Synaptic to circuit homeostasis in the Drosophila locomotor system

果蝇运动系统中的突触与电路稳态

基本信息

批准号：
10654556
负责人：
Ehud Isacoff
金额：
$ 30.87万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10654556
关键词：
3-Dimensional Action Potentials Address Axon Behavior Behavioral Brain Cells Compensation Disease Drosophila genus Electrophysiology (science)Ensure Equilibrium Evoked Potentials Excitatory Synapse Frequencies Genetic Glutamates Goals Health Heterogeneity Homeostasis Image Maps Methods Molecular Motor Neurons Muscle Musculoskeletal System Nervous System Neuromuscular Junction Neurons Noise Optics Output Pattern Preparation Probability Process Property Proteins RNA Interference Signal Transduction Site Synapses Synaptic Transmission Synaptic plasticity System Weight Work cell type genetic regulatory protein imaging system in vivo information processing insight knock-down neural neural circuit neuromechanism neurotransmitter release novel postsynaptic preservation presynaptic protein expression recruit superresolution imaging transcriptome transmission process ultra high resolution

项目摘要

What sets the transmission strength of synapses? What determines their plasticity properties? How do synapses homeostatically adjust synaptic weight to accommodate to changing conditions and ensure robust behavior? What happens if synaptic homeostasis is insufficient to compensate for a disruption or a change in demand, are other backup mechnisms of compensation recruited and, if so, how do they work? We combine in vivo super-resolution quantal imaging of synaptic transmission and behavioral analysis with focused RNAi knockdown in one cell type and single cell transcriptome analysis to address these questions. Our preparation is the Drosophila larval neuromuscular junction—an ideal system for imaging and genetics, which shares synaptic signaling machinery and functional properties with vertebrate central excitatory synapses. Our in vivo quantal analysis has revealed that two converging glutamatergic motor neuron (MN) inputs have great heterogeneity in evoked release probability (Pr) and short-term plasticity and that only Ib undergoes “synaptic homeostasis,” whereby transmitter release changes to compensate for altered postsynaptic sensitivity. Our goal is to identify the molecules responsible for the synapse to synapse and input to input differences. Equally exciting, preliminary work suggests the existence of a novel layer of gain control: “circuit homeostasis,” which is recruited when synaptic transmission is so compromised that “synaptic homeostasis” cannot compensate sufficiently. The circuit homeostasis system adjusts neural firing pattern in the presynaptic cell and upstream circuit to preserve locomotor behavior when synaptic transmission is inadequate. Our goal is to define the mechanisms that assure neural output by setting and adjusting transmitter release and firing dynamics. Progress will provide fundamental insight into the robustness of the nervous system that preserves health and which may cause disease when it goes awry.

突触的传输强度由什么决定？它们的可塑性是如何决定的？突触稳态地调整突触重量以适应不断变化的条件并确保稳健如果突触稳态不足以补偿神经元行为的破坏或变化，会发生什么？需求，是否招募了其他后备补偿机制？如果是，它们如何结合起来？突触传递的体内超分辨率定量成像和聚焦 RNAi 的行为分析我们的准备工作是通过一种细胞类型的敲除和单细胞转录组分析来解决这些问题。是果蝇幼虫神经肌肉接头——一个理想的成像和遗传学系统，它具有脊椎动物中枢兴奋性突触的突触信号机制和功能特性。定量分析表明，两个会聚的谷氨酸运动神经元（MN）输入具有很大的诱发释放概率（Pr）和短期可塑性的异质性，并且只有 Ib 经历“突触稳态，即递质释放变化以补偿突触后敏感性。目标是识别导致突触与突触以及输入与输入差异的分子。令人兴奋的初步工作表明存在一种新颖的增益控制层：“电路稳态”，它当突触传递严重受损以至于“突触稳态”无法补偿时，就会招募回路稳态系统充分调节突触前细胞和上游的神经放电模式。当突触传递不足时保持运动行为的电路我们的目标是定义通过设置和调整发射器释放和发射动态来确保神经输出的机制。进展将为维护健康和维持神经系统的稳健性提供基本的见解。一旦出现问题，可能会导致疾病。