. Transgenic strategies have been devised to (1) electrically silence pacemaker neurons and (2) electrically hyper-excite pacemaker neurons. Each of these manipulations of pacemaker neuronal electrical activity causes striking changes in circadian behavior. The Specific Aims are to: (1) Map the functional subsets of the pacemaker neural circuit by electrical silencing, neurotransmitter markers, and immunocytochemistry; (2) Determine the mechanism of electrically hyper-excitation induced rhythm splitting and NaChBac expression's functional rescue of the electrically silenced pacemaker neural circuit; (3) Map the electrophysiological properties of wild-type and modified channel-expressing Drosophila pacemakers. These studies will elucidate the physiological mechanisms that determine circadian behavior in a well studied model organism. Ultimately, this work may provide powerful new tools for the general study of neural circuits and novel molecular-genetic strategies for studying and treating human diseases of aberrant cellular electrical excitability.

描述（由申请人提供）：虽然人们对昼夜节律分子钟的核心组件和运作及其在模式生物果蝇中的神经解剖学位置了解很多，但对于这种昼夜节律分子钟如何与起搏器中的电信号相互作用却知之甚少神经元。关于昼夜节律分子钟如何控制起搏器神经元电活动和最终控制动物行为的突触输出，这是一个悬而未决的问题。将通过使用膜片钳和成人全脑神经元成像的直接生理分析以及果蝇昼夜节律起搏神经元中修饰离子通道的转基因表达来研究起搏神经元电信号传导与昼夜节律分子钟和动物行为之间的生理相互作用。转基因策略已被设计用于（1）电沉默起搏神经元和（2）电超兴奋起搏神经元。对起搏器神经元电活动的每一种操作都会引起昼夜节律行为的显着变化。 具体目标是： (1) 通过电沉默、神经递质标记和免疫细胞化学绘制起搏器神经回路的功能子集； (2)确定电超兴奋诱导节律分裂的机制和NaChBac表达对电沉默起搏器神经回路的功能性拯救； (3)绘制野生型和改良通道表达果蝇起搏器的电生理特性。 这些研究将阐明在经过充分研究的模型生物体中决定昼夜节律行为的生理机制。最终，这项工作可能为神经回路的一般研究提供强大的新工具，并为研究和治疗人类细胞电兴奋性异常疾病提供新的分子遗传学策略。