Electrical Signaling in a Circadian Pacemaker Circuit

昼夜节律起搏器电路中的电信号

• 批准号: 6895246
• 负责人: Todd C Holmes
• 金额: $ 24.67万
• 依托单位: NEW YORK UNIVERSITY
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895246
• 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）：虽然众所周知，循环分子时钟及其在模型有机体果蝇中的神经解剖位置的操作知之甚少，但对于这种昼夜节律分子时钟如何与起搏器神经元中的电信号相互作用，知之甚少。关于昼夜节律分子时钟如何控制起搏器神经元电活动和突触输出，最终控制动物行为是一个开放的问题。起搏器神经元电信号传导与昼夜节律分子时钟和动物行为之间的生理相互作用将通过直接的生理分析使用斑块夹和成年全脑神经元的成像以及在果蝇的昼夜节律起搏器神经元中修饰的离子通道的转基因表达。转基因策略已被设计为（1）电沉降起搏器神经元和（2）电气超级过度起搏器神经元。起搏器神经元电活动的这些操作中的每一个都会引起昼夜节律行为的惊人变化。 具体目的是：（1）通过电沉降，神经递质标记和免疫细胞化学来绘制起搏器神经回路的功能子集； （2）确定电性高兴奋的节奏分裂的机理和Nachbac表达的功能拯救电气沉默的起搏器神经回路； （3）绘制野生型和改良通道的果蝇起搏器的电生理特性。 这些研究将阐明在研究良好的模型生物中决定昼夜节律行为的生理机制。最终，这项工作可以为神经回路的一般研究和新的分子遗传策略提供强大的新工具，以研究和治疗异常细胞电兴奋性的人类疾病。